id: P14324
gene_symbol: FDPS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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).
alternative_products:
- name: '1'
  id: P14324-1
- name: '2'
  id: P14324-2
  sequence_note: VSP_046958
existing_annotations:
- term:
    id: GO:0004161
    label: dimethylallyltranstransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16684881
      supporting_text: >-
        catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl
        pyrophosphate and geranyl pyrophosphate
- term:
    id: GO:0004337
    label: (2E,6E)-farnesyl diphosphate synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16684881
      supporting_text: >-
        catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl
        pyrophosphate and geranyl pyrophosphate
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: file:human/FDPS/FDPS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000897621
        source_label: FPP/GGPP synthase family (mitochondrial-matrix sub-branch)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: >-
          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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Correct core localization. FPPS is a soluble cytosolic enzyme, consistent with the
      UniProt subcellular location and multiple Reactome-based cytosol annotations.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/FDPS/FDPS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0045337
    label: trans, trans-farnesyl diphosphate biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/FDPS/FDPS-uniprot.txt
      supporting_text: >-
        Isoprenoid biosynthesis; farnesyl diphosphate biosynthesis; farnesyl diphosphate from
        geranyl diphosphate and isopentenyl diphosphate: step 1/1.
- term:
    id: GO:0004161
    label: dimethylallyltranstransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
- term:
    id: GO:0004337
    label: (2E,6E)-farnesyl diphosphate synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
- term:
    id: GO:0004659
    label: prenyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Correct localization (matches the UniProt subcellular location "Cytoplasm"). More
      general than the cytosol annotation but not wrong; accept.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/FDPS/FDPS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.)
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/FDPS/FDPS-uniprot.txt
      supporting_text: Key enzyme in isoprenoid biosynthesis which catalyzes the
- term:
    id: GO:0016765
    label: transferase activity, transferring alkyl or aryl (other than methyl) groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0033384
    label: geranyl diphosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/FDPS/FDPS-uniprot.txt
      supporting_text: >-
        Isoprenoid biosynthesis; geranyl diphosphate biosynthesis; geranyl diphosphate from
        dimethylallyl diphosphate and isopentenyl diphosphate: step 1/1.
- term:
    id: GO:0045337
    label: trans, trans-farnesyl diphosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      Electronic (UniPathway) restatement of the core FPP-biosynthetic process, also
      supported by phylogeny (IBA). Redundant across evidence but correct core process;
      accept.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/FDPS/FDPS-uniprot.txt
      supporting_text: >-
        Isoprenoid biosynthesis; farnesyl diphosphate biosynthesis; farnesyl diphosphate from
        geranyl diphosphate and isopentenyl diphosphate: step 1/1.
- term:
    id: GO:0004161
    label: dimethylallyltranstransferase activity
  evidence_type: EXP
  original_reference_id: PMID:16684881
  qualifier: enables
  review:
    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.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16684881
      supporting_text: >-
        FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive
        condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl
        pyrophosphate.
- term:
    id: GO:0004337
    label: (2E,6E)-farnesyl diphosphate synthase activity
  evidence_type: EXP
  original_reference_id: PMID:16684881
  qualifier: enables
  review:
    summary: >-
      Experimentally demonstrated FPP-forming activity (EC 2.5.1.10) for the human enzyme.
      This is the defining core molecular function of FDPS.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16684881
      supporting_text: >-
        FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive
        condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl
        pyrophosphate.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:22658674
      supporting_text: >-
        We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655824
  qualifier: located_in
  review:
    summary: >-
      Reactome-asserted cytosolic localization, consistent with the UniProt subcellular
      location. Core localization; accept.
    action: ACCEPT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191303
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol annotation attached to the FPP-forming reaction (FDPS dimer transfers
      IPPP to GPP). Consistent with UniProt; accept.
    action: ACCEPT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191322
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol annotation attached to the GPP-forming reaction (FDPS dimer transfers
      IPPP to DMAPP). Consistent with UniProt; accept.
    action: ACCEPT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9717841
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol annotation attached to bisphosphonate binding by holo-FDPS. Consistent
      with UniProt; accept.
    action: ACCEPT
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:2690933
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
core_functions:
- description: >-
    Second condensation step of farnesyl diphosphate synthase: Mg(2+)-dependent head-to-tail
    condensation of isopentenyl diphosphate (IPP) with geranyl diphosphate (GPP) to form
    (2E,6E)-farnesyl diphosphate (FPP), EC 2.5.1.10. This is the defining activity of FDPS
    and the committed step producing the FPP branch-point metabolite of the isoprenoid
    pathway.
  molecular_function:
    id: GO:0004337
    label: (2E,6E)-farnesyl diphosphate synthase activity
  supported_by:
  - reference_id: PMID:16684881
    supporting_text: >-
      FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive
      condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl
      pyrophosphate.
  directly_involved_in:
  - id: GO:0045337
    label: farnesyl diphosphate biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
- description: >-
    First condensation step of farnesyl diphosphate synthase: Mg(2+)-dependent head-to-tail
    condensation of isopentenyl diphosphate (IPP) with the allylic primer dimethylallyl
    diphosphate (DMAPP) to form geranyl diphosphate (GPP), EC 2.5.1.1. GPP is the substrate
    for the subsequent FPP-forming step catalyzed by the same enzyme.
  molecular_function:
    id: GO:0004161
    label: dimethylallyltranstransferase activity
  supported_by:
  - reference_id: PMID:16684881
    supporting_text: >-
      FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive
      condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl
      pyrophosphate.
  directly_involved_in:
  - id: GO:0033384
    label: geranyl diphosphate biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16684881
  title: The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis
    drugs.
  findings:
  - statement: >-
      Human FPPS catalyzes the successive condensation of IPP with DMAPP and with GPP; it is
      the key branch-point enzyme of the mevalonate pathway and the target of
      nitrogen-containing bisphosphonate drugs. High-resolution structures of the human
      enzyme with risedronate/zoledronate and Mg(2+)/IPP define the catalytic mechanism.
    reference_section_type: ABSTRACT
    supporting_text: >-
      FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive
      condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl
      pyrophosphate.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; source of the EXP molecular-function annotations (EC 2.5.1.1 and
      2.5.1.10) and Mg(2+) cofactor for human FPPS. Abstract-only in cache but the abstract
      explicitly states the two sequential condensations. UniProt cites this PMID for both
      catalytic-activity statements.
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders
    of Purkinje cell degeneration.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified high-throughput ataxia interactome; source of an IntAct
      FDPS-ATXN1 "protein binding" annotation. No FDPS-specific functional characterization;
      relevant only as interaction evidence, not to core function.
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings:
  - statement: >-
      Systematic UV-crosslink "interactome capture" in HeLa cells identified 860 candidate
      mRNA-binding proteins, including many metabolic enzymes; FDPS was among the captured
      proteins (basis for the HDA RNA-binding annotation).
    reference_section_type: ABSTRACT
    supporting_text: >-
      We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; proteome-wide RBP capture, no gene-specific validation for FDPS.
      Supports only a non-core moonlighting-candidate RNA-binding annotation.
- id: PMID:2690933
  title: Cloning, analysis, and bacterial expression of human farnesyl pyrophosphate
    synthetase and its regulation in Hep G2 cells.
  findings:
  - statement: >-
      Cloning, bacterial expression and characterization of human farnesyl pyrophosphate
      synthetase, studied in the context of cholesterol/sterol biosynthesis regulation in
      Hep G2 cells (basis for the TAS cholesterol-biosynthesis annotation).
    reference_section_type: TITLE
    supporting_text: >-
      Cloning, analysis, and bacterial expression of human farnesyl pyrophosphate
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified original human FPPS cloning/expression paper. Abstract-only in cache.
      Supports the enzyme identity and its pathway context; cited for the (non-core) TAS
      cholesterol-biosynthesis annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified HuRI reference interactome; source of several IntAct FDPS "protein
      binding" annotations. High-throughput binary interactions, not core function.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified neurodegeneration interactome map; source of an IntAct FDPS-ATXN1
      "protein binding" annotation. Not relevant to FDPS core enzymatic function.
- id: Reactome:R-HSA-1655824
  title: Expression of Farnesyl Diphosphate Synthase (FDPS)
  findings: []
- id: Reactome:R-HSA-191303
  title: FDPS dimer transfers IPPP to GPP
  findings: []
- id: Reactome:R-HSA-191322
  title: FDPS dimer transfers IPPP to DMAPP
  findings: []
- id: Reactome:R-HSA-9717841
  title: holo-FDPS dimer binds NBPs
  findings: []
- id: file:human/FDPS/FDPS-uniprot.txt
  title: UniProt entry P14324 (FPPS_HUMAN), farnesyl pyrophosphate synthase
  findings:
  - statement: >-
      Key isoprenoid-pathway enzyme that catalyzes formation of farnesyl diphosphate via
      sequential condensations; cytoplasmic; homodimer; Mg(2+)-dependent (2 ions per
      subunit); two catalytic activities EC 2.5.1.1 and EC 2.5.1.10.
    reference_section_type: OTHER
    supporting_text: Key enzyme in isoprenoid biosynthesis which catalyzes the
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Authoritative UniProt record for human FDPS (P14324); source for function, catalytic
      activities, cofactor, subcellular location (Cytoplasm) and pathway steps.