id: Q03426
gene_symbol: MVK
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MVK encodes mevalonate kinase (MK; EC 2.7.1.36), a GHMP-kinase-family enzyme
  that catalyses the ATP-dependent, Mg2+-requiring phosphorylation of
  (R)-mevalonate to (R)-5-phosphomevalonate. This is the committed step
  immediately downstream of HMG-CoA reductase in the cytosolic
  mevalonate/isoprenoid pathway, feeding synthesis of isopentenyl diphosphate,
  farnesyl and geranylgeranyl diphosphate, dolichol, ubiquinone and cholesterol.
  The enzyme is a homodimer, requires Mg2+, and is subject to competitive
  feedback inhibition at its ATP-binding site by farnesyl and geranylgeranyl
  diphosphate, making it a key regulatory node of the pathway. Human MK is a
  cytosolic enzyme (with a minor/disputed peroxisomal pool inferred by
  similarity). Loss-of-function variants cause mevalonate kinase deficiency, a
  clinical spectrum ranging from the milder hyperimmunoglobulinaemia D and
  periodic fever syndrome (HIDS) to severe mevalonic aciduria (developmental
  delay, dysmorphic features, and recurrent febrile crises); MVK variants are
  also associated with porokeratosis.
existing_annotations:
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically-inferred core molecular function. Mevalonate kinase
      activity is the defining, experimentally established activity of this
      protein.
    action: ACCEPT
    reason: >-
      This is the well-characterized core catalytic function, directly
      demonstrated for the human enzyme by kinetics and mutagenesis, and
      supported by orthologs across the PANTHER family.
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: >-
        cDNA encoding human mevalonate kinase has been overexpressed and the
        recombinant enzyme isolated. This stable enzyme is a dimer of 42-kDa
        subunits
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Cytosolic localization, confirmed directly for the human enzyme by
      multiple biochemical and microscopy methods.
    action: ACCEPT
    reason: >-
      Human MK was shown to be exclusively cytosolic; the IBA cytosol call is
      consistent with the direct experimental data (PMID:14730012).
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      MK catalyses an early committed step of the mevalonate pathway that
      ultimately supplies cholesterol biosynthesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cholesterol biosynthesis is a valid downstream process, but it is one of
      several branch outputs (dolichol, ubiquinone, prenylation, isoprenoids)
      of the mevalonate pathway. The more precise, non-branch-committed process
      is isopentenyl diphosphate biosynthesis via the mevalonate pathway
      (GO:0019287), captured as core below; cholesterol biosynthesis is kept as
      a legitimate but non-core downstream role.
    supported_by:
    - reference_id: PMID:1377680
      supporting_text: >-
        Mevalonic aciduria is the first proposed inherited disorder of the
- term:
    id: GO:0019287
    label: isopentenyl diphosphate biosynthetic process, mevalonate pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      MK catalyses step 1 of the three-step conversion of (R)-mevalonate to
      isopentenyl diphosphate in the mevalonate pathway; this is the most
      precise biological process for the enzyme.
    action: ACCEPT
    reason: >-
      This is the pathway step directly downstream of HMG-CoA reductase and
      matches UniProt's PATHWAY statement (isopentenyl diphosphate from
      (R)-mevalonate: step 1/3). Core biological process.
    supported_by:
    - reference_id: PMID:18302342
      supporting_text: catalyzes a key reaction in polyisoprenoid and
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core mevalonate kinase activity (ARBA/InterPro,
      EC 2.7.1.36, RHEA:17065).
    action: ACCEPT
    reason: >-
      Consistent with the experimentally verified core activity; IEA mapping to
      the correct EC/RHEA reaction.
    supported_by:
    - reference_id: file:human/MVK/MVK-uniprot.txt
      supporting_text: >-
        Reaction=(R)-mevalonate + ATP = (R)-5-phosphomevalonate + ADP + H(+)
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      ATP is the phosphate donor for the kinase reaction; ATP binding is a
      direct molecular activity supported by kinetics, mutagenesis and the
      crystal structure.
    action: ACCEPT
    reason: >-
      MK binds Mg-ATP as co-substrate (KM(ATP) measured; ATP-binding residues
      mapped). InterPro-based ATP-binding IEA is correct and biologically
      supported.
    supported_by:
    - reference_id: file:human/MVK/MVK-uniprot.txt
      supporting_text: KM=74 uM for ATP
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization (parent of cytosol); consistent with the direct
      cytosolic evidence for human MK.
    action: ACCEPT
    reason: >-
      Correct but less specific than the experimentally supported cytosol term;
      retained as a valid broader location.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      MK acts within the mevalonate arm of isoprenoid biosynthesis; a valid but
      broad biological process.
    action: ACCEPT
    reason: >-
      Correct parent process; the more specific GO:0019287 (isopentenyl
      diphosphate biosynthesis, mevalonate pathway) is preferred as core, but
      this broader term is not wrong.
    supported_by:
    - reference_id: PMID:14680974
      supporting_text: cholesterol/isoprenoid biosynthetic
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      MK contributes to sterol (cholesterol) metabolism as an upstream pathway
      enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Sterol metabolic process is a broad downstream grouping; the enzyme's
      committed step is upstream of the sterol branch point. Valid but not the
      core process; the isoprenoid-diphosphate process is more precise.
    supported_by:
    - reference_id: file:human/MVK/MVK-uniprot.txt
      supporting_text: Cholesterol metabolism
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding IPI from a large-scale YFP protein-complementation
      screen (interaction with POT1/Q9NUX5).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 "protein binding" is uninformative and conveys nothing about
      molecular function. The interaction derives from a proteome-wide telomere
      regulator screen with no evidence for a specific, biologically meaningful
      MK function. Per curation policy this IPI is retained but flagged as
      over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:21044950
      supporting_text: >-
        a large-scale screen for regulators of telomeres
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein-binding IPI from a systematic binary interactome map
      (interaction with RNF141/Q8WVD5).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 is an uninformative molecular-function term derived from a
      proteome-scale yeast two-hybrid map; no specific functional role is
      implied. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Self-interaction (Q03426–Q03426), consistent with the enzyme being a
      homodimer.
    action: ACCEPT
    reason: >-
      Unlike bare protein binding, identical protein binding is informative here
      and matches the biochemically established homodimeric quaternary structure
      of MK (PMID:9325256; UniProt SUBUNIT Homodimer).
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: This stable enzyme is a dimer of 42-kDa subunits
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25502805
  qualifier: enables
  review:
    summary: >-
      Self-interaction detected in a high-throughput variant-clone
      interactome pipeline; consistent with homodimerization.
    action: ACCEPT
    reason: >-
      Corroborates the homodimeric state of MK; informative self-association
      term.
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: This stable enzyme is a dimer of 42-kDa subunits
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: >-
      Self-interaction from an alternative-splicing interactome study;
      consistent with homodimerization.
    action: ACCEPT
    reason: >-
      Corroborates MK homodimer formation.
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: This stable enzyme is a dimer of 42-kDa subunits
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: >-
      Self-interaction from a population-variant interaction-disruption study;
      consistent with homodimerization.
    action: ACCEPT
    reason: >-
      Corroborates MK homodimer formation.
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: This stable enzyme is a dimer of 42-kDa subunits
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Self-interaction (Q03426–Q03426) in the HuRI binary interactome;
      consistent with homodimerization.
    action: ACCEPT
    reason: >-
      Corroborates MK homodimer formation; informative self-association term.
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: This stable enzyme is a dimer of 42-kDa subunits
- term:
    id: GO:0019287
    label: isopentenyl diphosphate biosynthetic process, mevalonate pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic assignment of the mevalonate-pathway
      isopentenyl diphosphate biosynthetic process.
    action: ACCEPT
    reason: >-
      Matches the UniProt PATHWAY statement (step 1/3, isopentenyl diphosphate
      from (R)-mevalonate); duplicate of the IBA core BP call and equally valid.
    supported_by:
    - reference_id: file:human/MVK/MVK-uniprot.txt
      supporting_text: >-
        isopentenyl diphosphate from (R)-mevalonate
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (HPA) supports cytosolic localization.
    action: ACCEPT
    reason: >-
      Consistent with the definitive human cytosolic localization data
      (PMID:14730012).
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: EXP
  original_reference_id: PMID:11278915
  qualifier: enables
  review:
    summary: >-
      Experimentally verified mevalonate kinase activity via mutagenesis of
      invariant serine/threonine residues affecting KM(mevalonate) and Vmax.
    action: ACCEPT
    reason: >-
      Direct experimental characterization of the human enzyme's kinase
      activity, including the catalytic Ser-146 and the disease-relevant T243.
    supported_by:
    - reference_id: PMID:11278915
      supporting_text: V(max) for S146A is diminished by 4000-fold
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: EXP
  original_reference_id: PMID:9392419
  qualifier: enables
  review:
    summary: >-
      Experimentally verified mevalonate kinase activity; recombinant human MK
      assayed and shown to be feedback-inhibited at the ATP site.
    action: ACCEPT
    reason: >-
      Direct enzymatic assay of human MK confirms the core catalytic activity
      and its competitive inhibition by isoprenoid diphosphates.
    supported_by:
    - reference_id: PMID:9392419
      supporting_text: >-
        only MKase was inhibited through competitive interaction at the
        ATP-binding site
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:14730012
  qualifier: located_in
  review:
    summary: >-
      Experimental subcellular localization: human MK is cytoplasmic/cytosolic.
    action: ACCEPT
    reason: >-
      Direct experimental evidence (fractionation, digitonin permeabilization,
      immunofluorescence, immunocytochemistry) for cytoplasmic localization.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Peroxisomal localization transferred by similarity from rat P17256.
    action: REMOVE
    reason: >-
      This ISS is contradicted by direct experimental evidence in human: MK is
      exclusively cytosolic with no peroxisomal signal (PMID:14730012), and the
      same negation is explicitly recorded as a NOT|located_in peroxisome IDA in
      this GOA. Peroxisome-independent activity of the pathway enzymes was also
      shown (PMID:14680974). The similarity-based transfer is a demonstrably
      wrong inference for the human protein.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: No indication of a peroxisomal localisation was obtained
- term:
    id: GO:0000287
    label: magnesium ion binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Mg2+ binding, required cofactor for the kinase reaction (Mg-ATP), mapped
      to binding residues by similarity.
    action: ACCEPT
    reason: >-
      MK requires Mg2+ as cofactor and Mg2+-liganding residues (Ser-146,
      Glu-193) are supported by human mutagenesis; the ISS Mg-binding call is
      biologically correct.
    supported_by:
    - reference_id: file:human/MVK/MVK-uniprot.txt
      supporting_text: >-
        Name=Mg(2+); Xref=ChEBI:CHEBI:18420
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:18302342
  qualifier: enables
  review:
    summary: >-
      Direct assay and crystal structure (PDB 2R3V) of human MK, confirming
      kinase activity and defining feedback inhibition by farnesyl
      thiodiphosphate.
    action: ACCEPT
    reason: >-
      Structural/biochemical demonstration of the core catalytic activity and
      its regulation.
    supported_by:
    - reference_id: PMID:18302342
      supporting_text: Farnesyl thiodiphosphate competes
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ATP binding transferred by similarity; ATP is the phosphate donor for the
      kinase reaction.
    action: ACCEPT
    reason: >-
      Correct and directly supported by human kinetics and structure
      (KM(ATP), competitive feedback inhibition at the ATP site).
    supported_by:
    - reference_id: file:human/MVK/MVK-uniprot.txt
      supporting_text: KM=74 uM for ATP
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:9325256
  qualifier: enables
  review:
    summary: >-
      Direct assay of recombinant human MK; catalytic residues (Asp-204 base;
      Glu-193) identified by mutagenesis.
    action: ACCEPT
    reason: >-
      Foundational direct characterization of the human enzyme's core kinase
      activity and catalytic mechanism.
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: support assignment of a crucial catalytic role to
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:9325256
  qualifier: enables
  review:
    summary: >-
      Homodimerization directly demonstrated: MK is a dimer of 42-kDa subunits.
    action: ACCEPT
    reason: >-
      Informative self-association term directly supported by the biochemical
      demonstration that the enzyme is a homodimer.
    supported_by:
    - reference_id: PMID:9325256
      supporting_text: This stable enzyme is a dimer of 42-kDa subunits
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655846
  qualifier: located_in
  review:
    summary: >-
      Reactome curator assertion of cytosolic localization.
    action: ACCEPT
    reason: >-
      Consistent with the definitive human cytosolic localization evidence.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191380
  qualifier: located_in
  review:
    summary: >-
      Reactome curator assertion of cytosolic localization for the
      mevalonate-to-mevalonate-5-phosphate reaction.
    action: ACCEPT
    reason: >-
      Consistent with the definitive human cytosolic localization evidence, and
      the Reactome reaction is the MK-catalysed step.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:14730012
  qualifier: located_in
  negated: true
  review:
    summary: >-
      NOT|located_in peroxisome — direct experimental evidence that human MK is
      not peroxisomal.
    action: ACCEPT
    reason: >-
      Correctly captures the negative finding: no peroxisomal localization was
      detected for human MK by multiple methods, overturning earlier
      peroxisome proposals. This negation directly refutes the ISS peroxisome
      annotation.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: No indication of a peroxisomal localisation was obtained
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:16732551
  qualifier: involved_in
  review:
    summary: >-
      Inferred anti-inflammatory role from the autoinflammatory phenotype of
      mevalonate kinase deficiency (HIDS), cited via an AA amyloidosis case
      report.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      MK's molecular function is metabolic (kinase); the autoinflammatory HIDS
      phenotype is a downstream consequence of reduced isoprenoid output, not a
      direct regulatory activity of MVK in the inflammatory response. The cited
      reference is a two-patient case report of AA amyloidosis in HIDS and does
      not demonstrate a direct MK-mediated regulation of inflammation.
      Retained but flagged as an over-annotation (disease-consequence inference)
      rather than removed, per policy on experimental (IMP) annotations.
    supported_by:
    - reference_id: PMID:16732551
      supporting_text: >-
        hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IMP
  original_reference_id: PMID:10369261
  qualifier: enables
  review:
    summary: >-
      Reduced MK activity in HIDS patient cells demonstrates the enzyme's
      mevalonate kinase activity via mutational phenotype.
    action: ACCEPT
    reason: >-
      HIDS mutations reduce MK enzymatic activity, confirming MVK encodes the
      mevalonate kinase activity; the IMP is well supported.
    supported_by:
    - reference_id: PMID:10369261
      supporting_text: revealed reduced activities of mevalonate kinase
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:14730012
  qualifier: located_in
  review:
    summary: >-
      Direct experimental cytosolic localization of human MK.
    action: ACCEPT
    reason: >-
      Definitive direct evidence for cytosolic localization; the preferred,
      specific cellular-component annotation for this protein.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:1377680
  qualifier: enables
  review:
    summary: >-
      Molecular cloning of human MVK and functional expression confirming
      mevalonate kinase activity; MEVA missense mutation reduces activity.
    action: ACCEPT
    reason: >-
      Cloning + functional expression established the human enzyme's kinase
      activity and linked it to mevalonic aciduria.
    supported_by:
    - reference_id: PMID:1377680
      supporting_text: confirmed that the mutation produced an
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:14730012
  qualifier: enables
  review:
    summary: >-
      Direct measurement of endogenous human MK enzymatic activity in the
      subcellular-localization study.
    action: ACCEPT
    reason: >-
      Endogenous human MK activity was assayed (fractionation/permeabilization),
      confirming the core mevalonate kinase activity in a cytosolic context.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: >-
        We exclusively found a cytosolic localisation of both endogenous human
        MK
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1377680
  qualifier: involved_in
  review:
    summary: >-
      MK function within the cholesterol/isoprene biosynthetic pathway,
      inferred from the mevalonic aciduria metabolic defect.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cholesterol biosynthesis is a valid downstream output of the mevalonate
      pathway, but MK's committed step precedes the sterol/non-sterol branch
      point; kept as a legitimate non-core process (the core BP is isopentenyl
      diphosphate biosynthesis, GO:0019287).
    supported_by:
    - reference_id: PMID:1377680
      supporting_text: >-
        Mevalonic aciduria is the first proposed inherited disorder of the
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:14730012
  qualifier: involved_in
  review:
    summary: >-
      MK participates in isoprenoid biosynthesis; localization study frames MK
      within the isoprenoid/cholesterol pathway.
    action: ACCEPT
    reason: >-
      Valid (broad) biological process for MK; the isoprenoid pathway role is
      well established.
    supported_by:
    - reference_id: PMID:14730012
      supporting_text: isoprenoid/cholesterol biosynthesis
- term:
    id: GO:0004496
    label: mevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:14680974
  qualifier: enables
  review:
    summary: >-
      MK enzymatic activity measured directly in fibroblasts (activity present
      and peroxisome-independent).
    action: ACCEPT
    reason: >-
      Direct activity measurement of human MK; supports the core kinase
      function and confirms it does not require peroxisomes.
    supported_by:
    - reference_id: PMID:14680974
      supporting_text: >-
        all enzymes measured are at least as active in
- term:
    id: GO:0008299
    label: isoprenoid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:14680974
  qualifier: involved_in
  review:
    summary: >-
      MK operates in the cholesterol/isoprenoid biosynthetic pathway,
      independent of peroxisomes.
    action: ACCEPT
    reason: >-
      Valid biological process; the study measured MK as one of the
      presqualene-segment cholesterol/isoprenoid enzymes.
    supported_by:
    - reference_id: PMID:14680974
      supporting_text: cholesterol/isoprenoid biosynthetic
core_functions:
- description: >-
    Mevalonate kinase catalyses the ATP- and Mg2+-dependent phosphorylation of
    (R)-mevalonate to (R)-5-phosphomevalonate, the committed step immediately
    downstream of HMG-CoA reductase in the mevalonate/isoprenoid pathway.
  molecular_function:
    id: GO:0004496
    label: mevalonate kinase activity
  directly_involved_in:
  - id: GO:0019287
    label: isopentenyl diphosphate biosynthetic process, mevalonate pathway
  supported_by:
  - reference_id: PMID:9325256
    supporting_text: This stable enzyme is a dimer of 42-kDa subunits
  - reference_id: file:human/MVK/MVK-uniprot.txt
    supporting_text: >-
      Reaction=(R)-mevalonate + ATP = (R)-5-phosphomevalonate + ADP + H(+)
- description: >-
    ATP binding: MK binds Mg-ATP as the phosphate-donor co-substrate for the
    kinase reaction; farnesyl and geranylgeranyl diphosphate compete at this
    site to provide feedback inhibition.
  molecular_function:
    id: GO:0005524
    label: ATP binding
  supported_by:
  - reference_id: PMID:9392419
    supporting_text: >-
      only MKase was inhibited through competitive interaction at the
      ATP-binding site
- description: >-
    Magnesium ion binding: Mg2+ is the required cofactor coordinated with ATP
    for phosphoryl transfer.
  molecular_function:
    id: GO:0000287
    label: magnesium ion binding
  supported_by:
  - reference_id: file:human/MVK/MVK-uniprot.txt
    supporting_text: >-
      Name=Mg(2+); Xref=ChEBI:CHEBI:18420
- description: >-
    Mevalonate kinase is a cytosolic enzyme in humans.
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:14730012
    supporting_text: >-
      We exclusively found a cytosolic localisation of both endogenous human MK
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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: file:human/MVK/MVK-uniprot.txt
  title: UniProtKB entry Q03426 (KIME_HUMAN), Mevalonate kinase
  findings: []
- id: PMID:10369261
  title: Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia
    D and periodic fever syndrome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes that MVK loss-of-function mutations reduce MK
      activity and cause HIDS; supports the mevalonate kinase activity IMP.
- id: PMID:11278915
  title: Investigation of invariant serine/threonine residues in mevalonate kinase.
    Tests of the functional significance of a proposed substrate binding motif and
    a site implicated in human inherited disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Mutagenesis of Ser-146/T243 defines catalytic and substrate-binding roles
      in the human enzyme; supports mevalonate kinase activity.
- id: PMID:1377680
  title: Molecular cloning of human mevalonate kinase and identification of a missense
    mutation in the genetic disease mevalonic aciduria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning and functional expression of human MVK; links enzyme to mevalonic
      aciduria.
- id: PMID:14680974
  title: Cholesterol biosynthesis is not defective in peroxisome biogenesis defective
    fibroblasts.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Measured MK activity directly and showed the presqualene enzymes function
      independent of peroxisomes; supports cytosolic activity.
- id: PMID:14730012
  title: Mevalonate kinase is a cytosolic enzyme in humans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive multi-method demonstration that human MK is cytosolic, not
      peroxisomal; grounds the cytosol annotations and the NOT peroxisome call.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome map recording the MK self-interaction;
      consistent with homodimer but low individual informativeness.
- id: PMID:16732551
  title: 'AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever
    syndrome: a report of two cases.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Cited to support GO:0050728 negative regulation of inflammatory response,
      but this is a two-patient AA amyloidosis case report and does not
      demonstrate a direct MK-mediated regulation of inflammation; the
      inflammatory phenotype is a downstream consequence of MKD.
- id: PMID:18302342
  title: Biochemical and structural basis for feedback inhibition of mevalonate kinase
    and isoprenoid metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structure (PDB 2R3V) and biochemistry of human MK; defines
      competitive feedback inhibition at the ATP site.
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators
    for telomere signaling in human cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale telomere-regulator screen; the MK-POT1 interaction is an
      isolated high-throughput hit with no specific functional follow-up.
- id: PMID:25502805
  title: A massively parallel pipeline to clone DNA variants and examine molecular
    phenotypes of human disease mutations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput variant interactome pipeline recording MK self-interaction.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Alternative-splicing interactome study recording MK self-interaction.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Population-variant interaction study recording MK self-interaction.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome; records both MK self-interaction and an MK-RNF141
      interaction (bare protein binding, uninformative).
- id: PMID:9325256
  title: Identification of catalytic residues in human mevalonate kinase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct characterization of recombinant human MK as a homodimer and
      identification of catalytic residues (Asp-204, Glu-193).
- id: PMID:9392419
  title: Post-translational regulation of mevalonate kinase by intermediates of the
    cholesterol and nonsterol isoprene biosynthetic pathways.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Demonstrates competitive feedback inhibition of MK at the ATP site by
      isoprenoid diphosphates; supports the ATP-binding core function.
- id: Reactome:R-HSA-1655846
  title: Expression of Mevalonate Kinase (MVK)
  findings: []
- id: Reactome:R-HSA-191380
  title: Mevalonate is phosphorylated to mevalonate-5-phosphate
  findings: []