Affinage

PHGDH

D-3-phosphoglycerate dehydrogenase · UniProt O43175

Length
533 aa
Mass
56.7 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2014 High

    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

    PMID:25404730

    Open questions at the time
    • Did not define the p53 response element architecture
    • Did not address PTM-level regulation of the enzyme
  2. 2016 High

    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

    PMID:27110680

    Open questions at the time
    • Mechanism coupling glycolytic serine synthesis to exogenous-serine one-carbon flux not resolved
    • No structural basis for inhibitor binding at this stage
  3. 2019 High

    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

    PMID:29568346 PMID:31327531 PMID:31615983

    Open questions at the time
    • Allosteric regulatory sites not yet defined
    • Did not address oligomeric requirements for activity
  4. 2021 High

    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

    PMID:30157431 PMID:33753166

    Open questions at the time
    • Physiological regulation of oligomeric state in cells not established
    • Whether PTMs modulate dimerization untested
  5. 2021 High

    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

    PMID:34971423 PMID:35127383

    Open questions at the time
    • Endogenous regulators acting through these allosteric sites unknown
  6. 2021 High

    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

    PMID:34663976

    Open questions at the time
    • Quantitative contribution of nuclear malate oxidation in vivo unclear
    • Other nuclear PHGDH substrates not enumerated
  7. 2022 High

    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

    PMID:35585241

    Open questions at the time
    • Structural basis of the PHGDH–PFK interface unresolved
    • How metabolic state toggles the interaction not defined
  8. 2022 Medium

    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

    PMID:35788583 PMID:36583817

    Open questions at the time
    • JOSD2 finding rests on single-lab Co-IP without reciprocal depth
    • Interplay between RNF114 and JOSD2 in setting steady-state levels untested
  9. 2023 High

    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

    PMID:36823188 PMID:38383964

    Open questions at the time
    • Demethylase counteracting PRMT1 not identified
    • Crosstalk with phosphorylation/ubiquitination not integrated
  10. 2023 High

    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

    PMID:37078828 PMID:37726403

    Open questions at the time
    • Nuclear complex findings (cMyc/AF9) from single lab
    • Determinants of nuclear vs cytosolic partitioning incompletely defined
  11. 2023 Medium

    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

    PMID:34178629 PMID:37192160 PMID:37331567 PMID:37611825 PMID:40102981 PMID:40368902

    Open questions at the time
    • RMRP/DDX3X translational mechanism from low-confidence single study
    • Hierarchy among competing transcriptional regulators unresolved
  12. 2024 Medium

    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

    PMID:30017355 PMID:32023468 PMID:32571778 PMID:36804058 PMID:38409249

    Open questions at the time
    • Direct molecular coupling of serine to mTORC1 in each cell type incompletely mapped
    • Macrophage findings from single labs
  13. 2021 Medium

    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

    PMID:33792664

    Open questions at the time
    • Causal chain from SIL1/INPP5K loss to PHGDH dysregulation not mechanistically resolved
    • Human therapeutic translation of L-serine not established here

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0060090 molecular adaptor activity 3 GO:0016740 transferase activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-5357801 Programmed Cell Death 3
Partners
ASS1AXINHIPK2JOSD2MYCPFKLPRMT1RNF114
Complex memberships
PHGDH/AXIN/HIPK2/p53 complexPHGDH/p300/cMyc/AF9 nuclear transactivation complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 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. Quantitative high-throughput small-molecule screen; isotope tracing; orthotopic xenograft tumor models; cell viability assays Nature chemical biology High 27110680
2022 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. Co-immunoprecipitation; metabolomics; glycoproteomics; genetic silencing; migration/invasion assays; mouse metastasis models; pharmacological sialylation inhibition Nature High 35585241
2023 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. Integrative metabolomics/transcriptomics; in vitro methylation assay; site-directed mutagenesis; MS identification of methylation site; patient-derived xenograft; Co-IP Nature communications High 36823188
2024 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. 13C metabolic flux analysis; MS identification of methylation sites; mutagenesis; S-palmitoylation assays; imaging MS in clinical specimens; FASN/PRMT1 inhibition Cancer research High 38383964
2014 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. RNAi knockdown; luciferase reporter assay; ChIP; apoptosis assays; Nutlin-3 p53 activation The Journal of biological chemistry High 25404730
2021 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. Phosphoproteomic analysis; site-directed mutagenesis; in vitro enzymatic assays; subcellular fractionation; PARP1 activity assays; ChIP; cancer xenograft models Nature metabolism High 34663976
2023 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. 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 Cell research High 37726403
2018 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. EC-specific PHGDH knockout mice; siRNA knockdown; ETC enzyme activity assays; heme measurement; hemin rescue; metabolite supplementation; angiogenesis assays Cell metabolism High 30017355
2023 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. Metabolome and transcriptome analysis; EC-specific genetic PHGDH ablation; ATF4 ChIP; redox assays; T cell infiltration quantification; GBM xenograft models Cell metabolism High 36804058
2021 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. Analytical ultracentrifugation; size-exclusion chromatography; enzymatic activity assays; site-directed mutagenesis; molecular dynamics simulations; structural modeling The Journal of biological chemistry High 33753166
2021 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. Affinity-based protein profiling; biolayer interferometry; LC-MS/MS covalent site identification; mutagenesis; enzymatic activity assays; cellular ROS/glutathione measurements Acta pharmaceutica Sinica. B High 35127383
2021 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. X-ray crystallography; site-directed mutagenesis; enzymatic activity assays; natural product library screening Cellular and molecular life sciences High 34971423
2019 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. X-ray crystallography of PHGDH–inhibitor complexes; enzymatic IC50 assays; isotope-labeling serine synthesis assays; cancer cell proliferation assays Bioorganic & medicinal chemistry letters High 31327531
2016 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. Fragment soaking; X-ray crystallography; thermal shift assay; ITC competition experiments; siRNA knockdown; cell proliferation assays Oncotarget High 29568346
2018 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. NAD+ salvage pathway inhibitors; isotope-labeled serine synthesis assays; PHGDH enzymatic activity measurements; cell viability assays; proteomics Cell reports High 30157431
2020 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. Inverse data-driven modeling (COVRECON); metabolomics; proteomics; mRNA expression analysis; enzymatic activity measurements; TSC2-knockout macrophages Cell reports Medium 32023468
2024 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. Macrophage-specific genetic PHGDH ablation; metabolic flux analysis; mTORC1 activity assays; tumor-bearing mouse models; flow cytometry Cellular & molecular immunology Medium 38409249
2022 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. Kidney-specific Utx knockout mice; Co-IP; ubiquitination assays; LC-MS identification of ubiquitination sites; metabolite measurements; high-fat diet model Nature communications High 35788583
2022 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. Co-IP; mass spectrometry; RIP (RNA immunoprecipitation) assay; ubiquitination assays; ferroptosis measurement (C11 probes, electron microscopy); knockdown experiments International journal of biological sciences Medium 36147463
2023 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. Co-IP identifying PHGDH–cMyc–p300–AF9 complex; ChIP; nuclear/cytosolic fractionation; localization mutants; neutrophil depletion with neutralizing antibodies; liver cancer mouse models Advanced science Medium 37078828
2020 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. Inducible shRNA knock-in mouse model; lipidomics; metabolomics; liver and pancreatic function assays Cancer & metabolism Medium 32549981
2023 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. ChIP; luciferase reporter assay; 13C-glucose tracing; CRISPR Zeb1 conditional knockout mice; xenograft models Cellular and molecular gastroenterology and hepatology Medium 37331567
2022 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. Co-IP; ubiquitination assays; knockdown experiments; spheroid formation; in vivo xenograft Genes & genomics Low 36583817
2024 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. Co-IP identifying ASS1–PHGDH interaction; ubiquitination assays; PHGDH knockout rescue experiments; serine/glycine depletion proliferation assays Cell death & disease Medium 38710705
2023 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. Ribosome profiling; proteomics; m6A-RIP assay; eIF3i–mRNA interaction assays; eIF3i and PHGDH knockdown; in vivo xenograft The Journal of biological chemistry Medium 37611825
2021 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. Polysome profiling; RNA-protein binding assays (RIP); siRNA knockdown; cisplatin resistance assays; spheroid formation Frontiers in oncology Low 34178629
2020 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. Proteomics; metabolomics; multiple brain metastasis mouse models; genetic PHGDH suppression (shRNA); pharmacologic PHGDH inhibition; isotope-labeled nucleotide synthesis assays Cancer discovery High 32571778
2023 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. 13C-isotope tracing; transcriptomics; ChIP (ATF4/CEBPB); single-nucleus RNA-seq of patient-derived organoids; PHGDH inhibition under glutamine starvation PNAS Medium 37192160
2019 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. Genome-wide CRISPR/Cas9 library screen; RNAi knockdown; CRISPR/Cas9 knockout; metabolite measurement (αKG, serine, NADPH); ROS measurement; in vivo HCC xenograft Nature communications High 31615983
2019 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. PHGDH-knockout MEFs; PHGDH-transgenic mice; NAD+ measurement; SIRT1 activity assay; hepatic triglyceride measurement; high-fat diet model Metabolism: clinical and experimental Medium 31678070
2023 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. ChIP; transcriptomic and metabolomic analyses; genetic PHGDH ablation; pharmacological PHGDH inhibition; orthotopic GBM xenograft models Journal of experimental & clinical cancer research Medium 40102981
2025 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. Co-culture system; STAT1 ChIP; CXCR2 blockade; PHGDH knockdown; SAM measurement; in vivo mouse models Cell death & disease Medium 40368902
2023 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. Real-time qPCR; LC-MS/MS post-translational modification analysis; serine deprivation experiments; luciferase reporter (implied) Technology in cancer research & treatment Low 36707056
2023 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. Two distinct PHGDH inhibitors; puromycin-based protein synthesis assay; rapamycin control; IGF-1 stimulation; metabolomics; N-acetylcysteine rescue; C2C12 and human primary muscle cells American journal of physiology. Endocrinology and metabolism Medium 37991454
2021 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. Unbiased proteomic profiling of patient-derived cells; zebrafish knockout models (sil1, phgdh, inpp5k); L-serine supplementation rescue experiments Brain Medium 33792664

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nature chemical biology 452 27110680
2019 Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nature communications 329 31615983
2015 TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science (New York, N.Y.) 251 26068857
2020 Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition. Cancer discovery 219 32571778
2016 RETRACTED: PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis. Cancer research 205 27280394
2020 Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science (New York, N.Y.) 187 33303683
2022 PHGDH heterogeneity potentiates cancer cell dissemination and metastasis. Nature 185 35585241
2014 Phage neutralization by sera of patients receiving phage therapy. Viral immunology 166 24893003
2018 Serine Synthesis via PHGDH Is Essential for Heme Production in Endothelial Cells. Cell metabolism 163 30017355
2022 PHGDH Inhibits Ferroptosis and Promotes Malignant Progression by Upregulating SLC7A11 in Bladder Cancer. International journal of biological sciences 145 36147463
2004 NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. Carcinogenesis 135 15358636
2014 p53 Protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. The Journal of biological chemistry 123 25404730
2023 PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma. Nature communications 116 36823188
2023 PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy. Cell metabolism 111 36804058
2006 Chronic urticaria sera increase basophil CD203c expression. The Journal of allergy and clinical immunology 90 16751009
2020 Inverse Data-Driven Modeling and Multiomics Analysis Reveals Phgdh as a Metabolic Checkpoint of Macrophage Polarization and Proliferation. Cell reports 81 32023468
2017 PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma. Cancer research 76 28951458
1988 Antibody to threonyl-transfer RNA synthetase in myositis sera. Arthritis and rheumatism 71 3128989
2021 The alternative activity of nuclear PHGDH contributes to tumour growth under nutrient stress. Nature metabolism 69 34663976
2024 Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling. Cellular & molecular immunology 62 38409249
2024 PHGDH: a novel therapeutic target in cancer. Experimental & molecular medicine 59 38945960
2018 The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis. Cell reports 57 30157431
2007 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer. Prostaglandins & other lipid mediators 57 17481556
2020 The PHGDH enigma: Do cancer cells only need serine or also a redox modulator? Cancer letters 55 32032680
2021 A retrospective overview of PHGDH and its inhibitors for regulating cancer metabolism. European journal of medicinal chemistry 52 33756126
2014 miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth. Molecular cancer research : MCR 52 24699315
1998 Cytokine assays in human sera and tissues. Toxicology 52 9769110
2019 Identification of hepadnavirus in the sera of cats. Scientific reports 50 31337847
2013 Detection of contaminants in cell cultures, sera and trypsin. Biologicals : journal of the International Association of Biological Standardization 50 24071554
2009 HGF/Met signalling promotes PGE(2) biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells. Carcinogenesis 49 19638428
2023 Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate. Cell research 47 37726403
2016 Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells. Molecular oncology 47 27522468
2022 ADH1C inhibits progression of colorectal cancer through the ADH1C/PHGDH /PSAT1/serine metabolic pathway. Acta pharmacologica Sinica 46 35354963
2003 Cytokeratin 20, AN43, PGDH, and COX-2 expression in transitional and squamous cell carcinoma of the bladder. Urologic oncology 46 12954496
2019 Downregulation of PHGDH expression and hepatic serine level contribute to the development of fatty liver disease. Metabolism: clinical and experimental 44 31678070
2014 Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis. The Journal of clinical investigation 44 24837432
2024 PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer. Cancer research 43 38383964
2021 Identification of a novel PHGDH covalent inhibitor by chemical proteomics and phenotypic profiling. Acta pharmaceutica Sinica. B 43 35127383
2019 Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells. Bioorganic & medicinal chemistry letters 42 31327531
2022 Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver. Nature communications 41 35788583
2020 PHGDH as a mechanism for resistance in metabolically-driven cancers. Cancer drug resistance (Alhambra, Calif.) 41 33511334
2013 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1. Oncogene 41 23542179
2008 Expression of 15-PGDH is downregulated by COX-2 in gastric cancer. Carcinogenesis 40 18174234
2020 Targeting PHGDH Upregulation Reduces Glutathione Levels and Resensitizes Resistant NRAS-Mutant Melanoma to MAPK Kinase Inhibition. The Journal of investigative dermatology 39 32389536
2017 Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH. Scientific reports 36 28894120
2023 PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress. Proceedings of the National Academy of Sciences of the United States of America 35 37192160
2016 Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer. Oncotarget 35 29568346
2022 PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma. The Journal of clinical investigation 34 35316216
2015 Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression. Cancer research 34 25691459
2015 High level PHGDH expression in breast is predominantly associated with keratin 5-positive cell lineage independently of malignancy. Molecular oncology 33 26026368
2009 Expression of prostaglandin metabolising enzymes COX-2 and 15-PGDH and VDR in human granulosa cells. Anticancer research 33 19667156
2021 Recent advances in studies of 15-PGDH as a key enzyme for the degradation of prostaglandins. International immunopharmacology 32 34655851
2022 PHGDH expression increases with progression of Alzheimer's disease pathology and symptoms. Cell metabolism 31 35508105
2011 Regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins & other lipid mediators 31 21763448
1969 'Nuclear' antigens and antinuclear antibodies in mink sera. Immunology 31 4181511
2020 PHGDH supports liver ceramide synthesis and sustains lipid homeostasis. Cancer & metabolism 30 32549981
2017 15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide (LPS)-induced acute liver injury. PloS one 30 28423012
2001 Indomethacin, a cox inhibitor, enhances 15-PGDH and decreases human tumoral C cells proliferation. Prostaglandins & other lipid mediators 30 11352223
2021 Phosphoglycerate dehydrogenase (PHGDH) inhibitors: a comprehensive review 2015-2020. Expert opinion on therapeutic patents 29 33571419
2021 Pinoresinol diglucoside (PDG) attenuates cardiac hypertrophy via AKT/mTOR/NF-κB signaling in pressure overload-induced rats. Journal of ethnopharmacology 28 33607200
2021 PHGDH Is Upregulated at Translational Level and Implicated in Platin-Resistant in Ovarian Cancer Cells. Frontiers in oncology 28 34178629
2020 Pharmacologic Blockade of 15-PGDH Protects Against Acute Renal Injury Induced by LPS in Mice. Frontiers in physiology 27 32231583
2020 Characterization of PHGDH expression in bladder cancer: potential targeting therapy with gemcitabine/cisplatin and the contribution of promoter DNA hypomethylation. Molecular oncology 27 32386122
2023 Elevated Nuclear PHGDH Synergistically Functions with cMyc to Reshape the Immune Microenvironment of Liver Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 37078828
2020 Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis. Scientific reports 25 32669620
2018 Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas. Oncogene 25 30250298
1999 Anti-human RP105 sera induces lymphocyte proliferation. Journal of leukocyte biology 25 9886245
2024 ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis. Cell death & disease 24 38710705
2023 ZEB1 Transcriptionally Activates PHGDH to Facilitate Carcinogenesis and Progression of HCC. Cellular and molecular gastroenterology and hepatology 23 37331567
2017 miR-21 modulates prostaglandin signaling and promotes gastric tumorigenesis by targeting 15-PGDH. Biochemical and biophysical research communications 23 29101039
2004 Regulation of 15-hydroxyprostaglandin dehydrogenase (PGDH) gene activity, messenger ribonucleic acid processing, and protein abundance in the human chorion in late gestation and labor. The Journal of clinical endocrinology and metabolism 23 15531523
2021 15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration. JCI insight 21 33600377
2019 Novel and recurrent PHGDH and PSAT1 mutations in Chinese patients with Neu-Laxova syndrome. European journal of dermatology : EJD 20 31903955
1999 The catalytic mechanism of a pyrimidine dimer-specific glycosylase (pdg)/abasic lyase, Chlorella virus-pdg. The Journal of biological chemistry 20 10092668
1980 EAE, EAN and galactocerebroside sera bind to oligodendrocytes and Schwann cells. Journal of the neurological sciences 20 7000981
2023 PHGDH promotes esophageal squamous cell carcinoma progression via Wnt/β-catenin pathway. Cellular signalling 19 37263462
2023 Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism, and mTORC1 signaling. American journal of physiology. Endocrinology and metabolism 18 37991454
2022 Tumor microenvironmental 15-PGDH depletion promotes fibrotic tumor formation and angiogenesis in pancreatic cancer. Cancer science 18 35848891
2021 INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain : a journal of neurology 18 33792664
2023 Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC. Frontiers in pharmacology 17 37284309
2021 Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors. Cellular and molecular life sciences : CMLS 17 34971423
2014 Hypoxia activates 15-PGDH and its metabolite 15-KETE to promote pulmonary artery endothelial cells proliferation via ERK1/2 signalling. British journal of pharmacology 17 24467360
2023 eIF3i promotes colorectal cancer cell survival via augmenting PHGDH translation. The Journal of biological chemistry 16 37611825
2021 Dimerization of PHGDH via the catalytic unit is essential for its enzymatic function. The Journal of biological chemistry 16 33753166
2018 Influence of amygdalin on PDG, IGF and PDGFR expression in HSC-T6 cells. Experimental and therapeutic medicine 16 29556259
2018 Chemopreventive Efficacy of the Cyclooxygenase-2 (Cox-2) Inhibitor, Celecoxib, Is Predicted by Adenoma Expression of Cox-2 and 15-PGDH. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 16 29769213
2014 Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-specific mechanisms. The Journal of clinical endocrinology and metabolism 16 24471568
2012 15-PGDH is reduced and induces apoptosis and cell cycle arrest in gastric carcinoma. World journal of gastroenterology 15 22416177
2025 PHGDH activation fuels glioblastoma progression and radioresistance via serine synthesis pathway. Journal of experimental & clinical cancer research : CR 14 40102981
2023 Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy. Journal of medicinal chemistry 14 36594670
2023 Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion. JHEP reports : innovation in hepatology 14 37942226
2014 15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway. Cellular signalling 14 24657469
2022 Deubiquitinating enzyme Josephin-2 stabilizes PHGDH to promote a cancer stem cell phenotype in hepatocellular carcinoma. Genes & genomics 13 36583817
2020 Association between COX-2 and 15-PGDH polymorphisms and SLE susceptibility. International journal of rheumatic diseases 13 32100450
2025 Chemotherapy-induced macrophage CXCL7 expression drives tumor chemoresistance via the STAT1/PHGDH-serine metabolism axis and SAM paracrine feedback to M2 polarization. Cell death & disease 12 40368902
2023 Multi-omics Analysis of the Role of PHGDH in Colon Cancer. Technology in cancer research & treatment 12 36707056
2020 Down regulating PHGDH affects the lactate production of sertoli cells in varicocele. Reproductive biology and endocrinology : RB&E 12 32664979
2019 Increased PHGDH expression promotes aberrant melanin accumulation. BMC cancer 12 31331318
2017 Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy. Scientific reports 12 28887458
2016 HSP90 Inhibition Suppresses PGE2 Production via Modulating COX-2 and 15-PGDH Expression in HT-29 Colorectal Cancer Cells. Inflammation 12 27075590

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