Affinage

FDPS

Farnesyl pyrophosphate synthase · UniProt P14324

Length
419 aa
Mass
48.3 kDa
Annotated
2026-06-09
19 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FDPS is a mevalonate-pathway enzyme whose synthesis of farnesyl pyrophosphate fuels post-translational prenylation of small GTPases, positioning it as an upstream control point for proliferative, metabolic, and immune signaling (PMID:30914801, PMID:34467534). Across multiple cancers, FDPS drives oncogenic growth by prenylating Rho-family and Ras-family GTPases (RhoA, RhoG, CDC42, Rac1, Ras, Rheb), thereby activating downstream AKT, ERK, STAT3, and mTOR pathways; this function is targetable with aminobisphosphonate inhibitors such as zoledronic acid, pamidronate, and alendronic acid, which disrupt prenylation, suppress tumor growth, and in pancreatic and hepatocellular models alter the immune microenvironment and synergize with anti-PD-1 therapy (PMID:30914801, PMID:34971971, PMID:29075041, PMID:41979127, PMID:41706364). In glioma, FDPS additionally engages Wnt/β-catenin signaling to induce CCL20 and recruit tumor-promoting macrophages (PMID:32596949). The dependence on correct FPP supply is illustrated in the heart, where cardiac-specific FDPS deletion causes accumulation of geranyl pyrophosphate, aberrant Ras/Rheb prenylation, and mTOR/ERK-driven cardiac remodeling that is rescued by farnesyltransferase inhibition (PMID:34467534). FDPS activity also tunes immune effector function, as the isoprenoid metabolite iPA enhances FDPS-dependent prenylation in NK cells to augment MAPK signaling and cytotoxicity (PMID:23847096). FDPS expression is controlled by Pax5 and OCT-1 at its basal promoter (PMID:19056481), by estrogen through ERα (PMID:41683980), and post-transcriptionally by miR-128-3p (PMID:37700222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 Medium

    Established how FDPS transcription is controlled by mapping functional cis-elements in its minimal basal promoter, the first step toward understanding its regulated expression.

    Evidence Deletion-mutant luciferase reporter assays and cross-species promoter sequence comparison identifying Pax5, OCT-1, NF-Y, SP1, SRE3, and YY1 sites

    PMID:19056481

    Open questions at the time
    • Does not show which factors dominate in specific tissues or disease states
    • No link between promoter activity and downstream prenylation output
  2. 2013 Medium

    Demonstrated that FDPS enzymatic activity is dynamically modulated by an isoprenoid metabolite to shape immune effector function, linking FDPS to prenylation-dependent MAPK signaling beyond housekeeping metabolism.

    Evidence Ex vivo iPA treatment of human NK cells with FDPS activity measurement, NK activation/cytotoxicity assays, and MAPK immunoblot

    PMID:23847096

    Open questions at the time
    • Prenylation link partly inferred rather than directly traced to specific GTPase substrates
    • Mechanism of iPA action on FDPS not structurally defined
  3. 2015 Medium

    Showed FDPS expression is hormonally regulated, tying it to estrogen-driven proliferation in reproductive tissue and endometrial cancer.

    Evidence Mouse estrous cycle and ovariectomy/estrogen/ERα-antagonist experiments plus Ishikawa cell proliferation assays

    PMID:41683980

    Open questions at the time
    • Whether ERα acts directly at the FDPS promoter not established
    • Functional contribution of FDPS prenylation in endometrial cells not dissected
  4. 2017 Medium

    Connected elevated FDPS enzyme activity to glioblastoma survival, indicating a cancer-cell-selective dependency on FDPS.

    Evidence Enzyme activity and expression profiling in a 49-patient cohort, FDPS silencing in GBM cells versus normal astrocytes, apoptosis assays, and STAT3/ERK/AKT immunoblot

    PMID:29075041

    Open questions at the time
    • Link between FDPS activity and signaling nodes is correlative
    • Specific prenylated effectors not identified in this study
  5. 2019 High

    Defined the core oncogenic mechanism: FDPS prenylates Rho-family GTPases to activate AKT/ERK, with synergy upon PTEN loss, and is druggable by zoledronic acid.

    Evidence FDPS overexpression/knockdown in prostate cancer cells, 3D tumoroids, PTEN conditional knockout mice, zoledronic acid inhibition, and AKT/ERK immunoblot

    PMID:30914801

    Open questions at the time
    • Direct enzymatic-to-GTPase prenylation step inferred from pathway readouts
    • Whether other prenyltransferases compensate not addressed
  6. 2020 Medium

    Extended FDPS oncogenic signaling to the tumor microenvironment by showing it drives Wnt/β-catenin–dependent CCL20 expression and macrophage recruitment.

    Evidence FDPS gain/loss in glioma cells, Wnt reporter and CCL20 assays, macrophage recruitment assays, and pharmacological macrophage depletion rescue

    PMID:32596949

    Open questions at the time
    • Mechanistic link from prenylation to Wnt activation not resolved
    • Single-lab study without reciprocal in vivo validation of CCL20 axis
  7. 2021 High

    Showed FDPS inhibition radiosensitizes pancreatic cancer by impairing Rac1/Rho prenylation, disrupting DNA damage response signaling and activating systemic immunity, broadening therapeutic context.

    Evidence CRISPR/Cas9 knockout and zoledronic acid in PDAC, RNA-Seq of xenografts and patient PBMCs, orthotopic models, tumoroids, and clinical correlates

    PMID:34971971

    Open questions at the time
    • Which DNA-damage-response components depend on prenylated GTPases not pinpointed
    • Systemic immune activation mechanism not fully traced
  8. 2021 High

    Revealed that proper FDPS function is required to prevent toxic geranyl pyrophosphate accumulation, with cardiac loss causing aberrant Ras/Rheb prenylation and mTOR/ERK-driven cardiomyopathy.

    Evidence Cardiac-specific Fdps knockout mice with echocardiography, histology, Ras/Rheb/mTOR/ERK immunoblot, farnesyltransferase inhibitor rescue, and human cardiomyopathy samples

    PMID:34467534

    Open questions at the time
    • How GPP accumulation mechanistically redirects prenylation not fully defined
    • Relevance to human cardiomyopathy is associative
  9. 2021 Low

    Linked FDPS coding variants to a human keratinization disorder, implicating FDPS-dependent mevalonate metabolism in epidermal disease.

    Evidence Sanger sequencing of FDPS exons in DSAP patients, family members, and 100 controls identifying c.C535T

    PMID:34751146

    Open questions at the time
    • No functional validation of the variant's effect on FDPS activity
    • Causality versus association not established
  10. 2023 Medium

    Identified a post-transcriptional regulator of FDPS, showing miR-128-3p directly represses FDPS to control adipocyte differentiation.

    Evidence 3'UTR luciferase reporter, miR-128-3p mimic/inhibitor, RNA-seq, and adipocyte differentiation assays in chicken intramuscular adipocytes

    PMID:37700222

    Open questions at the time
    • Demonstrated in chicken, not mammalian, model
    • Downstream prenylation effectors in adipogenesis not identified
  11. 2026 Medium

    Provided systems-level confirmation of FDPS signaling reach and its metabolic-immune role in hepatocellular carcinoma, supporting combination with immune checkpoint blockade.

    Evidence FDPS silencing/overexpression in HCC with phosphoproteomics, cholesterol metabolic profiling, xenograft and orthotopic models, pamidronate and alendronic acid plus anti-PD-1 treatment, and single-cell RNA-seq

    PMID:41706364 PMID:41979127

    Open questions at the time
    • Phosphoproteomic changes are broad and not all causally attributed to specific GTPases
    • Direct mechanism of immune infiltration enhancement not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how FDPS-generated FPP supply is selectively partitioned among individual GTPase substrates to produce the distinct AKT, ERK, STAT3, mTOR, and Wnt outputs observed across tissues.
  • No substrate-resolved prenylation quantification
  • No structural basis for context-specific FPP allocation
  • Compensation by alternative isoprenoid routes unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0016874 ligase activity 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 FDPS promotes prostate cancer cell proliferation and colony formation by prenylating small GTPases (RhoA, RhoG, CDC42), which activates downstream AKT and ERK signaling; this oncogenic function is synergistic with PTEN loss. Pharmacological inhibition by zoledronic acid disrupts GTPase prenylation and attenuates AKT/ERK signaling. Ectopic overexpression and knockdown of FDPS in PCa cells, 3D tumoroids, PTEN conditional knockout mouse model, pharmacological inhibition with zoledronic acid, immunoblot for AKT/ERK signaling, colony formation and proliferation assays Oncogene High 30914801
2021 FDPS inhibition (CRISPR/Cas9 or zoledronic acid) radiosensitizes pancreatic ductal adenocarcinoma by attenuating Rac1 and Rho GTPase prenylation, thereby disrupting DNA damage response signaling and activating systemic immune cells. CRISPR/Cas9 knockout, pharmacological inhibition (zoledronic acid), RNA-Seq of xenografts and patient PBMCs, in vitro cell assays, orthotopic mouse models, patient-derived tumoroids, clinical trial correlates EBioMedicine High 34971971
2021 Cardiac-specific deletion of FDPS leads to cardiac remodeling and dysfunction through accumulation of geranyl pyrophosphate, which causes abnormal prenylation-dependent activation of Ras and Rheb small GTPases, stimulating downstream mTOR and ERK pathways. Farnesyltransferase inhibitor treatment rescued this phenotype. Cardiac-specific Fdps knockout mice (c-Fdps-/-), echocardiography, histological analysis, immunoblot for Ras/Rheb/mTOR/ERK pathways, farnesyltransferase inhibitor rescue experiment, human cardiomyopathy samples The Journal of pathology High 34467534
2017 FDPS enzymatic activity is elevated in glioblastoma tumor tissue compared to normal brain; FDPS knockdown in GBM cells (but not normal astrocytes) enhances apoptosis, and FDPS expression correlates with activation of STAT3, ERK, and AKT oncogenic signaling pathways. FDPS mRNA, protein, and enzyme activity measurement in patient cohort (N=49) and primary derived cells; FDPS silencing in U87 and GBM primary cells vs. normal human astrocytes; apoptosis assays; immunoblot for STAT3/ERK/AKT Scientific reports Medium 29075041
2020 FDPS activates the Wnt/β-catenin signaling pathway in glioma cells, which induces CCL20 expression and promotes macrophage recruitment into the tumor microenvironment; pharmacological macrophage depletion abrogated the oncogenic functions of FDPS. FDPS overexpression/knockdown in glioma cells, Wnt/β-catenin pathway reporter assays, CCL20 expression analysis, macrophage recruitment assays, pharmacological macrophage depletion Journal of cellular and molecular medicine Medium 32596949
2013 The isoprenoid metabolite iPA (N6-isopentenyladenosine) modulates FDPS enzymatic activity in human NK cells, causing enhanced post-translational prenylation of Ras and other key signaling proteins, which activates MAPK signaling downstream of IL-2R and augments NK cell cytotoxicity and cytokine production. Ex vivo treatment of human NK cells with iPA, measurement of FDPS activity, flow cytometry for NK activation markers (CD69, CD107a, activating receptors), cytokine secretion assays (CCL5, CCL3, TNF-α, IFN-γ), cytotoxicity assays against tumor targets, MAPK pathway immunoblot Journal of leukocyte biology Medium 23847096
2008 The human FDPS gene minimal basal promoter contains functional cis-acting elements recognized by Pax5 and OCT-1 transcription factors, which modulate FDPS gene expression; conserved binding sites for NF-Y, SP1, SRE3, and YY1 were also identified. Deletion mutant analysis of FDPS 5' flanking region, luciferase reporter assays, genomic sequence comparison across species (rat, mouse, dog, chimpanzee, human), transcription factor binding site characterization Genomics Medium 19056481
2015 Estrogen regulates FDPS expression in the mouse uterus in an estrogen receptor alpha (ERα)-dependent manner; FDPS expression peaks during proestrus, is induced by estrogen in ovariectomized mice, and is suppressed by ERα antagonist ICI 182,780. FDPS contributes to endometrial cancer cell proliferation. In vivo mouse estrous cycle analysis, ovariectomized mouse model with estrogen treatment and ERα antagonist ICI 182,780 treatment, FDPS expression quantification, histological analysis of human endometrial cancer tissues, functional cell proliferation assays in Ishikawa cells International journal of molecular sciences Medium 41683980
2023 miR-128-3p inhibits chicken intramuscular adipocyte differentiation by directly targeting and downregulating FDPS; luciferase assay confirmed miR-128-3p targets the 3' UTR of FDPS, and functional assays showed FDPS knockdown phenocopies miR-128-3p overexpression in suppressing adipocyte differentiation. Luciferase 3' UTR reporter assay, miR-128-3p mimic/inhibitor transfection, RNA-seq for DEG identification, functional adipocyte differentiation assays in chicken intramuscular adipocytes BMC genomics Medium 37700222
2026 FDPS silencing in HCC cells reduced proliferation, migration, invasion, and tumorigenicity and increased apoptosis; phosphoproteomic profiling revealed FDPS depletion causes broad phosphorylation changes in GTPase signaling, protein kinase C activation, glucose metabolism, cytoskeletal remodeling, cell cycle, mTOR (reduced pSer2448), and apoptosis (decreased BCL2, reduced Caspase-9 pSer196, increased cleaved Caspase-3). FDPS inhibitor pamidronate suppressed tumor growth in vivo. siRNA silencing, lentiviral overexpression, phosphoproteomic profiling, Western blot validation, in vitro proliferation/migration/invasion/apoptosis assays, xenograft mouse models, pamidronate treatment Biomolecules & biomedicine Medium 41979127
2026 FDPS genetic silencing in HCC suppresses tumor cell cholesterol metabolism and proliferation; FDPS inhibition with alendronic acid combined with anti-PD-1 therapy increased lymphoid immune infiltration and enhanced anti-tumor efficacy in orthotopic mouse models. Genetic silencing, metabolic profiling (intracellular cholesterol levels), orthotopic mouse models, anti-PD-1 combination treatment, immune infiltration analysis, single-cell RNA sequencing, hdWGCNA Cellular oncology Medium 41706364
2021 Novel missense mutations in the FDPS gene (exon 5, c.C535T) were identified in patients with disseminated superficial actinic porokeratosis (DSAP), supporting FDPS's role in the mevalonate pathway underlying epidermal keratinization disorders. Sanger sequencing of all FDPS exons and flanking introns in patients and unaffected family members; mutation analysis in 100 unrelated control individuals Clinica chimica acta Low 34751146

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis. Oncogene 52 30914801
2017 Deregulated expression and activity of Farnesyl Diphosphate Synthase (FDPS) in Glioblastoma. Scientific reports 46 29075041
2008 Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis. Current medical research and opinion 37 18687167
2021 Disruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling. EBioMedicine 29 34971971
2020 FDPS promotes glioma growth and macrophage recruitment by regulating CCL20 via Wnt/β-catenin signalling pathway. Journal of cellular and molecular medicine 29 32596949
2013 N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation. Journal of leukocyte biology 24 23847096
2008 Characterization and functional analysis of cis-acting elements of the human farnesyl diphosphate synthetase (FDPS) gene 5' flanking region. Genomics 21 19056481
2023 miR-128-3p inhibits intramuscular adipocytes differentiation in chickens by downregulating FDPS. BMC genomics 17 37700222
2013 The NF-κB pathway: regulation of the instability of atherosclerotic plaques activated by Fg, Fb, and FDPs. Molecular and cellular biochemistry 14 23839109
2019 Polymorphisms of FDPS, LRP5, SOST and VKORC1 genes and their relation with osteoporosis in postmenopausal Romanian women. PloS one 12 31774873
2021 Cardiac-specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP-binding proteins. The Journal of pathology 10 34467534
2021 Novel missense mutations of MVK and FDPS gene in Chinese patients with disseminated superficial actinic porokeratosis. Clinica chimica acta; international journal of clinical chemistry 5 34751146
2011 Effects of differences in polymorphism of gene encoding enzyme faenesyl diphosphate synthase (FDPS), rs2297480, on bone mineral density and biochemical markers of bone turnover in Thai postmenopausal women. Journal of the Medical Association of Thailand = Chotmaihet thangphaet 4 22338925
2026 Estrogen-Dependent Regulation of FDPS in the Mouse Uterus and Its Expression in Endometrial Cancer. International journal of molecular sciences 0 41683980
2026 The association between single-nucleotide polymorphisms of FDPS Rs2297480 and MECP2 Rs2734647 genes and the susceptibility to rheumatoid arthritis in Egyptian patients. Journal of immunoassay & immunochemistry 0 41689836
2026 Single-cell mapping of cholesterol metabolism reveals FDPS as a therapeutic vulnerability in hepatocellular carcinoma. Cellular oncology (Dordrecht, Netherlands) 0 41706364
2026 Correction: Identification of two novel MVD mutations and one novel FDPS mutation in Chinese patients with porokeratosis. Frontiers in medicine 0 41737382
2026 Identification of two novel MVD mutations and one novel FDPS mutation in Chinese patients with porokeratosis. Frontiers in medicine 0 41737384
2026 FDPS links tumor progression, phosphoproteomic reprogramming, and therapeutic vulnerability in hepatocellular carcinoma. Biomolecules & biomedicine 0 41979127

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