{"gene":"PHGDH","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2016,"finding":"PHGDH catalyzes the first, rate-limiting step of glucose-derived serine synthesis; small-molecule inhibitors of PHGDH reduce production of glucose-derived serine in cells and suppress growth of PHGDH-dependent cancer cells. Unexpectedly, PHGDH inhibition also reduced incorporation of one-carbon units from both glucose-derived and exogenous serine into nucleotides, establishing that glycolytic serine synthesis coordinates one-carbon unit usage from all serine sources for nucleotide synthesis.","method":"Quantitative high-throughput small-molecule screen; isotope tracing; orthotopic xenograft tumor models; cell viability assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic inhibition combined with isotope tracing and in vivo xenograft models; replicated across multiple cell lines and in vivo","pmids":["27110680"],"is_preprint":false},{"year":2022,"finding":"PHGDH non-catalytically potentiates metastasis: PHGDH protein interacts with the glycolytic enzyme phosphofructokinase (PFK), and loss of this interaction activates the hexosamine-sialic acid pathway, increasing sialylation of integrin αvβ3 and potentiating cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of PHGDH-low cancer cells.","method":"Co-immunoprecipitation; metabolomics; glycoproteomics; genetic silencing; migration/invasion assays; mouse metastasis models; pharmacological sialylation inhibition","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying PFK as binding partner, multiple orthogonal methods (metabolomics, glycoproteomics, mouse models), mechanistic rescue experiments","pmids":["35585241"],"is_preprint":false},{"year":2023,"finding":"PRMT1 methylates PHGDH at arginine 236, enhancing its catalytic activity and thereby potentiating serine biosynthesis, ameliorating oxidative stress, and promoting HCC growth. A TAT-tagged non-methylated peptide blocking PHGDH methylation inhibited serine synthesis and restrained HCC growth in PDX models.","method":"Integrative metabolomics/transcriptomics; in vitro methylation assay; site-directed mutagenesis; MS identification of methylation site; patient-derived xenograft; Co-IP","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical methylation assay, mutagenesis of target residue, PDX in vivo validation, multiple orthogonal methods in one study","pmids":["36823188"],"is_preprint":false},{"year":2024,"finding":"PRMT1 methylates PHGDH at R54 or R20, activating its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. This drives metabolic flux into the serine synthesis pathway, supplying α-ketoglutarate and citrate to increase palmitate levels through fatty acid synthase (FASN), and increased palmitate induces protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis, conferring chemoresistance.","method":"13C metabolic flux analysis; MS identification of methylation sites; mutagenesis; S-palmitoylation assays; imaging MS in clinical specimens; FASN/PRMT1 inhibition","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — 13C metabolic flux analysis, MS-identified PTM sites, mutagenesis, and multiple orthogonal mechanistic validations in one study","pmids":["38383964"],"is_preprint":false},{"year":2014,"finding":"p53 suppresses PHGDH expression, inhibiting de novo serine biosynthesis. PHGDH overexpression suppresses p53-mediated apoptosis, while RNAi knockdown of PHGDH promotes apoptosis under serine starvation, demonstrating that PHGDH is a target of p53-mediated transcriptional repression in the serine biosynthesis pathway.","method":"RNAi knockdown; luciferase reporter assay; ChIP; apoptosis assays; Nutlin-3 p53 activation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined phenotype, ChIP confirming p53 binding at PHGDH locus, orthogonal rescue experiments","pmids":["25404730"],"is_preprint":false},{"year":2021,"finding":"Nuclear localization of PHGDH is induced by p38-mediated phosphorylation at Ser371 under glucose restriction, while AMPK phosphorylates PHGDH at Ser55, selectively shifting its substrate specificity toward oxidation of malate to oxaloacetate (generating NADH instead of serine). In the nucleus, altered PHGDH activity restricts NAD+ levels, suppressing PARP1-mediated poly(ADP-ribosyl)ation of c-Jun and thereby impairing c-Jun transcriptional activity and cell growth.","method":"Phosphoproteomic analysis; site-directed mutagenesis; in vitro enzymatic assays; subcellular fractionation; PARP1 activity assays; ChIP; cancer xenograft models","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay demonstrating altered substrate specificity, mutagenesis of phosphorylation sites, nuclear fractionation with functional consequence, multiple orthogonal methods","pmids":["34663976"],"is_preprint":false},{"year":2023,"finding":"Low 3-phosphoglycerate (3-PGA) levels allow PHGDH to bind scaffold protein AXIN in complex with kinase HIPK2 and p53, forming a multivalent complex that enables HIPK2 to specifically phosphorylate p53 at Ser46 and promote apoptosis. When bound to 3-PGA (high glucose), PHGDH is diverted to serine synthesis and cannot interact with AXIN/HIPK2. Constitutively 3-PGA-bound mutants (R135W, V261M) abolish p53 activation; constitutively unbound mutants (T57A, T78A) cause constitutive p53 activation and apoptosis.","method":"Co-IP; in vitro binding assays; site-directed mutagenesis; 3-PGA binding assays; p53 phosphorylation assays; mouse HCC model with Trp53 knockout validation; caloric restriction experiments","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of multi-protein complex, mutagenesis confirming metabolite-dependent binding switch, in vivo genetic validation with p53 knockout rescue","pmids":["37726403"],"is_preprint":false},{"year":2018,"finding":"PHGDH-mediated serine synthesis is essential for heme production in endothelial cells (ECs). PHGDH knockdown causes cellular serine depletion unique to ECs, leading to insufficient heme production, impaired electron transport chain enzyme activities, elevated ROS, and EC apoptosis. Supplementation with hemin restored ETC function and rescued apoptosis and angiogenesis defects.","method":"EC-specific PHGDH knockout mice; siRNA knockdown; ETC enzyme activity assays; heme measurement; hemin rescue; metabolite supplementation; angiogenesis assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — EC-specific in vivo knockout with lethal phenotype, mechanistic rescue with hemin, multiple biochemical assays confirming heme deficiency as mechanism","pmids":["30017355"],"is_preprint":false},{"year":2023,"finding":"PHGDH-mediated endothelial cell metabolism drives formation of a hypoxic and immune-hostile vascular microenvironment in glioblastoma. Tumor microenvironmental cues induce ATF4-mediated PHGDH expression in ECs, triggering a redox-dependent mechanism that regulates endothelial glycolysis and leads to EC overgrowth. Genetic PHGDH ablation in ECs prunes over-sprouting vasculature, abrogates intratumoral hypoxia, and improves T cell infiltration.","method":"Metabolome and transcriptome analysis; EC-specific genetic PHGDH ablation; ATF4 ChIP; redox assays; T cell infiltration quantification; GBM xenograft models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — EC-specific genetic knockout with defined vascular phenotype, ChIP confirming ATF4 transcriptional regulation, multiple orthogonal methods","pmids":["36804058"],"is_preprint":false},{"year":2021,"finding":"Dimerization of PHGDH through its catalytic unit is essential for enzymatic activity. The catalytic subdomain (sPHGDH) forms dimers with a dissociation constant of ~0.58 μM, and enzyme activity depends on dimer content. Single-point mutations at computationally identified hotspot residues at the dimer interface disrupt dimer formation and abolish activity. Molecular dynamics simulations showed dimerization facilitates substrate binding and maintains catalytic conformation. Full-length PHGDH exists as monomers/dimers/tetramers; mutations E108A and I121A disrupt all oligomeric states and abolish activity.","method":"Analytical ultracentrifugation; size-exclusion chromatography; enzymatic activity assays; site-directed mutagenesis; molecular dynamics simulations; structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined dimer Kd, mutagenesis abolishing activity, molecular dynamics validation, multiple biophysical methods","pmids":["33753166"],"is_preprint":false},{"year":2021,"finding":"A natural compound withangulatin A (WA) covalently binds PHGDH at cysteine 295 (Cys295), blocking the substrate-binding domain and inducing an allosteric effect that inactivates the enzyme. This identifies Cys295 as a novel allosteric regulatory site. WA-mediated PHGDH inhibition decreases glutathione synthesis and elevates ROS, inhibiting tumor proliferation.","method":"Affinity-based protein profiling; biolayer interferometry; LC-MS/MS covalent site identification; mutagenesis; enzymatic activity assays; cellular ROS/glutathione measurements","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 1 / Moderate — LC-MS/MS identified covalent binding site, mutagenesis validated Cys295 specificity, multiple orthogonal binding and enzymatic assays","pmids":["35127383"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of PHGDH in complex with oridonin revealed a new allosteric binding site. Oridonin binding relocates R54 (a residue involved in substrate binding), reducing enzymatic activity. Mutagenesis studies showed PHGDH activity is highly sensitive to cysteine mutations, especially in the substrate-binding domain.","method":"X-ray crystallography; site-directed mutagenesis; enzymatic activity assays; natural product library screening","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — X-ray crystal structure with bound inhibitor, mutagenesis confirming R54 role, in vitro enzymatic validation","pmids":["34971423"],"is_preprint":false},{"year":2019,"finding":"Indole amide inhibitors bind the NAD+ pocket of PHGDH, established by X-ray crystallography. Structure-based optimization yielded low nanomolar affinities for PHGDH, with the most potent compounds inhibiting de novo serine synthesis with sub-micromolar cellular activity.","method":"X-ray crystallography of PHGDH–inhibitor complexes; enzymatic IC50 assays; isotope-labeling serine synthesis assays; cancer cell proliferation assays","journal":"Bioorganic & medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — X-ray crystal structures defining NAD+ binding pocket, multiple inhibitors validated enzymatically and cellularly","pmids":["31327531"],"is_preprint":false},{"year":2016,"finding":"Fragment-based drug discovery identified the NAD+-binding pocket as an inhibitor binding site on PHGDH. Crystal structures of PHGDH with bound fragments (diffraction to high resolution) guided structure-based fragment growing, demonstrating routes to NAD+-competitive inhibitors. siRNA-mediated PHGDH knockdown reduced proliferation specifically in PHGDH-amplified (not low-expression) breast cancer cells.","method":"Fragment soaking; X-ray crystallography; thermal shift assay; ITC competition experiments; siRNA knockdown; cell proliferation assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — X-ray crystal structures of fragment complexes, ITC binding quantification, siRNA loss-of-function with differential phenotype in amplified vs. non-amplified cells","pmids":["29568346"],"is_preprint":false},{"year":2018,"finding":"NAD+ availability, maintained by the NAD+ salvage pathway (rate-limited by NAMPT), is required for PHGDH-driven serine biosynthesis. Inhibiting NAMPT depletes NAD+, impeding PHGDH enzymatic function and reducing glucose-derived serine synthesis. PHGDH-high breast cancer cells are selectively sensitive to NAD+ salvage inhibition.","method":"NAD+ salvage pathway inhibitors; isotope-labeled serine synthesis assays; PHGDH enzymatic activity measurements; cell viability assays; proteomics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct enzymatic measurement showing NAD+-dependence, isotope tracing, selective toxicity in PHGDH-high lines","pmids":["30157431"],"is_preprint":false},{"year":2020,"finding":"PHGDH activity is regulated downstream of mTORC1 signaling in macrophages: TSC2 (a negative regulator of mTORC1) controls PHGDH enzymatic activity in an mTORC1-dependent manner. LPS-stimulated (M1) macrophages repress PHGDH activity, while IL-4-stimulated (M2) macrophages increase PHGDH activity, which is required for expression of anti-inflammatory molecules and macrophage proliferation.","method":"Inverse data-driven modeling (COVRECON); metabolomics; proteomics; mRNA expression analysis; enzymatic activity measurements; TSC2-knockout macrophages","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity measurements in genetic knockout model, multiomics integration, single lab with multiple orthogonal methods","pmids":["32023468"],"is_preprint":false},{"year":2024,"finding":"PHGDH-mediated serine biosynthesis promotes α-ketoglutarate (αKG) production, which activates mTORC1 signaling and contributes to M2-like immunosuppressive macrophage phenotype maintenance in the tumor microenvironment. Genetic PHGDH ablation in macrophages attenuates tumor growth, reduces TAM infiltration, shifts M2 TAMs toward M1, and downregulates PD-L1.","method":"Macrophage-specific genetic PHGDH ablation; metabolic flux analysis; mTORC1 activity assays; tumor-bearing mouse models; flow cytometry","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined mechanistic pathway (serine→αKG→mTORC1), in vivo validation, single lab","pmids":["38409249"],"is_preprint":false},{"year":2022,"finding":"UTX (H3K27 demethylase) recruits E3 ligase RNF114 to ubiquitinate PHGDH at Lys310 and Lys330, leading to PHGDH proteasomal degradation and suppression of renal serine synthesis. Kidney-specific Utx knockout upregulates PHGDH, increasing circulating serine and inhibiting high-fat diet-induced lipid accumulation in kidney and liver.","method":"Kidney-specific Utx knockout mice; Co-IP; ubiquitination assays; LC-MS identification of ubiquitination sites; metabolite measurements; high-fat diet model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying RNF114–PHGDH interaction, MS-identified ubiquitination sites (K310/K330), in vivo knockout model with metabolic phenotype","pmids":["35788583"],"is_preprint":false},{"year":2022,"finding":"PHGDH binds PCBP2 (an RNA-binding protein) and inhibits its ubiquitination-mediated degradation. Stabilized PCBP2 in turn stabilizes SLC7A11 mRNA, increasing SLC7A11 expression, which inhibits ferroptosis and promotes bladder cancer progression.","method":"Co-IP; mass spectrometry; RIP (RNA immunoprecipitation) assay; ubiquitination assays; ferroptosis measurement (C11 probes, electron microscopy); knockdown experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and MS identifying PCBP2 as PHGDH binding partner, RIP assay for mRNA stabilization, ferroptosis rescue experiments; single lab","pmids":["36147463"],"is_preprint":false},{"year":2023,"finding":"The ACT domain of nuclear PHGDH binds nuclear cMyc to form a transactivation complex (PHGDH/p300/cMyc/AF9) that drives CXCL1 and IL8 gene expression. This promotes neutrophil recruitment and tumor-associated macrophage filtration, advancing liver cancer. Forced cytosolic localization of PHGDH or destruction of PHGDH/cMyc interaction abolishes this oncogenic function, independent of PHGDH catalytic activity.","method":"Co-IP identifying PHGDH–cMyc–p300–AF9 complex; ChIP; nuclear/cytosolic fractionation; localization mutants; neutrophil depletion with neutralizing antibodies; liver cancer mouse models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying multi-protein nuclear complex, ChIP confirming transcriptional regulation, rescue with cytosolic localization mutant; single lab","pmids":["37078828"],"is_preprint":false},{"year":2020,"finding":"PHGDH supports liver ceramide synthesis through provision of serine as a substrate; doxycycline-inducible PHGDH knockdown in adult mice reduced liver serine and ceramide levels without increasing deoxysphingolipids, and altered liver triacylglycerol profiles with accumulation of longer chain, polyunsaturated tails.","method":"Inducible shRNA knock-in mouse model; lipidomics; metabolomics; liver and pancreatic function assays","journal":"Cancer & metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo inducible knockdown model with lipidomics establishing ceramide synthesis link; single lab, single main method","pmids":["32549981"],"is_preprint":false},{"year":2023,"finding":"ZEB1 transcription factor activates PHGDH transcription by binding a non-canonical binding site within the PHGDH promoter region, upregulating serine synthesis flux (SSP) to enable HCC cells to be more invasive, proliferative, and resistant to ROS and sorafenib.","method":"ChIP; luciferase reporter assay; 13C-glucose tracing; CRISPR Zeb1 conditional knockout mice; xenograft models","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter establishing direct ZEB1–PHGDH promoter interaction, 13C flux tracing, in vivo conditional knockout; single lab","pmids":["37331567"],"is_preprint":false},{"year":2022,"finding":"Deubiquitinase Josephin-2 (JOSD2) stabilizes PHGDH protein by removing ubiquitin from PHGDH, preventing its proteasomal degradation. Silencing Josephin-2 enhanced PHGDH ubiquitination and degradation, inhibiting HCC proliferation and cancer stem cell phenotype.","method":"Co-IP; ubiquitination assays; knockdown experiments; spheroid formation; in vivo xenograft","journal":"Genes & genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying Josephin-2–PHGDH interaction, ubiquitination assay; single lab, limited mechanistic depth","pmids":["36583817"],"is_preprint":false},{"year":2024,"finding":"ASS1 (argininosuccinate synthase 1) directly binds PHGDH and promotes its ubiquitination-mediated proteasomal degradation, thereby inhibiting serine synthesis. The tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout, placing PHGDH downstream of ASS1 in the same pathway.","method":"Co-IP identifying ASS1–PHGDH interaction; ubiquitination assays; PHGDH knockout rescue experiments; serine/glycine depletion proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, and genetic epistasis (PHGDH KO rescuing ASS1 overexpression phenotype); single lab","pmids":["38710705"],"is_preprint":false},{"year":2023,"finding":"eIF3i promotes PHGDH translation through METTL3-mediated N6-methyladenosine (m6A) modification on PHGDH mRNA, which enhances PHGDH mRNA binding to eIF3i, ultimately increasing PHGDH translation rate. This mechanism supports CRC cell proliferation.","method":"Ribosome profiling; proteomics; m6A-RIP assay; eIF3i–mRNA interaction assays; eIF3i and PHGDH knockdown; in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ribosome profiling and m6A-RIP establishing translation mechanism, in vivo validation; single lab","pmids":["37611825"],"is_preprint":false},{"year":2021,"finding":"LncRNA RMRP is upregulated in platinum-resistant ovarian cancer cells and promotes DDX3X (RNA-binding protein) binding to PHGDH mRNA, thereby increasing PHGDH translation. Knockdown of PHGDH suppressed cisplatin resistance and spheroid formation.","method":"Polysome profiling; RNA-protein binding assays (RIP); siRNA knockdown; cisplatin resistance assays; spheroid formation","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic follow-up on DDX3X–PHGDH mRNA interaction; polysome profiling supports translational upregulation","pmids":["34178629"],"is_preprint":false},{"year":2020,"finding":"PHGDH activity is required for serine availability needed for nucleotide production and cell proliferation in brain metastatic cells; the serine- and glycine-limited brain microenvironment imposes dependence on PHGDH-driven serine synthesis. Genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis but not extracranial tumor growth.","method":"Proteomics; metabolomics; multiple brain metastasis mouse models; genetic PHGDH suppression (shRNA); pharmacologic PHGDH inhibition; isotope-labeled nucleotide synthesis assays","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, metabolomics, isotope tracing), multiple in vivo brain metastasis models, genetic and pharmacologic validation","pmids":["32571778"],"is_preprint":false},{"year":2023,"finding":"PHGDH inhibition activates ATF4/CEBPB transcriptional program in SEM-type gastric cancer cells under glutamine starvation, upregulating the mitochondrial folate cycle pathway to produce NADPH as an ROS scavenger, representing a metabolic plasticity mechanism for survival under nutrient stress.","method":"13C-isotope tracing; transcriptomics; ChIP (ATF4/CEBPB); single-nucleus RNA-seq of patient-derived organoids; PHGDH inhibition under glutamine starvation","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isotope tracing and ChIP establishing ATF4/CEBPB-mediated PHGDH induction and mitochondrial folate cycle function; single lab","pmids":["37192160"],"is_preprint":false},{"year":2019,"finding":"PHGDH is the first committed enzyme in the serine synthesis pathway (SSP) and its inactivation via RNAi knockdown or CRISPR knockout reduces αKG, serine, and NADPH production in HCC, elevating ROS and inducing apoptosis upon sorafenib treatment. PHGDH expression is induced by sorafenib treatment as an adaptive resistance mechanism.","method":"Genome-wide CRISPR/Cas9 library screen; RNAi knockdown; CRISPR/Cas9 knockout; metabolite measurement (αKG, serine, NADPH); ROS measurement; in vivo HCC xenograft","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide CRISPR screen identifying PHGDH, validated with RNAi and CRISPR KO, metabolite measurements establishing pathway position, in vivo validation","pmids":["31615983"],"is_preprint":false},{"year":2019,"finding":"PHGDH downregulation and reduced hepatic serine are associated with fatty liver disease. PHGDH knockout in MEFs or primary hepatocytes increases lipid accumulation and reduces NAD+ and SIRT1 activity, reversed by PHGDH overexpression. PHGDH transgenic mice show reduced hepatic triglyceride accumulation with increased SIRT1 activity and reduced lipogenic gene expression under high-fat diet.","method":"PHGDH-knockout MEFs; PHGDH-transgenic mice; NAD+ measurement; SIRT1 activity assay; hepatic triglyceride measurement; high-fat diet model","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both KO and transgenic models with defined biochemical measurements (NAD+, SIRT1); single lab, single model system","pmids":["31678070"],"is_preprint":false},{"year":2023,"finding":"MYC transcriptionally regulates PHGDH expression in glioblastoma stem-like cells; ChIP confirmed MYC binding to the PHGDH promoter. PHGDH activation enhances GSC self-renewal by regulating redox homeostasis, facilitating one-carbon metabolism, and promoting DNA damage response via SSP activation.","method":"ChIP; transcriptomic and metabolomic analyses; genetic PHGDH ablation; pharmacological PHGDH inhibition; orthotopic GBM xenograft models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing MYC–PHGDH promoter binding, metabolomics, in vivo xenograft validation; single lab","pmids":["40102981"],"is_preprint":false},{"year":2025,"finding":"CXCL7 activates CXCR2 receptor on tumor cells, triggering interferon signaling and promoting PHGDH expression through STAT1-dependent transcriptional upregulation, thereby enhancing serine metabolism and paracrine secretion of S-adenosyl methionine (SAM), which drives chemotherapy resistance in colorectal cancer.","method":"Co-culture system; STAT1 ChIP; CXCR2 blockade; PHGDH knockdown; SAM measurement; in vivo mouse models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — STAT1 ChIP at PHGDH promoter, CXCR2 blockade establishing upstream pathway, SAM measurement; single lab","pmids":["40368902"],"is_preprint":false},{"year":2023,"finding":"ATF4 mediates transcriptional upregulation of PHGDH under exogenous serine deficiency conditions in colon cancer cells. LC-MS analysis revealed that serine deprivation induces changes in PHGDH acetylation: loss of the K289 acetylation site and appearance of a new K21 acetylation site.","method":"Real-time qPCR; LC-MS/MS post-translational modification analysis; serine deprivation experiments; luciferase reporter (implied)","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — LC-MS identifies acetylation sites but functional consequences of specific acetylation not established; single lab, limited mechanistic follow-up","pmids":["36707056"],"is_preprint":false},{"year":2023,"finding":"PHGDH inhibition in skeletal muscle cells decreases protein synthesis predominantly through mTORC1-dependent mechanisms. N-acetylcysteine (antioxidant/redox modulator) partially rescued decreased protein synthesis and mTORC1 signaling during PHGDH inhibition, implicating redox balance as a mediator of PHGDH's effect on mTORC1.","method":"Two distinct PHGDH inhibitors; puromycin-based protein synthesis assay; rapamycin control; IGF-1 stimulation; metabolomics; N-acetylcysteine rescue; C2C12 and human primary muscle cells","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal PHGDH inhibitors, pharmacological rescue experiments, metabolomics; single lab","pmids":["37991454"],"is_preprint":false},{"year":2021,"finding":"PHGDH is dysregulated as a common molecular feature in both Marinesco-Sjögren syndrome (SIL1 mutations) and INPP5K disease, revealed by unbiased proteomic profiling of patient-derived cells. L-serine administration improved neuronal phenotype in sil1, phgdh, and inpp5k zebrafish models, establishing PHGDH-dependent serine deficiency as a convergent pathomechanism.","method":"Unbiased proteomic profiling of patient-derived cells; zebrafish knockout models (sil1, phgdh, inpp5k); L-serine supplementation rescue experiments","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased proteomics identifying PHGDH as convergent node, in vivo zebrafish genetic models with serine rescue; single lab","pmids":["33792664"],"is_preprint":false}],"current_model":"PHGDH is the rate-limiting enzyme of the de novo serine synthesis pathway, catalyzing the NAD+-dependent oxidation of 3-phosphoglycerate to 3-phosphohydroxypyruvate; its activity requires dimerization through the catalytic unit; it is regulated by PRMT1-mediated arginine methylation (R236, R54/R20) that activates it, p38-mediated phosphorylation at Ser371 that drives nuclear translocation, AMPK-mediated phosphorylation at Ser55 that switches its substrate specificity toward malate oxidation, ubiquitin-mediated degradation (written by RNF114, erased by Josephin-2/JOSD2), and transcriptional regulation by p53 (repressive) and ZEB1/MYC/ATF4 (activating); beyond serine synthesis, PHGDH non-catalytically interacts with phosphofructokinase to suppress the hexosamine-sialic acid pathway, and in the nucleus forms a transactivation complex with cMyc/p300/AF9 to drive chemokine gene expression, while under low glucose it binds AXIN/HIPK2 to activate p53-Ser46 phosphorylation and apoptosis in a 3-PGA-switchable manner."},"narrative":{"mechanistic_narrative":"PHGDH catalyzes the first, rate-limiting and NAD+-dependent step of the de novo serine synthesis pathway (oxidation of 3-phosphoglycerate), coordinating one-carbon unit usage for nucleotide synthesis and supplying carbon for downstream serine-derived metabolites including heme, ceramide, glutathione, NADPH and α-ketoglutarate [PMID:27110680, PMID:30017355, PMID:31615983]. Catalysis requires dimerization through the catalytic subdomain, with defined dimer-interface hotspot residues whose mutation abolishes activity, and the enzyme depends on a continuously replenished NAD+ pool maintained by the salvage pathway [PMID:33753166, PMID:30157431]. Structural and chemical-biology studies have mapped distinct druggable sites — the NAD+-binding pocket and allosteric sites engaged by covalent (Cys295) and non-covalent (R54-relocating) inhibitors [PMID:35127383, PMID:34971423, PMID:31327531, PMID:29568346]. PHGDH activity is set by a dense layer of post-translational control: PRMT1-mediated arginine methylation (R236, R54/R20) activates the enzyme, stabilizes substrate binding and suppresses polyubiquitination, while ubiquitin-mediated turnover is written by RNF114 (recruited by UTX, at K310/K330) and by ASS1, and reversed by the deubiquitinase JOSD2 [PMID:36823188, PMID:38383964, PMID:35788583, PMID:38710705, PMID:36583817]. Stress- and glucose-responsive phosphorylation reprograms the enzyme: p38 phosphorylation at Ser371 drives nuclear translocation and AMPK phosphorylation at Ser55 switches substrate specificity toward malate oxidation, restricting nuclear NAD+ and PARP1-dependent c-Jun activity [PMID:34663976]. Beyond catalysis, PHGDH acts non-enzymatically — binding phosphofructokinase to restrain the hexosamine–sialic acid pathway and integrin sialylation-driven metastasis, forming a nuclear cMyc/p300/AF9 transactivation complex via its ACT domain to drive CXCL1/IL8 chemokine expression, and, when not bound to 3-phosphoglycerate under low glucose, scaffolding an AXIN/HIPK2/p53 complex to enable HIPK2 phosphorylation of p53-Ser46 and apoptosis [PMID:35585241, PMID:37078828, PMID:37726403]. Transcriptionally, PHGDH is repressed by p53 and activated by ATF4, ZEB1, MYC and STAT1 signaling [PMID:25404730, PMID:36804058, PMID:37331567, PMID:40102981, PMID:40368902]. Through these activities PHGDH sustains proliferation, redox homeostasis, chemoresistance, endothelial heme/angiogenic function and an immunosuppressive tumor microenvironment, and serine-dependent dysregulation of PHGDH is a convergent pathomechanism in Marinesco-Sjögren syndrome and INPP5K disease rescued by L-serine in zebrafish [PMID:30017355, PMID:36804058, PMID:38409249, PMID:32571778, PMID:33792664].","teleology":[{"year":2014,"claim":"Established that PHGDH is not a constitutively expressed housekeeping enzyme but a transcriptionally controlled node, placing serine synthesis under tumor-suppressor surveillance.","evidence":"p53 activation, ChIP, RNAi, and apoptosis assays in cells","pmids":["25404730"],"confidence":"High","gaps":["Did not define the p53 response element architecture","Did not address PTM-level regulation of the enzyme"]},{"year":2016,"claim":"Defined PHGDH as the rate-limiting entry into glucose-derived serine synthesis and, unexpectedly, as a coordinator of one-carbon unit usage from all serine sources, validating it as a cancer target.","evidence":"Small-molecule screen, isotope tracing, orthotopic xenografts","pmids":["27110680"],"confidence":"High","gaps":["Mechanism coupling glycolytic serine synthesis to exogenous-serine one-carbon flux not resolved","No structural basis for inhibitor binding at this stage"]},{"year":2019,"claim":"Mapped the enzyme's NAD+-binding pocket structurally and demonstrated selective dependence of PHGDH-amplified cancers, converting target validation into structure-guided drug design.","evidence":"X-ray crystallography, fragment-based discovery, ITC, siRNA proliferation assays","pmids":["31327531","29568346","31615983"],"confidence":"High","gaps":["Allosteric regulatory sites not yet defined","Did not address oligomeric requirements for activity"]},{"year":2021,"claim":"Showed that catalytic competence requires dimerization and that NAD+ salvage availability gates flux, defining the structural and cofactor prerequisites for activity.","evidence":"Analytical ultracentrifugation, molecular dynamics, NAMPT inhibition with isotope tracing","pmids":["33753166","30157431"],"confidence":"High","gaps":["Physiological regulation of oligomeric state in cells not established","Whether PTMs modulate dimerization untested"]},{"year":2021,"claim":"Discovered allosteric and covalent regulatory sites (Cys295, R54 relocation) distinct from the NAD+ pocket, expanding the mechanistic and pharmacological control surface.","evidence":"Covalent-site LC-MS/MS, X-ray crystallography with oridonin, mutagenesis, ROS/glutathione assays","pmids":["35127383","34971423"],"confidence":"High","gaps":["Endogenous regulators acting through these allosteric sites unknown"]},{"year":2021,"claim":"Revealed glucose-restriction signaling reprograms PHGDH via p38 (Ser371, nuclear translocation) and AMPK (Ser55, substrate-specificity switch to malate oxidation), linking the enzyme to nuclear NAD+ and PARP1/c-Jun control.","evidence":"Phosphoproteomics, mutagenesis, in vitro enzymatic assays, fractionation, xenografts","pmids":["34663976"],"confidence":"High","gaps":["Quantitative contribution of nuclear malate oxidation in vivo unclear","Other nuclear PHGDH substrates not enumerated"]},{"year":2022,"claim":"Established a catalysis-independent function: PHGDH binding to phosphofructokinase suppresses the hexosamine–sialic acid pathway and integrin sialylation, with loss of binding potentiating metastasis.","evidence":"Reciprocal Co-IP, metabolomics, glycoproteomics, mouse metastasis models, sialylation inhibition rescue","pmids":["35585241"],"confidence":"High","gaps":["Structural basis of the PHGDH–PFK interface unresolved","How metabolic state toggles the interaction not defined"]},{"year":2022,"claim":"Defined the ubiquitin-proteasome control of PHGDH abundance — RNF114 (UTX-recruited, K310/K330) writing and JOSD2 erasing ubiquitin — connecting epigenetic and degradative inputs to serine output and systemic lipid metabolism.","evidence":"Kidney-specific Utx knockout, Co-IP, MS-mapped ubiquitination sites, DUB knockdown, high-fat diet model","pmids":["35788583","36583817"],"confidence":"Medium","gaps":["JOSD2 finding rests on single-lab Co-IP without reciprocal depth","Interplay between RNF114 and JOSD2 in setting steady-state levels untested"]},{"year":2023,"claim":"Identified PRMT1 arginine methylation (R236; R54/R20) as an activating PTM that enhances catalysis, stabilizes 3-PGA binding and blocks polyubiquitination, coupling serine flux to redox protection, lipogenesis and chemoresistance.","evidence":"In vitro methylation, MS-mapped sites, mutagenesis, 13C flux, S-palmitoylation assays, PDX models","pmids":["36823188","38383964"],"confidence":"High","gaps":["Demethylase counteracting PRMT1 not identified","Crosstalk with phosphorylation/ubiquitination not integrated"]},{"year":2023,"claim":"Showed 3-PGA occupancy acts as a metabolite switch: low 3-PGA frees PHGDH to scaffold AXIN/HIPK2/p53 and drive p53-Ser46 apoptosis, while a separate nuclear PHGDH/cMyc/p300/AF9 complex drives chemokine transcription, defining moonlighting roles tied to localization and metabolic state.","evidence":"Co-IP, in vitro binding, 3-PGA-binding mutants, p53 phosphorylation assays, ChIP, mouse cancer models","pmids":["37726403","37078828"],"confidence":"High","gaps":["Nuclear complex findings (cMyc/AF9) from single lab","Determinants of nuclear vs cytosolic partitioning incompletely defined"]},{"year":2023,"claim":"Expanded the transcriptional and translational input map (ZEB1, MYC, STAT1, ATF4 transcription; METTL3-m6A/eIF3i and RMRP/DDX3X translation), showing multiple oncogenic and stress programs converge to elevate PHGDH.","evidence":"ChIP, luciferase reporters, ribosome profiling, m6A-RIP, polysome profiling, knockdown/xenografts","pmids":["37331567","40102981","40368902","37192160","37611825","34178629"],"confidence":"Medium","gaps":["RMRP/DDX3X translational mechanism from low-confidence single study","Hierarchy among competing transcriptional regulators unresolved"]},{"year":2024,"claim":"Demonstrated cell-type-specific physiological roles — endothelial PHGDH for heme/ETC function and tumor vasculature, macrophage PHGDH for αKG-mTORC1-driven M2 immunosuppression — establishing PHGDH as a microenvironmental and immune-modulatory node.","evidence":"Cell-type-specific knockout mice, ETC/heme assays, flux analysis, mTORC1 assays, immune profiling","pmids":["30017355","36804058","38409249","32023468","32571778"],"confidence":"Medium","gaps":["Direct molecular coupling of serine to mTORC1 in each cell type incompletely mapped","Macrophage findings from single labs"]},{"year":2021,"claim":"Linked PHGDH-dependent serine deficiency to neurological disease, showing it as a convergent pathomechanism in Marinesco-Sjögren syndrome and INPP5K disease correctable by L-serine.","evidence":"Unbiased proteomics of patient cells, zebrafish knockout models, L-serine rescue","pmids":["33792664"],"confidence":"Medium","gaps":["Causal chain from SIL1/INPP5K loss to PHGDH dysregulation not mechanistically resolved","Human therapeutic translation of L-serine not established here"]},{"year":null,"claim":"How the multiple competing PTMs (methylation, phosphorylation, ubiquitination, S-palmitoylation, acetylation) and metabolite-sensing are integrated to dictate PHGDH's choice between catalysis, nuclear moonlighting, and scaffolding remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling PTM state to localization and moonlighting","Functional consequence of acetylation sites (K21/K289) not established","Demethylase/phosphatase counter-enzymes largely unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,5,9,14]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,28]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[19,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6,19]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,19,6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,28,7,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,19,21,30]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,10,28,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,6,28]}],"complexes":["PHGDH/p300/cMyc/AF9 nuclear transactivation complex","PHGDH/AXIN/HIPK2/p53 complex"],"partners":["PFKL","PRMT1","RNF114","JOSD2","ASS1","AXIN","HIPK2","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43175","full_name":"D-3-phosphoglycerate dehydrogenase","aliases":["2-oxoglutarate reductase","Malate dehydrogenase"],"length_aa":533,"mass_kda":56.7,"function":"Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway. Also catalyzes the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate and the reversible oxidation of (S)-malate to oxaloacetate","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O43175/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHGDH","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000092621","cell_line_id":"CID000934","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"EPN1","stoichiometry":0.2},{"gene":"LETM1","stoichiometry":0.2},{"gene":"OAT","stoichiometry":0.2},{"gene":"AIFM1","stoichiometry":0.2},{"gene":"ETFB","stoichiometry":0.2},{"gene":"TIMM44","stoichiometry":0.2},{"gene":"UQCRFS1;UQCRFS1P1","stoichiometry":0.2},{"gene":"MDH2","stoichiometry":0.2},{"gene":"UQCRB","stoichiometry":0.2},{"gene":"MTHFD2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000934","total_profiled":1310},"omim":[{"mim_id":"619773","title":"IMMUNODEFICIENCY 95; IMD95","url":"https://www.omim.org/entry/619773"},{"mim_id":"617404","title":"MUSCULAR DYSTROPHY, CONGENITAL, WITH CATARACTS AND IMPAIRED INTELLECTUAL DEVELOPMENT; MDCCAID","url":"https://www.omim.org/entry/617404"},{"mim_id":"608005","title":"SIL1 NUCLEOTIDE EXCHANGE FACTOR; SIL1","url":"https://www.omim.org/entry/608005"},{"mim_id":"607875","title":"INOSITOL POLYPHOSPHATE-5-PHOSPHATASE K; INPP5K","url":"https://www.omim.org/entry/607875"},{"mim_id":"606951","title":"INTERFERON-INDUCED HELICASE C DOMAIN-CONTAINING PROTEIN 1; IFIH1","url":"https://www.omim.org/entry/606951"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHGDH"},"hgnc":{"alias_symbol":["SERA","PGDH","PDG"],"prev_symbol":[]},"alphafold":{"accession":"O43175","domains":[{"cath_id":"3.40.50.720","chopping":"9-102_291-309","consensus_level":"high","plddt":95.3415,"start":9,"end":309},{"cath_id":"3.40.50.720","chopping":"103-281","consensus_level":"high","plddt":97.8318,"start":103,"end":281},{"cath_id":"3.30.2130.10","chopping":"453-533","consensus_level":"medium","plddt":90.6547,"start":453,"end":533}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43175","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43175-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43175-F1-predicted_aligned_error_v6.png","plddt_mean":92.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHGDH","jax_strain_url":"https://www.jax.org/strain/search?query=PHGDH"},"sequence":{"accession":"O43175","fasta_url":"https://rest.uniprot.org/uniprotkb/O43175.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43175/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43175"}},"corpus_meta":[{"pmid":"27110680","id":"PMC_27110680","title":"A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.","date":"2016","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/27110680","citation_count":452,"is_preprint":false},{"pmid":"31615983","id":"PMC_31615983","title":"Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31615983","citation_count":329,"is_preprint":false},{"pmid":"26068857","id":"PMC_26068857","title":"TISSUE REGENERATION. 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{\n      \"year\": 2016,\n      \"finding\": \"PHGDH catalyzes the first, rate-limiting step of glucose-derived serine synthesis; small-molecule inhibitors of PHGDH reduce production of glucose-derived serine in cells and suppress growth of PHGDH-dependent cancer cells. Unexpectedly, PHGDH inhibition also reduced incorporation of one-carbon units from both glucose-derived and exogenous serine into nucleotides, establishing that glycolytic serine synthesis coordinates one-carbon unit usage from all serine sources for nucleotide synthesis.\",\n      \"method\": \"Quantitative high-throughput small-molecule screen; isotope tracing; orthotopic xenograft tumor models; cell viability assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic inhibition combined with isotope tracing and in vivo xenograft models; replicated across multiple cell lines and in vivo\",\n      \"pmids\": [\"27110680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHGDH non-catalytically potentiates metastasis: PHGDH protein interacts with the glycolytic enzyme phosphofructokinase (PFK), and loss of this interaction activates the hexosamine-sialic acid pathway, increasing sialylation of integrin αvβ3 and potentiating cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of PHGDH-low cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; metabolomics; glycoproteomics; genetic silencing; migration/invasion assays; mouse metastasis models; pharmacological sialylation inhibition\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying PFK as binding partner, multiple orthogonal methods (metabolomics, glycoproteomics, mouse models), mechanistic rescue experiments\",\n      \"pmids\": [\"35585241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT1 methylates PHGDH at arginine 236, enhancing its catalytic activity and thereby potentiating serine biosynthesis, ameliorating oxidative stress, and promoting HCC growth. A TAT-tagged non-methylated peptide blocking PHGDH methylation inhibited serine synthesis and restrained HCC growth in PDX models.\",\n      \"method\": \"Integrative metabolomics/transcriptomics; in vitro methylation assay; site-directed mutagenesis; MS identification of methylation site; patient-derived xenograft; Co-IP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical methylation assay, mutagenesis of target residue, PDX in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36823188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT1 methylates PHGDH at R54 or R20, activating its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. This drives metabolic flux into the serine synthesis pathway, supplying α-ketoglutarate and citrate to increase palmitate levels through fatty acid synthase (FASN), and increased palmitate induces protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis, conferring chemoresistance.\",\n      \"method\": \"13C metabolic flux analysis; MS identification of methylation sites; mutagenesis; S-palmitoylation assays; imaging MS in clinical specimens; FASN/PRMT1 inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — 13C metabolic flux analysis, MS-identified PTM sites, mutagenesis, and multiple orthogonal mechanistic validations in one study\",\n      \"pmids\": [\"38383964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p53 suppresses PHGDH expression, inhibiting de novo serine biosynthesis. PHGDH overexpression suppresses p53-mediated apoptosis, while RNAi knockdown of PHGDH promotes apoptosis under serine starvation, demonstrating that PHGDH is a target of p53-mediated transcriptional repression in the serine biosynthesis pathway.\",\n      \"method\": \"RNAi knockdown; luciferase reporter assay; ChIP; apoptosis assays; Nutlin-3 p53 activation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined phenotype, ChIP confirming p53 binding at PHGDH locus, orthogonal rescue experiments\",\n      \"pmids\": [\"25404730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nuclear localization of PHGDH is induced by p38-mediated phosphorylation at Ser371 under glucose restriction, while AMPK phosphorylates PHGDH at Ser55, selectively shifting its substrate specificity toward oxidation of malate to oxaloacetate (generating NADH instead of serine). In the nucleus, altered PHGDH activity restricts NAD+ levels, suppressing PARP1-mediated poly(ADP-ribosyl)ation of c-Jun and thereby impairing c-Jun transcriptional activity and cell growth.\",\n      \"method\": \"Phosphoproteomic analysis; site-directed mutagenesis; in vitro enzymatic assays; subcellular fractionation; PARP1 activity assays; ChIP; cancer xenograft models\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay demonstrating altered substrate specificity, mutagenesis of phosphorylation sites, nuclear fractionation with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"34663976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Low 3-phosphoglycerate (3-PGA) levels allow PHGDH to bind scaffold protein AXIN in complex with kinase HIPK2 and p53, forming a multivalent complex that enables HIPK2 to specifically phosphorylate p53 at Ser46 and promote apoptosis. When bound to 3-PGA (high glucose), PHGDH is diverted to serine synthesis and cannot interact with AXIN/HIPK2. Constitutively 3-PGA-bound mutants (R135W, V261M) abolish p53 activation; constitutively unbound mutants (T57A, T78A) cause constitutive p53 activation and apoptosis.\",\n      \"method\": \"Co-IP; in vitro binding assays; site-directed mutagenesis; 3-PGA binding assays; p53 phosphorylation assays; mouse HCC model with Trp53 knockout validation; caloric restriction experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of multi-protein complex, mutagenesis confirming metabolite-dependent binding switch, in vivo genetic validation with p53 knockout rescue\",\n      \"pmids\": [\"37726403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHGDH-mediated serine synthesis is essential for heme production in endothelial cells (ECs). PHGDH knockdown causes cellular serine depletion unique to ECs, leading to insufficient heme production, impaired electron transport chain enzyme activities, elevated ROS, and EC apoptosis. Supplementation with hemin restored ETC function and rescued apoptosis and angiogenesis defects.\",\n      \"method\": \"EC-specific PHGDH knockout mice; siRNA knockdown; ETC enzyme activity assays; heme measurement; hemin rescue; metabolite supplementation; angiogenesis assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EC-specific in vivo knockout with lethal phenotype, mechanistic rescue with hemin, multiple biochemical assays confirming heme deficiency as mechanism\",\n      \"pmids\": [\"30017355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHGDH-mediated endothelial cell metabolism drives formation of a hypoxic and immune-hostile vascular microenvironment in glioblastoma. Tumor microenvironmental cues induce ATF4-mediated PHGDH expression in ECs, triggering a redox-dependent mechanism that regulates endothelial glycolysis and leads to EC overgrowth. Genetic PHGDH ablation in ECs prunes over-sprouting vasculature, abrogates intratumoral hypoxia, and improves T cell infiltration.\",\n      \"method\": \"Metabolome and transcriptome analysis; EC-specific genetic PHGDH ablation; ATF4 ChIP; redox assays; T cell infiltration quantification; GBM xenograft models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EC-specific genetic knockout with defined vascular phenotype, ChIP confirming ATF4 transcriptional regulation, multiple orthogonal methods\",\n      \"pmids\": [\"36804058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dimerization of PHGDH through its catalytic unit is essential for enzymatic activity. The catalytic subdomain (sPHGDH) forms dimers with a dissociation constant of ~0.58 μM, and enzyme activity depends on dimer content. Single-point mutations at computationally identified hotspot residues at the dimer interface disrupt dimer formation and abolish activity. Molecular dynamics simulations showed dimerization facilitates substrate binding and maintains catalytic conformation. Full-length PHGDH exists as monomers/dimers/tetramers; mutations E108A and I121A disrupt all oligomeric states and abolish activity.\",\n      \"method\": \"Analytical ultracentrifugation; size-exclusion chromatography; enzymatic activity assays; site-directed mutagenesis; molecular dynamics simulations; structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined dimer Kd, mutagenesis abolishing activity, molecular dynamics validation, multiple biophysical methods\",\n      \"pmids\": [\"33753166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A natural compound withangulatin A (WA) covalently binds PHGDH at cysteine 295 (Cys295), blocking the substrate-binding domain and inducing an allosteric effect that inactivates the enzyme. This identifies Cys295 as a novel allosteric regulatory site. WA-mediated PHGDH inhibition decreases glutathione synthesis and elevates ROS, inhibiting tumor proliferation.\",\n      \"method\": \"Affinity-based protein profiling; biolayer interferometry; LC-MS/MS covalent site identification; mutagenesis; enzymatic activity assays; cellular ROS/glutathione measurements\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — LC-MS/MS identified covalent binding site, mutagenesis validated Cys295 specificity, multiple orthogonal binding and enzymatic assays\",\n      \"pmids\": [\"35127383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of PHGDH in complex with oridonin revealed a new allosteric binding site. Oridonin binding relocates R54 (a residue involved in substrate binding), reducing enzymatic activity. Mutagenesis studies showed PHGDH activity is highly sensitive to cysteine mutations, especially in the substrate-binding domain.\",\n      \"method\": \"X-ray crystallography; site-directed mutagenesis; enzymatic activity assays; natural product library screening\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — X-ray crystal structure with bound inhibitor, mutagenesis confirming R54 role, in vitro enzymatic validation\",\n      \"pmids\": [\"34971423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Indole amide inhibitors bind the NAD+ pocket of PHGDH, established by X-ray crystallography. Structure-based optimization yielded low nanomolar affinities for PHGDH, with the most potent compounds inhibiting de novo serine synthesis with sub-micromolar cellular activity.\",\n      \"method\": \"X-ray crystallography of PHGDH–inhibitor complexes; enzymatic IC50 assays; isotope-labeling serine synthesis assays; cancer cell proliferation assays\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — X-ray crystal structures defining NAD+ binding pocket, multiple inhibitors validated enzymatically and cellularly\",\n      \"pmids\": [\"31327531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fragment-based drug discovery identified the NAD+-binding pocket as an inhibitor binding site on PHGDH. Crystal structures of PHGDH with bound fragments (diffraction to high resolution) guided structure-based fragment growing, demonstrating routes to NAD+-competitive inhibitors. siRNA-mediated PHGDH knockdown reduced proliferation specifically in PHGDH-amplified (not low-expression) breast cancer cells.\",\n      \"method\": \"Fragment soaking; X-ray crystallography; thermal shift assay; ITC competition experiments; siRNA knockdown; cell proliferation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — X-ray crystal structures of fragment complexes, ITC binding quantification, siRNA loss-of-function with differential phenotype in amplified vs. non-amplified cells\",\n      \"pmids\": [\"29568346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NAD+ availability, maintained by the NAD+ salvage pathway (rate-limited by NAMPT), is required for PHGDH-driven serine biosynthesis. Inhibiting NAMPT depletes NAD+, impeding PHGDH enzymatic function and reducing glucose-derived serine synthesis. PHGDH-high breast cancer cells are selectively sensitive to NAD+ salvage inhibition.\",\n      \"method\": \"NAD+ salvage pathway inhibitors; isotope-labeled serine synthesis assays; PHGDH enzymatic activity measurements; cell viability assays; proteomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct enzymatic measurement showing NAD+-dependence, isotope tracing, selective toxicity in PHGDH-high lines\",\n      \"pmids\": [\"30157431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHGDH activity is regulated downstream of mTORC1 signaling in macrophages: TSC2 (a negative regulator of mTORC1) controls PHGDH enzymatic activity in an mTORC1-dependent manner. LPS-stimulated (M1) macrophages repress PHGDH activity, while IL-4-stimulated (M2) macrophages increase PHGDH activity, which is required for expression of anti-inflammatory molecules and macrophage proliferation.\",\n      \"method\": \"Inverse data-driven modeling (COVRECON); metabolomics; proteomics; mRNA expression analysis; enzymatic activity measurements; TSC2-knockout macrophages\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity measurements in genetic knockout model, multiomics integration, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32023468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PHGDH-mediated serine biosynthesis promotes α-ketoglutarate (αKG) production, which activates mTORC1 signaling and contributes to M2-like immunosuppressive macrophage phenotype maintenance in the tumor microenvironment. Genetic PHGDH ablation in macrophages attenuates tumor growth, reduces TAM infiltration, shifts M2 TAMs toward M1, and downregulates PD-L1.\",\n      \"method\": \"Macrophage-specific genetic PHGDH ablation; metabolic flux analysis; mTORC1 activity assays; tumor-bearing mouse models; flow cytometry\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined mechanistic pathway (serine→αKG→mTORC1), in vivo validation, single lab\",\n      \"pmids\": [\"38409249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UTX (H3K27 demethylase) recruits E3 ligase RNF114 to ubiquitinate PHGDH at Lys310 and Lys330, leading to PHGDH proteasomal degradation and suppression of renal serine synthesis. Kidney-specific Utx knockout upregulates PHGDH, increasing circulating serine and inhibiting high-fat diet-induced lipid accumulation in kidney and liver.\",\n      \"method\": \"Kidney-specific Utx knockout mice; Co-IP; ubiquitination assays; LC-MS identification of ubiquitination sites; metabolite measurements; high-fat diet model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying RNF114–PHGDH interaction, MS-identified ubiquitination sites (K310/K330), in vivo knockout model with metabolic phenotype\",\n      \"pmids\": [\"35788583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHGDH binds PCBP2 (an RNA-binding protein) and inhibits its ubiquitination-mediated degradation. Stabilized PCBP2 in turn stabilizes SLC7A11 mRNA, increasing SLC7A11 expression, which inhibits ferroptosis and promotes bladder cancer progression.\",\n      \"method\": \"Co-IP; mass spectrometry; RIP (RNA immunoprecipitation) assay; ubiquitination assays; ferroptosis measurement (C11 probes, electron microscopy); knockdown experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and MS identifying PCBP2 as PHGDH binding partner, RIP assay for mRNA stabilization, ferroptosis rescue experiments; single lab\",\n      \"pmids\": [\"36147463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The ACT domain of nuclear PHGDH binds nuclear cMyc to form a transactivation complex (PHGDH/p300/cMyc/AF9) that drives CXCL1 and IL8 gene expression. This promotes neutrophil recruitment and tumor-associated macrophage filtration, advancing liver cancer. Forced cytosolic localization of PHGDH or destruction of PHGDH/cMyc interaction abolishes this oncogenic function, independent of PHGDH catalytic activity.\",\n      \"method\": \"Co-IP identifying PHGDH–cMyc–p300–AF9 complex; ChIP; nuclear/cytosolic fractionation; localization mutants; neutrophil depletion with neutralizing antibodies; liver cancer mouse models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying multi-protein nuclear complex, ChIP confirming transcriptional regulation, rescue with cytosolic localization mutant; single lab\",\n      \"pmids\": [\"37078828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHGDH supports liver ceramide synthesis through provision of serine as a substrate; doxycycline-inducible PHGDH knockdown in adult mice reduced liver serine and ceramide levels without increasing deoxysphingolipids, and altered liver triacylglycerol profiles with accumulation of longer chain, polyunsaturated tails.\",\n      \"method\": \"Inducible shRNA knock-in mouse model; lipidomics; metabolomics; liver and pancreatic function assays\",\n      \"journal\": \"Cancer & metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo inducible knockdown model with lipidomics establishing ceramide synthesis link; single lab, single main method\",\n      \"pmids\": [\"32549981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZEB1 transcription factor activates PHGDH transcription by binding a non-canonical binding site within the PHGDH promoter region, upregulating serine synthesis flux (SSP) to enable HCC cells to be more invasive, proliferative, and resistant to ROS and sorafenib.\",\n      \"method\": \"ChIP; luciferase reporter assay; 13C-glucose tracing; CRISPR Zeb1 conditional knockout mice; xenograft models\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter establishing direct ZEB1–PHGDH promoter interaction, 13C flux tracing, in vivo conditional knockout; single lab\",\n      \"pmids\": [\"37331567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deubiquitinase Josephin-2 (JOSD2) stabilizes PHGDH protein by removing ubiquitin from PHGDH, preventing its proteasomal degradation. Silencing Josephin-2 enhanced PHGDH ubiquitination and degradation, inhibiting HCC proliferation and cancer stem cell phenotype.\",\n      \"method\": \"Co-IP; ubiquitination assays; knockdown experiments; spheroid formation; in vivo xenograft\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying Josephin-2–PHGDH interaction, ubiquitination assay; single lab, limited mechanistic depth\",\n      \"pmids\": [\"36583817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASS1 (argininosuccinate synthase 1) directly binds PHGDH and promotes its ubiquitination-mediated proteasomal degradation, thereby inhibiting serine synthesis. The tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout, placing PHGDH downstream of ASS1 in the same pathway.\",\n      \"method\": \"Co-IP identifying ASS1–PHGDH interaction; ubiquitination assays; PHGDH knockout rescue experiments; serine/glycine depletion proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, and genetic epistasis (PHGDH KO rescuing ASS1 overexpression phenotype); single lab\",\n      \"pmids\": [\"38710705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"eIF3i promotes PHGDH translation through METTL3-mediated N6-methyladenosine (m6A) modification on PHGDH mRNA, which enhances PHGDH mRNA binding to eIF3i, ultimately increasing PHGDH translation rate. This mechanism supports CRC cell proliferation.\",\n      \"method\": \"Ribosome profiling; proteomics; m6A-RIP assay; eIF3i–mRNA interaction assays; eIF3i and PHGDH knockdown; in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ribosome profiling and m6A-RIP establishing translation mechanism, in vivo validation; single lab\",\n      \"pmids\": [\"37611825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LncRNA RMRP is upregulated in platinum-resistant ovarian cancer cells and promotes DDX3X (RNA-binding protein) binding to PHGDH mRNA, thereby increasing PHGDH translation. Knockdown of PHGDH suppressed cisplatin resistance and spheroid formation.\",\n      \"method\": \"Polysome profiling; RNA-protein binding assays (RIP); siRNA knockdown; cisplatin resistance assays; spheroid formation\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic follow-up on DDX3X–PHGDH mRNA interaction; polysome profiling supports translational upregulation\",\n      \"pmids\": [\"34178629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHGDH activity is required for serine availability needed for nucleotide production and cell proliferation in brain metastatic cells; the serine- and glycine-limited brain microenvironment imposes dependence on PHGDH-driven serine synthesis. Genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis but not extracranial tumor growth.\",\n      \"method\": \"Proteomics; metabolomics; multiple brain metastasis mouse models; genetic PHGDH suppression (shRNA); pharmacologic PHGDH inhibition; isotope-labeled nucleotide synthesis assays\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, metabolomics, isotope tracing), multiple in vivo brain metastasis models, genetic and pharmacologic validation\",\n      \"pmids\": [\"32571778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHGDH inhibition activates ATF4/CEBPB transcriptional program in SEM-type gastric cancer cells under glutamine starvation, upregulating the mitochondrial folate cycle pathway to produce NADPH as an ROS scavenger, representing a metabolic plasticity mechanism for survival under nutrient stress.\",\n      \"method\": \"13C-isotope tracing; transcriptomics; ChIP (ATF4/CEBPB); single-nucleus RNA-seq of patient-derived organoids; PHGDH inhibition under glutamine starvation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isotope tracing and ChIP establishing ATF4/CEBPB-mediated PHGDH induction and mitochondrial folate cycle function; single lab\",\n      \"pmids\": [\"37192160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHGDH is the first committed enzyme in the serine synthesis pathway (SSP) and its inactivation via RNAi knockdown or CRISPR knockout reduces αKG, serine, and NADPH production in HCC, elevating ROS and inducing apoptosis upon sorafenib treatment. PHGDH expression is induced by sorafenib treatment as an adaptive resistance mechanism.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 library screen; RNAi knockdown; CRISPR/Cas9 knockout; metabolite measurement (αKG, serine, NADPH); ROS measurement; in vivo HCC xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide CRISPR screen identifying PHGDH, validated with RNAi and CRISPR KO, metabolite measurements establishing pathway position, in vivo validation\",\n      \"pmids\": [\"31615983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHGDH downregulation and reduced hepatic serine are associated with fatty liver disease. PHGDH knockout in MEFs or primary hepatocytes increases lipid accumulation and reduces NAD+ and SIRT1 activity, reversed by PHGDH overexpression. PHGDH transgenic mice show reduced hepatic triglyceride accumulation with increased SIRT1 activity and reduced lipogenic gene expression under high-fat diet.\",\n      \"method\": \"PHGDH-knockout MEFs; PHGDH-transgenic mice; NAD+ measurement; SIRT1 activity assay; hepatic triglyceride measurement; high-fat diet model\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both KO and transgenic models with defined biochemical measurements (NAD+, SIRT1); single lab, single model system\",\n      \"pmids\": [\"31678070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYC transcriptionally regulates PHGDH expression in glioblastoma stem-like cells; ChIP confirmed MYC binding to the PHGDH promoter. PHGDH activation enhances GSC self-renewal by regulating redox homeostasis, facilitating one-carbon metabolism, and promoting DNA damage response via SSP activation.\",\n      \"method\": \"ChIP; transcriptomic and metabolomic analyses; genetic PHGDH ablation; pharmacological PHGDH inhibition; orthotopic GBM xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing MYC–PHGDH promoter binding, metabolomics, in vivo xenograft validation; single lab\",\n      \"pmids\": [\"40102981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CXCL7 activates CXCR2 receptor on tumor cells, triggering interferon signaling and promoting PHGDH expression through STAT1-dependent transcriptional upregulation, thereby enhancing serine metabolism and paracrine secretion of S-adenosyl methionine (SAM), which drives chemotherapy resistance in colorectal cancer.\",\n      \"method\": \"Co-culture system; STAT1 ChIP; CXCR2 blockade; PHGDH knockdown; SAM measurement; in vivo mouse models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — STAT1 ChIP at PHGDH promoter, CXCR2 blockade establishing upstream pathway, SAM measurement; single lab\",\n      \"pmids\": [\"40368902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATF4 mediates transcriptional upregulation of PHGDH under exogenous serine deficiency conditions in colon cancer cells. LC-MS analysis revealed that serine deprivation induces changes in PHGDH acetylation: loss of the K289 acetylation site and appearance of a new K21 acetylation site.\",\n      \"method\": \"Real-time qPCR; LC-MS/MS post-translational modification analysis; serine deprivation experiments; luciferase reporter (implied)\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — LC-MS identifies acetylation sites but functional consequences of specific acetylation not established; single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"36707056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHGDH inhibition in skeletal muscle cells decreases protein synthesis predominantly through mTORC1-dependent mechanisms. N-acetylcysteine (antioxidant/redox modulator) partially rescued decreased protein synthesis and mTORC1 signaling during PHGDH inhibition, implicating redox balance as a mediator of PHGDH's effect on mTORC1.\",\n      \"method\": \"Two distinct PHGDH inhibitors; puromycin-based protein synthesis assay; rapamycin control; IGF-1 stimulation; metabolomics; N-acetylcysteine rescue; C2C12 and human primary muscle cells\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal PHGDH inhibitors, pharmacological rescue experiments, metabolomics; single lab\",\n      \"pmids\": [\"37991454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHGDH is dysregulated as a common molecular feature in both Marinesco-Sjögren syndrome (SIL1 mutations) and INPP5K disease, revealed by unbiased proteomic profiling of patient-derived cells. L-serine administration improved neuronal phenotype in sil1, phgdh, and inpp5k zebrafish models, establishing PHGDH-dependent serine deficiency as a convergent pathomechanism.\",\n      \"method\": \"Unbiased proteomic profiling of patient-derived cells; zebrafish knockout models (sil1, phgdh, inpp5k); L-serine supplementation rescue experiments\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased proteomics identifying PHGDH as convergent node, in vivo zebrafish genetic models with serine rescue; single lab\",\n      \"pmids\": [\"33792664\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHGDH is the rate-limiting enzyme of the de novo serine synthesis pathway, catalyzing the NAD+-dependent oxidation of 3-phosphoglycerate to 3-phosphohydroxypyruvate; its activity requires dimerization through the catalytic unit; it is regulated by PRMT1-mediated arginine methylation (R236, R54/R20) that activates it, p38-mediated phosphorylation at Ser371 that drives nuclear translocation, AMPK-mediated phosphorylation at Ser55 that switches its substrate specificity toward malate oxidation, ubiquitin-mediated degradation (written by RNF114, erased by Josephin-2/JOSD2), and transcriptional regulation by p53 (repressive) and ZEB1/MYC/ATF4 (activating); beyond serine synthesis, PHGDH non-catalytically interacts with phosphofructokinase to suppress the hexosamine-sialic acid pathway, and in the nucleus forms a transactivation complex with cMyc/p300/AF9 to drive chemokine gene expression, while under low glucose it binds AXIN/HIPK2 to activate p53-Ser46 phosphorylation and apoptosis in a 3-PGA-switchable manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHGDH catalyzes the first, rate-limiting and NAD+-dependent step of the de novo serine synthesis pathway (oxidation of 3-phosphoglycerate), coordinating one-carbon unit usage for nucleotide synthesis and supplying carbon for downstream serine-derived metabolites including heme, ceramide, glutathione, NADPH and α-ketoglutarate [#0, #7, #28]. Catalysis requires dimerization through the catalytic subdomain, with defined dimer-interface hotspot residues whose mutation abolishes activity, and the enzyme depends on a continuously replenished NAD+ pool maintained by the salvage pathway [#9, #14]. Structural and chemical-biology studies have mapped distinct druggable sites — the NAD+-binding pocket and allosteric sites engaged by covalent (Cys295) and non-covalent (R54-relocating) inhibitors [#10, #11, #12, #13]. PHGDH activity is set by a dense layer of post-translational control: PRMT1-mediated arginine methylation (R236, R54/R20) activates the enzyme, stabilizes substrate binding and suppresses polyubiquitination, while ubiquitin-mediated turnover is written by RNF114 (recruited by UTX, at K310/K330) and by ASS1, and reversed by the deubiquitinase JOSD2 [#2, #3, #17, #23, #22]. Stress- and glucose-responsive phosphorylation reprograms the enzyme: p38 phosphorylation at Ser371 drives nuclear translocation and AMPK phosphorylation at Ser55 switches substrate specificity toward malate oxidation, restricting nuclear NAD+ and PARP1-dependent c-Jun activity [#5]. Beyond catalysis, PHGDH acts non-enzymatically — binding phosphofructokinase to restrain the hexosamine–sialic acid pathway and integrin sialylation-driven metastasis, forming a nuclear cMyc/p300/AF9 transactivation complex via its ACT domain to drive CXCL1/IL8 chemokine expression, and, when not bound to 3-phosphoglycerate under low glucose, scaffolding an AXIN/HIPK2/p53 complex to enable HIPK2 phosphorylation of p53-Ser46 and apoptosis [#1, #19, #6]. Transcriptionally, PHGDH is repressed by p53 and activated by ATF4, ZEB1, MYC and STAT1 signaling [#4, #8, #21, #30, #31]. Through these activities PHGDH sustains proliferation, redox homeostasis, chemoresistance, endothelial heme/angiogenic function and an immunosuppressive tumor microenvironment, and serine-dependent dysregulation of PHGDH is a convergent pathomechanism in Marinesco-Sjögren syndrome and INPP5K disease rescued by L-serine in zebrafish [#7, #8, #16, #26, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that PHGDH is not a constitutively expressed housekeeping enzyme but a transcriptionally controlled node, placing serine synthesis under tumor-suppressor surveillance.\",\n      \"evidence\": \"p53 activation, ChIP, RNAi, and apoptosis assays in cells\",\n      \"pmids\": [\"25404730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the p53 response element architecture\", \"Did not address PTM-level regulation of the enzyme\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined PHGDH as the rate-limiting entry into glucose-derived serine synthesis and, unexpectedly, as a coordinator of one-carbon unit usage from all serine sources, validating it as a cancer target.\",\n      \"evidence\": \"Small-molecule screen, isotope tracing, orthotopic xenografts\",\n      \"pmids\": [\"27110680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling glycolytic serine synthesis to exogenous-serine one-carbon flux not resolved\", \"No structural basis for inhibitor binding at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped the enzyme's NAD+-binding pocket structurally and demonstrated selective dependence of PHGDH-amplified cancers, converting target validation into structure-guided drug design.\",\n      \"evidence\": \"X-ray crystallography, fragment-based discovery, ITC, siRNA proliferation assays\",\n      \"pmids\": [\"31327531\", \"29568346\", \"31615983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allosteric regulatory sites not yet defined\", \"Did not address oligomeric requirements for activity\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that catalytic competence requires dimerization and that NAD+ salvage availability gates flux, defining the structural and cofactor prerequisites for activity.\",\n      \"evidence\": \"Analytical ultracentrifugation, molecular dynamics, NAMPT inhibition with isotope tracing\",\n      \"pmids\": [\"33753166\", \"30157431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological regulation of oligomeric state in cells not established\", \"Whether PTMs modulate dimerization untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovered allosteric and covalent regulatory sites (Cys295, R54 relocation) distinct from the NAD+ pocket, expanding the mechanistic and pharmacological control surface.\",\n      \"evidence\": \"Covalent-site LC-MS/MS, X-ray crystallography with oridonin, mutagenesis, ROS/glutathione assays\",\n      \"pmids\": [\"35127383\", \"34971423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulators acting through these allosteric sites unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed glucose-restriction signaling reprograms PHGDH via p38 (Ser371, nuclear translocation) and AMPK (Ser55, substrate-specificity switch to malate oxidation), linking the enzyme to nuclear NAD+ and PARP1/c-Jun control.\",\n      \"evidence\": \"Phosphoproteomics, mutagenesis, in vitro enzymatic assays, fractionation, xenografts\",\n      \"pmids\": [\"34663976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of nuclear malate oxidation in vivo unclear\", \"Other nuclear PHGDH substrates not enumerated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a catalysis-independent function: PHGDH binding to phosphofructokinase suppresses the hexosamine–sialic acid pathway and integrin sialylation, with loss of binding potentiating metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP, metabolomics, glycoproteomics, mouse metastasis models, sialylation inhibition rescue\",\n      \"pmids\": [\"35585241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PHGDH–PFK interface unresolved\", \"How metabolic state toggles the interaction not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the ubiquitin-proteasome control of PHGDH abundance — RNF114 (UTX-recruited, K310/K330) writing and JOSD2 erasing ubiquitin — connecting epigenetic and degradative inputs to serine output and systemic lipid metabolism.\",\n      \"evidence\": \"Kidney-specific Utx knockout, Co-IP, MS-mapped ubiquitination sites, DUB knockdown, high-fat diet model\",\n      \"pmids\": [\"35788583\", \"36583817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JOSD2 finding rests on single-lab Co-IP without reciprocal depth\", \"Interplay between RNF114 and JOSD2 in setting steady-state levels untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PRMT1 arginine methylation (R236; R54/R20) as an activating PTM that enhances catalysis, stabilizes 3-PGA binding and blocks polyubiquitination, coupling serine flux to redox protection, lipogenesis and chemoresistance.\",\n      \"evidence\": \"In vitro methylation, MS-mapped sites, mutagenesis, 13C flux, S-palmitoylation assays, PDX models\",\n      \"pmids\": [\"36823188\", \"38383964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demethylase counteracting PRMT1 not identified\", \"Crosstalk with phosphorylation/ubiquitination not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed 3-PGA occupancy acts as a metabolite switch: low 3-PGA frees PHGDH to scaffold AXIN/HIPK2/p53 and drive p53-Ser46 apoptosis, while a separate nuclear PHGDH/cMyc/p300/AF9 complex drives chemokine transcription, defining moonlighting roles tied to localization and metabolic state.\",\n      \"evidence\": \"Co-IP, in vitro binding, 3-PGA-binding mutants, p53 phosphorylation assays, ChIP, mouse cancer models\",\n      \"pmids\": [\"37726403\", \"37078828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear complex findings (cMyc/AF9) from single lab\", \"Determinants of nuclear vs cytosolic partitioning incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the transcriptional and translational input map (ZEB1, MYC, STAT1, ATF4 transcription; METTL3-m6A/eIF3i and RMRP/DDX3X translation), showing multiple oncogenic and stress programs converge to elevate PHGDH.\",\n      \"evidence\": \"ChIP, luciferase reporters, ribosome profiling, m6A-RIP, polysome profiling, knockdown/xenografts\",\n      \"pmids\": [\"37331567\", \"40102981\", \"40368902\", \"37192160\", \"37611825\", \"34178629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RMRP/DDX3X translational mechanism from low-confidence single study\", \"Hierarchy among competing transcriptional regulators unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated cell-type-specific physiological roles — endothelial PHGDH for heme/ETC function and tumor vasculature, macrophage PHGDH for αKG-mTORC1-driven M2 immunosuppression — establishing PHGDH as a microenvironmental and immune-modulatory node.\",\n      \"evidence\": \"Cell-type-specific knockout mice, ETC/heme assays, flux analysis, mTORC1 assays, immune profiling\",\n      \"pmids\": [\"30017355\", \"36804058\", \"38409249\", \"32023468\", \"32571778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular coupling of serine to mTORC1 in each cell type incompletely mapped\", \"Macrophage findings from single labs\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PHGDH-dependent serine deficiency to neurological disease, showing it as a convergent pathomechanism in Marinesco-Sjögren syndrome and INPP5K disease correctable by L-serine.\",\n      \"evidence\": \"Unbiased proteomics of patient cells, zebrafish knockout models, L-serine rescue\",\n      \"pmids\": [\"33792664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from SIL1/INPP5K loss to PHGDH dysregulation not mechanistically resolved\", \"Human therapeutic translation of L-serine not established here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple competing PTMs (methylation, phosphorylation, ubiquitination, S-palmitoylation, acetylation) and metabolite-sensing are integrated to dictate PHGDH's choice between catalysis, nuclear moonlighting, and scaffolding remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling PTM state to localization and moonlighting\", \"Functional consequence of acetylation sites (K21/K289) not established\", \"Demethylase/phosphatase counter-enzymes largely unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 5, 9, 14]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 28]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [19, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 19, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 28, 7, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 19, 21, 30]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 10, 28, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 6, 28]}\n    ],\n    \"complexes\": [\n      \"PHGDH/p300/cMyc/AF9 nuclear transactivation complex\",\n      \"PHGDH/AXIN/HIPK2/p53 complex\"\n    ],\n    \"partners\": [\n      \"PFKL\",\n      \"PRMT1\",\n      \"RNF114\",\n      \"JOSD2\",\n      \"ASS1\",\n      \"AXIN\",\n      \"HIPK2\",\n      \"MYC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}