FDPS encodes farnesyl pyrophosphate synthase (farnesyl diphosphate synthase, FPPS), a cytosolic trans-prenyltransferase of the mevalonate/isoprenoid pathway. Acting as a homodimer and requiring Mg(2+), it catalyzes two sequential head-to-tail (1'-4) condensations of isopentenyl diphosphate (IPP): first with dimethylallyl diphosphate (DMAPP) to give geranyl diphosphate (GPP), and then with GPP to give (2E,6E)-farnesyl diphosphate (FPP). FPP is a central branch-point metabolite that feeds into the biosynthesis of sterols (via squalene), dolichols, ubiquinone, heme A, and the isoprenoid substrates for protein prenylation (farnesylation and, downstream via GGPP, geranylgeranylation). Because it controls flux at this branch point, FPPS is the molecular target of nitrogen-containing bisphosphonate drugs (e.g. alendronate, risedronate, zoledronate) used to treat osteoporosis and other bone-resorption disorders; these drugs mimic a carbocation intermediate and bind the allylic substrate pocket. Loss-of-function/hypomorphic variants in FDPS cause an autosomal disorder of keratinization (porokeratosis 9).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004161 dimethylallyltranstransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: First (GPP-forming) prenyltransferase step of FPPS: condensation of IPP with the allylic primer DMAPP to yield geranyl diphosphate (EC 2.5.1.1). This is a core molecular function, phylogenetically conserved across the FPP/GGPP synthase family and directly demonstrated experimentally for the human enzyme. Supporting Evidence: PMID:16684881 catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate |
| GO:0004337 (2E,6E)-farnesyl diphosphate synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Second (FPP-forming) prenyltransferase step of FPPS: condensation of IPP with GPP to yield (2E,6E)-farnesyl diphosphate (EC 2.5.1.10). This is the defining core molecular function of the gene product, conserved across the family and experimentally verified. Supporting Evidence: PMID:16684881 catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate |
| GO:0005759 mitochondrial matrix | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Human FDPS is a cytosolic enzyme; UniProt records only Cytoplasm as the subcellular location. This mitochondrial-matrix IBA is propagated from a distinct PANTHER sub-branch supported by fly/rat orthologs (some prenyl synthases have organellar pools) and is not supported for the human protein. Marked as over-annotated rather than removed, since an organellar pool cannot be strictly excluded and this is an evolutionary inference, not a demonstrably wrong IEA. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000897621 · FPP/GGPP synthase family (mitochondrial-matrix sub-branch) SUPPORTS SOURCE BUT NOT TARGET Distinct PANTHER node from the cytosolic FPPS node (PTN000162949); backed by fly (FBgn0025373) and rat (RGD:68953) orthologs, not by the human protein, whose only curated location is Cytoplasm. Supporting Evidence: file:human/FDPS/FDPS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core localization. FPPS is a soluble cytosolic enzyme, consistent with the UniProt subcellular location and multiple Reactome-based cytosol annotations. Supporting Evidence: file:human/FDPS/FDPS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. |
| GO:0045337 trans, trans-farnesyl diphosphate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. FPPS is the dedicated enzyme producing (2E,6E)-farnesyl diphosphate in the mevalonate/isoprenoid pathway; this process annotation is the BP counterpart of its FPP-synthase molecular function. Supporting Evidence: file:human/FDPS/FDPS-uniprot.txt Isoprenoid biosynthesis; farnesyl diphosphate biosynthesis; farnesyl diphosphate from geranyl diphosphate and isopentenyl diphosphate: step 1/1. |
| GO:0004161 dimethylallyltranstransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (RHEA/EC 2.5.1.1) restatement of the GPP-forming activity that is also supported experimentally and by phylogeny. Redundant across evidence types but correct core function; accept. |
| GO:0004337 (2E,6E)-farnesyl diphosphate synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (RHEA/EC 2.5.1.10) restatement of the FPP-forming activity that is also supported experimentally and by phylogeny. Redundant across evidence types but correct core function; accept. |
| GO:0004659 prenyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Correct but non-informative parent term. The precise activities of FDPS (dimethylallyltranstransferase, GO:0004161, and (2E,6E)-farnesyl diphosphate synthase, GO:0004337) are already annotated with stronger evidence, so this generic InterPro-derived parent is an over-annotation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Correct localization (matches the UniProt subcellular location "Cytoplasm"). More general than the cytosol annotation but not wrong; accept. Supporting Evidence: file:human/FDPS/FDPS-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. |
| GO:0006695 cholesterol biosynthetic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: FPP is an upstream precursor of sterols, so FDPS contributes to cholesterol biosynthesis, but its direct, dedicated function is FPP synthesis; cholesterol synthesis proper is carried out by downstream squalene/sterol enzymes. This is a valid pathway-context annotation but not the gene's core process. Keep as non-core. (Duplicated below as a TAS/PMID:2690933 annotation.) |
| GO:0008299 isoprenoid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: Correct high-level pathway process: FPPS is a central enzyme of isoprenoid biosynthesis. More general than the specific FPP-biosynthesis annotation but accurately describes the gene's core pathway; accept. Supporting Evidence: file:human/FDPS/FDPS-uniprot.txt Key enzyme in isoprenoid biosynthesis which catalyzes the |
| GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: High-level parent of prenyltransferase activity. Correct by classification but far less informative than the specific EC 2.5.1.1 / 2.5.1.10 activities already annotated; over-annotation. |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | MARK AS OVER ANNOTATED | Summary: IntAct-curated binary interaction (with ATXN1/P54253) from a high-throughput ataxia interactome screen. Bare "protein binding" is uninformative and does not describe a distinct molecular function of FPPS; retained per curation policy but marked as over-annotated. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IntAct-curated binary interaction(s) from the HuRI reference interactome (with ABHD16A/O95870, RNF19B/Q6ZMZ0, SSMEM1/Q8WWF3, SLC30A2/Q9BRI3). Uninformative "protein binding"; retained per policy but marked as over-annotated. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IntAct-curated binary interaction (with ATXN1/P54253) from a neurodegenerative-disease interactome map. Uninformative "protein binding"; retained per policy but marked as over-annotated. |
| GO:0033384 geranyl diphosphate biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: Core process counterpart of the dimethylallyltranstransferase activity: FPPS produces geranyl diphosphate as the intermediate of its first condensation step. Supported by the UniPathway/UniProt pathway record; accept. Supporting Evidence: file:human/FDPS/FDPS-uniprot.txt Isoprenoid biosynthesis; geranyl diphosphate biosynthesis; geranyl diphosphate from dimethylallyl diphosphate and isopentenyl diphosphate: step 1/1. |
| GO:0045337 trans, trans-farnesyl diphosphate biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic (UniPathway) restatement of the core FPP-biosynthetic process, also supported by phylogeny (IBA). Redundant across evidence but correct core process; accept. Supporting Evidence: file:human/FDPS/FDPS-uniprot.txt Isoprenoid biosynthesis; farnesyl diphosphate biosynthesis; farnesyl diphosphate from geranyl diphosphate and isopentenyl diphosphate: step 1/1. |
| GO:0004161 dimethylallyltranstransferase activity | EXP PMID:16684881 The molecular mechanism of nitrogen-containing bisphosphonat... | ACCEPT | Summary: Experimentally demonstrated GPP-forming activity (EC 2.5.1.1) for the human enzyme, established by crystallography and enzyme kinetics of human FPPS with substrates and bisphosphonate inhibitors. This is a core molecular function. Supporting Evidence: PMID:16684881 FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. |
| GO:0004337 (2E,6E)-farnesyl diphosphate synthase activity | EXP PMID:16684881 The molecular mechanism of nitrogen-containing bisphosphonat... | ACCEPT | Summary: Experimentally demonstrated FPP-forming activity (EC 2.5.1.10) for the human enzyme. This is the defining core molecular function of FDPS. Supporting Evidence: PMID:16684881 FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: FDPS was captured in a high-throughput HeLa mRNA-interactome study ("interactome capture") that flagged many metabolic enzymes as candidate RNA-binding proteins. This is a proteome-wide screen with no gene-specific functional follow-up for FDPS, and no RNA-dependent function is known for this prenyltransferase. Not a core function; kept as a non-core moonlighting-candidate annotation. Supporting Evidence: PMID:22658674 We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655824 | ACCEPT | Summary: Reactome-asserted cytosolic localization, consistent with the UniProt subcellular location. Core localization; accept. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-191303 | ACCEPT | Summary: Reactome cytosol annotation attached to the FPP-forming reaction (FDPS dimer transfers IPPP to GPP). Consistent with UniProt; accept. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-191322 | ACCEPT | Summary: Reactome cytosol annotation attached to the GPP-forming reaction (FDPS dimer transfers IPPP to DMAPP). Consistent with UniProt; accept. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9717841 | ACCEPT | Summary: Reactome cytosol annotation attached to bisphosphonate binding by holo-FDPS. Consistent with UniProt; accept. |
| GO:0006695 cholesterol biosynthetic process | TAS PMID:2690933 Cloning, analysis, and bacterial expression of human farnesy... | KEEP AS NON CORE | Summary: Author (TAS) annotation from the original cloning/characterization paper, which framed human FPP synthetase in the context of cholesterol/sterol biosynthesis. FDPS provides the FPP precursor for the sterol branch but the dedicated cholesterol-synthesis reactions are downstream; contributory, not core. Keep as non-core. |
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