PMVK

UniProt ID: Q15126
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

Phosphomevalonate kinase (PMVK; EC 2.7.4.2) is a small (192-residue) cytosolic enzyme of the nucleoside-monophosphate kinase family (P-loop/Walker-A fold) that catalyses the reversible, ATP- and cation-dependent phosphorylation of (R)-mevalonate 5-phosphate to (R)-mevalonate 5-diphosphate, generating ADP. This is the fifth reaction of the mevalonate/isoprenoid biosynthetic pathway, acting between mevalonate kinase (MVK) and diphosphomevalonate decarboxylase (MVD), and constitutes step 2 of the three-step conversion of (R)-mevalonate to isopentenyl diphosphate (IPP), the universal isoprenoid precursor from which sterols (including cholesterol) and nonsterol isoprenoids are built. The enzyme acts as a monomer and uses ATP as the phosphoryl donor, with conserved basic active-site residues (e.g. K22, R110) neutralising the pentacoordinate phosphoryl-transfer intermediate. PMVK is expressed broadly (highest in heart, liver, skeletal muscle, kidney and pancreas) and its transcription is upregulated by sterol depletion, consistent with coordinate regulation of the cholesterol biosynthetic program. Although it carries a C-terminal Ser-Arg-Leu type-1 peroxisomal targeting signal and was historically proposed to be peroxisomal, multiple biochemical and microscopy studies establish that human PMVK is a cytosolic protein. Loss-of-function variants cause autosomal-dominant porokeratosis.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004631 phosphomevalonate kinase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) assignment of the defining molecular function. This is the correct, experimentally corroborated core catalytic activity of PMVK.
Reason: PMVK is the human phosphomevalonate kinase; the activity is directly demonstrated for the recombinant human enzyme and encoded by UniProt EC 2.7.4.2.
Supporting Evidence:
PMID:16519518
Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
GO:0006695 cholesterol biosynthetic process
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic assignment placing PMVK in cholesterol biosynthesis. This is correct but represents a downstream branch of the pathway; the enzymatic step feeds the whole isoprenoid program, of which cholesterol is one output.
Reason: Cholesterol is a downstream product of the mevalonate pathway; the more precise pathway role of PMVK is IPP biosynthesis (GO:0019287, step 2/3 to IPP), from which the sterol and nonsterol isoprenoid branches diverge. Keep as a valid but non-core (broader downstream) process annotation.
Supporting Evidence:
PMID:27052676
PMVK catalyzes the fifth reaction of the cholesterol/isoprenoid biosynthetic pathway
GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment to IPP biosynthesis via the mevalonate pathway. This is the most precise biological-process term for PMVK and matches the UniProt PATHWAY statement (IPP from (R)-mevalonate, step 2/3).
Reason: PMVK catalyses the direct precursor step to IPP; the UniProt PATHWAY line places it at "isopentenyl diphosphate from (R)-mevalonate, step 2/3", making this the core process annotation.
Supporting Evidence:
file:human/PMVK/PMVK-uniprot.txt
isopentenyl diphosphate from (R)-mevalonate:
GO:0004631 phosphomevalonate kinase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of the phosphomevalonate kinase activity via ARBA/InterPro (IPR005919, RHEA:16341, EC 2.7.4.2). Correct and consistent with the experimental evidence.
Reason: Correctly captures the core molecular function (duplicate of the EXP/IDA/IBA GO:0004631 annotations); the electronic mapping is accurate.
Supporting Evidence:
file:human/PMVK/PMVK-uniprot.txt
Reaction=(R)-5-phosphomevalonate + ATP = (R)-5-diphosphomevalonate +
GO:0005737 cytoplasm
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro2GO electronic mapping to cytoplasm. Consistent with the established cytosolic localization, but less precise than the cytosol (GO:0005829) IDA/TAS terms.
Reason: Cytoplasm is a broader parent of the more precise, experimentally supported cytosol term; correct but non-core given the specific cytosol annotations.
Supporting Evidence:
file:human/PMVK/PMVK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
IEA
GO_REF:0000044 		ACCEPT
Summary: UniProt Subcellular-Location keyword mapping to cytosol. Correct; matches the experimental IDA cytosol annotations.
Reason: Correctly captures the core cytosolic location (duplicate of the experimental IDA GO:0005829 annotations).
Supporting Evidence:
file:human/PMVK/PMVK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006695 cholesterol biosynthetic process
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic (ARBA/InterPro) assignment to cholesterol biosynthesis. Correct but a downstream branch rather than the most precise pathway role.
Reason: Duplicate of the cholesterol biosynthetic process annotation; correct but downstream/broad relative to the core IPP biosynthesis role (GO:0019287).
Supporting Evidence:
PMID:27052676
PMVK catalyzes the fifth reaction of the cholesterol/isoprenoid biosynthetic pathway
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: Bare "protein binding" from the HuRI high-throughput yeast-two-hybrid binary interactome map (interactors ZNF177 Q13360-2 and DDIT4L Q96D03). Uninformative and not connected to a characterised biological function of PMVK.
Reason: GO:0005515 (protein binding) is uninformative and per curation guidelines should not be used as a stand-in for a specific molecular function. The interactors (a zinc-finger protein and a DDIT4-like protein) come from a proteome-wide binary screen with no follow-up establishing a physiological complex or function for PMVK. Marked as over-annotated rather than removed (experimental IPI, full text not read).
Supporting Evidence:
PMID:32296183
Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'.
GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic (ARBA/UniPathway UPA00057) assignment to IPP biosynthesis via the mevalonate pathway. Correct and matches the core pathway role.
Reason: Correctly captures the core pathway role (duplicate of the IBA GO:0019287 annotation); matches the UniProt PATHWAY statement (IPP from (R)-mevalonate, step 2/3).
Supporting Evidence:
file:human/PMVK/PMVK-uniprot.txt
isopentenyl diphosphate from (R)-mevalonate:
GO:0006695 cholesterol biosynthetic process
TAS
Reactome:R-HSA-9969896 		KEEP AS NON CORE
Summary: Reactome (Lanosterol biosynthesis) traceable-author annotation to cholesterol biosynthesis. Correct but a downstream branch relative to the core IPP-precursor role.
Reason: Correct pathway membership but downstream/broad; duplicate of the cholesterol biosynthetic process annotations kept as non-core (core process is GO:0019287).
Supporting Evidence:
PMID:27052676
PMVK catalyzes the fifth reaction of the cholesterol/isoprenoid biosynthetic pathway
GO:0004631 phosphomevalonate kinase activity
TAS
Reactome:R-HSA-191422 		ACCEPT
Summary: Reactome reaction "Mevalonate-5-phosphate is further phosphorylated" attributes the phosphomevalonate kinase activity to PMVK. Correct core molecular function.
Reason: Correctly captures the core molecular function (duplicate of the experimental GO:0004631 annotations).
Supporting Evidence:
PMID:16519518
Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
GO:0005829 cytosol
TAS
Reactome:R-HSA-1655839 		ACCEPT
Summary: Reactome (Expression of PMVK) traceable-author cytosol location. Consistent with the experimental IDA cytosol annotations.
Reason: Correctly captures the core cytosolic location (duplicate of the experimental IDA GO:0005829 annotations).
Supporting Evidence:
PMID:14729858
exclusive cytosolic localization of both endogenously expressed human
GO:0005829 cytosol
TAS
Reactome:R-HSA-191422 		ACCEPT
Summary: Reactome (mevalonate-5-phosphate phosphorylation reaction) traceable-author cytosol location. Consistent with the established cytosolic localization.
Reason: Correctly captures the core cytosolic location (duplicate of the experimental IDA GO:0005829 annotations).
Supporting Evidence:
PMID:14729858
exclusive cytosolic localization of both endogenously expressed human
GO:0004631 phosphomevalonate kinase activity
EXP
PMID:17902708
Functional evaluation of conserved basic residues in human p... 		ACCEPT
Summary: Experimental demonstration of phosphomevalonate kinase activity for human PMVK via kinetic and mutagenesis analysis of conserved active-site basic residues.
Reason: Direct experimental evidence for the core catalytic activity; identifies catalytic (R110, K48, R73) and substrate/ATP-binding (R111, R84, R141) residues.
Supporting Evidence:
PMID:17902708
Phosphomevalonate kinase (PMK) catalyzes the cation-dependent reaction of
GO:0004631 phosphomevalonate kinase activity
EXP
PMID:9392419
Post-translational regulation of mevalonate kinase by interm... 		ACCEPT
Summary: Experimental study expressing and assaying recombinant human PMKase (alongside MKase and MDDase); confirms phosphomevalonate kinase activity for PMVK.
Reason: Direct experimental evidence for the core catalytic activity (the enzyme was purified and assayed spectrophotometrically); underpins UniProt EC 2.7.4.2.
Supporting Evidence:
PMID:9392419
phosphomevalonate kinase (PMKase), and
GO:0005777 peroxisome
IDA NOT
PMID:14729858
Phosphomevalonate kinase is a cytosolic protein in humans. 		ACCEPT
Summary: Correct NOT annotation. Multiple techniques (subcellular fractionation, digitonin permeabilization, immunofluorescence, immunoelectron microscopy) found no peroxisomal PMVK, overturning the earlier peroxisomal claim.
Reason: This negated annotation captures the definitive finding that human PMVK is not peroxisomal; it is corroborated by PMID:27052676 (no co-localization with PEX14) and by the UniProt CAUTION note.
Supporting Evidence:
PMID:14729858
No indication of a peroxisomal localization was obtained.
GO:0005829 cytosol
IDA
PMID:27052676
Loss-of-function Mutation in PMVK Causes Autosomal Dominant ... 		ACCEPT
Summary: Direct assay (immunofluorescence in HaCaT/ARPE-19 cells) showing wild-type PMVK has a dispersed cytoplasmic (cytosolic) distribution that does not co-localize with the peroxisomal marker PEX14.
Reason: Experimental confirmation of the core cytosolic localization of PMVK.
Supporting Evidence:
PMID:27052676
The wild-type PMVK exhibited dispersed cytoplasmic localization and showed little co-localization with the peroxisomal marker PEX14
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: High-throughput detection of PMVK in an NK-cell "membrane proteome" preparation. This is a soluble cytosolic kinase; membrane co-purification in a large-scale MS dataset is not a functional membrane localization.
Reason: PMVK is an established soluble, cytosolic enzyme with no transmembrane domain or lipid anchor (UniProt). Its appearance in a bulk membrane-enriched MS dataset most likely reflects incomplete fractionation/contamination rather than a physiological membrane location.
Supporting Evidence:
PMID:19946888
define the composition of the membrane
file:human/PMVK/PMVK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		MARK AS OVER ANNOTATED
Summary: High-throughput MS identification of PMVK in a urinary-exosome proteome. This is a bulk proteomic catalogue rather than evidence of a functional exosomal role for this cytosolic kinase.
Reason: Detection in a large-scale exosome proteomics survey is a common finding for abundant cytosolic proteins and does not indicate a biological function of PMVK in exosomes; the enzyme's characterised location is the cytosol.
Supporting Evidence:
PMID:19056867
LC-MS/MS to profile the proteome of human urinary exosomes
file:human/PMVK/PMVK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005777 peroxisome
IDA
PMID:17180682
Localization of the pre-squalene segment of the isoprenoid b... 		MARK AS OVER ANNOTATED
Summary: Minority-view IDA reporting peroxisomal localization of presqualene enzymes (including PMVK) using isotopomer and immunofluorescence methods. This conclusion has been rejected by the field; the consensus (and UniProt) is that human PMVK is cytosolic.
Reason: Directly contradicted by PMID:14729858 (exclusive cytosolic localization; NOT peroxisome) and PMID:27052676 (no PEX14 co-localization), and by the UniProt CAUTION note stating PMVK "was later shown to be cytosolic". Retained rather than removed because it is an experimental IDA whose full text was not read, but flagged as an over-annotation superseded by stronger, concordant evidence.
Supporting Evidence:
PMID:17180682
segment of the cholesterol biosynthetic pathway is localized to peroxisomes
file:human/PMVK/PMVK-uniprot.txt
Was originally thought to be located in the peroxisome
GO:0005829 cytosol
IDA
PMID:14729858
Phosphomevalonate kinase is a cytosolic protein in humans. 		ACCEPT
Summary: Direct experimental determination (subcellular fractionation, digitonin permeabilization, immunofluorescence, immunoelectron microscopy) that endogenous and overexpressed human PMVK localize exclusively to the cytosol.
Reason: Definitive experimental evidence for the core cytosolic localization; this is the study that established PMVK as cytosolic and underlies the UniProt annotation.
Supporting Evidence:
PMID:14729858
exclusive cytosolic localization of both endogenously expressed human
GO:0004631 phosphomevalonate kinase activity
IDA
PMID:16519518
Phosphomevalonate kinase: functional investigation of the re... 		ACCEPT
Summary: Direct assay of recombinant His-tagged human PMVK confirming phosphomevalonate kinase activity; kinetic constants determined for both forward and reverse reactions.
Reason: Primary experimental evidence for the core catalytic activity of the human enzyme, with determined KM and Vmax values.
Supporting Evidence:
PMID:16519518
Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
GO:0005524 ATP binding
IDA
PMID:16519518
Phosphomevalonate kinase: functional investigation of the re... 		ACCEPT
Summary: ATP is the phosphoryl donor for the kinase reaction; the study identifies an N-terminal Walker-A-like basic-residue motif and demonstrates ATP binding via mutagenesis (e.g. K22M abolishes activity).
Reason: ATP binding is directly supported and mechanistically integral to the core phosphotransferase function (ATP + mevalonate-5-P -> mevalonate-5-PP + ADP).
Supporting Evidence:
PMID:16519518
an N-terminal basic
file:human/PMVK/PMVK-uniprot.txt
ligand="ATP"
GO:0016126 sterol biosynthetic process
IDA
PMID:16519518
Phosphomevalonate kinase: functional investigation of the re... 		KEEP AS NON CORE
Summary: Places PMVK in sterol biosynthesis. Correct at a broad level but downstream of the direct enzymatic step; the more precise process is IPP biosynthesis (GO:0019287).
Reason: Sterol biosynthesis is a downstream/broad process relative to the direct IPP-precursor role; retained as a valid but non-core process annotation.
Supporting Evidence:
PMID:16519518
catalyzes a key step in isoprenoid/sterol
GO:0070723 response to cholesterol
IEP
PMID:10191291
Characterization of phosphomevalonate kinase: chromosomal lo... 		KEEP AS NON CORE
Summary: Expression-pattern evidence that PMVK message and activity are regulated in response to dietary/cellular sterol levels, coordinately with HMG-CoA reductase. This reflects transcriptional (SREBP-type) regulation of the gene, not a core enzymatic function.
Reason: The sterol-responsive regulation of PMVK is a genuine, documented property but is a regulatory/response process distinct from the enzyme's molecular function; kept as a valid non-core annotation.
Supporting Evidence:
PMID:10191291
activity of rat liver phosphomevalonate kinase are regulated in response to
GO:0004631 phosphomevalonate kinase activity
IDA
PMID:8663599
Molecular cloning of human phosphomevalonate kinase and iden... 		ACCEPT
Summary: Original molecular cloning of human liver PMKase with expression of PMKase catalytic activity in bacteria from the cloned cDNA, establishing the enzyme's identity and activity.
Reason: Foundational experimental evidence for the core phosphomevalonate kinase activity of human PMVK.
Supporting Evidence:
PMID:8663599
expression of PMKase activity in bacteria
GO:0006695 cholesterol biosynthetic process
IDA
PMID:8663599
Molecular cloning of human phosphomevalonate kinase and iden... 		KEEP AS NON CORE
Summary: Assigns PMVK to cholesterol biosynthesis. Correct membership but a downstream/broad process relative to the direct IPP-precursor step.
Reason: Cholesterol biosynthesis is downstream of PMVK's direct reaction; duplicate of the cholesterol biosynthetic process annotations, kept as non-core (core process is GO:0019287 IPP biosynthesis).
Supporting Evidence:
PMID:8663599
cholesterol biosynthetic protein which contains a consensus PTS-1
GO:0004631 phosphomevalonate kinase activity
IDA
PMID:14680974
Cholesterol biosynthesis is not defective in peroxisome biog... 		ACCEPT
Summary: Directly measured phosphomevalonate kinase protein level and enzymatic activity in fibroblasts (among five presqualene-pathway enzymes) while assessing peroxisomal involvement in cholesterol biosynthesis.
Reason: Provides direct experimental measurement of PMVK activity, supporting the core catalytic function; also shows the activity is retained in peroxisome-deficient cells.
Supporting Evidence:
PMID:14680974
determined the protein levels and activities of five different

Core Functions

Phosphomevalonate kinase activity - ATP-dependent phosphorylation of (R)-mevalonate 5-phosphate to (R)-mevalonate 5-diphosphate, the direct precursor step to isopentenyl diphosphate in the mevalonate pathway.

Molecular Function:
phosphomevalonate kinase activity
Directly Involved In:
isopentenyl diphosphate biosynthetic process, mevalonate pathway
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:16519518
    Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
  • file:human/PMVK/PMVK-uniprot.txt
    isopentenyl diphosphate from (R)-mevalonate:

ATP binding required for phosphoryl transfer; ATP is the phosphate donor consumed in the phosphomevalonate kinase reaction, coordinated by an N-terminal Walker-A-like basic-residue motif.

Molecular Function:
ATP binding
Directly Involved In:
isopentenyl diphosphate biosynthetic process, mevalonate pathway
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:16519518
    an N-terminal basic
  • file:human/PMVK/PMVK-uniprot.txt
    ligand="ATP"

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10191291
Characterization of phosphomevalonate kinase: chromosomal localization, regulation, and subcellular targeting.
PMID:14680974
Cholesterol biosynthesis is not defective in peroxisome biogenesis defective fibroblasts.
PMID:14729858
Phosphomevalonate kinase is a cytosolic protein in humans.
PMID:16519518
Phosphomevalonate kinase: functional investigation of the recombinant human enzyme.
PMID:17180682
Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway in mammalian peroxisomes.
PMID:17902708
Functional evaluation of conserved basic residues in human phosphomevalonate kinase.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:27052676
Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:8663599
Molecular cloning of human phosphomevalonate kinase and identification of a consensus peroxisomal targeting sequence.
PMID:9392419
Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways.
Reactome:R-HSA-1655839
Expression of Phosphomevalonate Kinase (PMVK)
Reactome:R-HSA-191422
Mevalonate-5-phosphate is further phosphorylated
Reactome:R-HSA-9969896
Lanosterol biosynthesis
file:human/PMVK/PMVK-uniprot.txt
UniProtKB Q15126 (PMVK_HUMAN) record

📚 Additional Documentation

Notes

(PMVK-notes.md)

PMVK (phosphomevalonate kinase, UniProtKB:Q15126) — review notes

Deep research status

Falcon deep research is OUT OF CREDITS (HTTP 402); no -deep-research-falcon.md was
generated. This review is grounded in the UniProt record (PMVK-uniprot.txt), the seeded
GOA (PMVK-goa.tsv), and the cached publications in publications/PMID_*.md (all 12 GOA
PMIDs are present).

Core biology

PMVK is phosphomevalonate kinase (EC 2.7.4.2), a 192-aa cytosolic enzyme of the
nucleoside-monophosphate (NMP) kinase family (P-loop fold). It catalyses the reversible,
ATP- and cation-dependent phosphorylation of (R)-mevalonate 5-phosphate to (R)-mevalonate
5-diphosphate (+ADP) — the step between mevalonate kinase (MVK) and diphosphomevalonate
decarboxylase (MVD) in the mevalonate/isoprenoid pathway.

  • UniProt CATALYTIC ACTIVITY: "Reaction=(R)-5-phosphomevalonate + ATP = (R)-5-diphosphomevalonate + ADP; ... EC=2.7.4.2" [Rhea:16341].
  • UniProt PATHWAY: "Isoprenoid biosynthesis; isopentenyl diphosphate biosynthesis via mevalonate pathway; isopentenyl diphosphate from (R)-mevalonate: step 2/3."
  • PMID:16519518 — recombinant human enzyme; monomer; kinetics both directions.
  • PMID:17902708 — Walker-A / basic-residue mutagenesis (K48, R73, R110, R111, R84, R141).
  • PMID:8663599 cloning of human liver PMKase; PMKase activity expressed in bacteria; sterol-regulated transcription; identified a C-terminal PTS-1 (Ser-Arg-Leu) but this is now known NOT to drive peroxisomal targeting.
  • PMID:9392419 PMKase (with MKase, MDDase) expressed in E. coli and assayed; only MKase (not PMKase) was feedback-inhibited by isoprene intermediates.

Localization: cytosolic (peroxisomal claim retracted)

Early reports (rat, and PTS-1 motif reasoning) proposed peroxisomal localization
PMID:10191291. This was overturned:
- PMID:14729858 — GOA uses this as NOT|peroxisome (IDA) and as cytosol (IDA).
- [PMID:27052676 "The wild-type PMVK exhibited dispersed cytoplasmic localization and showed little co-localization with the peroxisomal marker PEX14"; "PMVK and MVK were predominantly cytosolically localized"] — confirms cytosol.
- UniProt CAUTION: "Was originally thought to be located in the peroxisome (PubMed:10191291). However, was later shown to be cytosolic (PubMed:14729858, PubMed:27052676)."
- PMID:14680974 shows cholesterol biosynthesis is normal in peroxisome-biogenesis-deficient fibroblasts (presqualene enzymes including PMK retain activity), arguing against obligate peroxisomal function.

The conflicting IDA peroxisome annotation from PMID:17180682 (Kovacs/Krisans) is the
minority view that the field and UniProt have since rejected. Per curation policy (do not
REMOVE an experimental IDA whose full text I cannot read), this is kept but marked
over-annotated with the contradicting evidence noted.

Disease

Heterozygous loss-of-function PMVK variants cause autosomal-dominant porokeratosis
(POROK1) — a keratinization disorder — PMID:27052676, PMID:26202976. This is a
downstream phenotype of impaired mevalonate-pathway flux in skin, not the molecular
function; not treated as a core function.

Annotation decisions summary

  • MF phosphomevalonate kinase activity (GO:0004631): multiple EXP/IDA + IBA + IEA/TAS — ACCEPT (core). IEA/TAS/IBA duplicates KEEP_AS_NON_CORE.
  • ATP binding (GO:0005524) IDA PMID:16519518: ACCEPT (supports mechanism; ATP is the phosphate donor; Walker-A motif).
  • BP isopentenyl diphosphate biosynthetic process, mevalonate pathway (GO:0019287): the most precise pathway BP — ACCEPT (core, matches UniProt PATHWAY step 2/3).
  • BP cholesterol biosynthetic process (GO:0006695) / sterol biosynthetic process (GO:0016126): correct but downstream/broad — KEEP_AS_NON_CORE (cholesterol is one branch downstream of IPP).
  • CC cytosol (GO:0005829) IDA/TAS: ACCEPT (core location). cytoplasm (GO:0005737) IEA: KEEP_AS_NON_CORE (broader parent).
  • CC peroxisome (GO:0005777) IDA PMID:17180682: MARK_AS_OVER_ANNOTATED (contradicted by field/UniProt CAUTION; do not REMOVE experimental IDA).
  • CC NOT|peroxisome (GO:0005777) IDA PMID:14729858: ACCEPT (correct negation).
  • CC membrane (GO:0016020) HDA / extracellular exosome (GO:0070062) HDA: MARK_AS_OVER_ANNOTATED (large-scale proteomics; not a functional location for a cytosolic kinase).
  • MF protein binding (GO:0005515) IPI PMID:32296183: MARK_AS_OVER_ANNOTATED (bare, uninformative HuRI Y2H hits; per curation policy, not REMOVE).
  • BP response to cholesterol (GO:0070723) IEP PMID:10191291: KEEP_AS_NON_CORE (sterol-regulated transcription of the gene; regulatory response, not core enzymatic function).

📄 View Raw YAML

 
id: Q15126
gene_symbol: PMVK
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Phosphomevalonate kinase (PMVK; EC 2.7.4.2) is a small (192-residue) cytosolic
  enzyme of the nucleoside-monophosphate kinase family (P-loop/Walker-A fold) that catalyses
  the reversible, ATP- and cation-dependent phosphorylation of (R)-mevalonate 5-phosphate
  to (R)-mevalonate 5-diphosphate, generating ADP. This is the fifth reaction of the
  mevalonate/isoprenoid biosynthetic pathway, acting between mevalonate kinase (MVK) and
  diphosphomevalonate decarboxylase (MVD), and constitutes step 2 of the three-step
  conversion of (R)-mevalonate to isopentenyl diphosphate (IPP), the universal isoprenoid
  precursor from which sterols (including cholesterol) and nonsterol isoprenoids are built.
  The enzyme acts as a monomer and uses ATP as the phosphoryl donor, with conserved basic
  active-site residues (e.g. K22, R110) neutralising the pentacoordinate phosphoryl-transfer
  intermediate. PMVK is expressed broadly (highest in heart, liver, skeletal muscle, kidney
  and pancreas) and its transcription is upregulated by sterol depletion, consistent with
  coordinate regulation of the cholesterol biosynthetic program. Although it carries a
  C-terminal Ser-Arg-Leu type-1 peroxisomal targeting signal and was historically proposed
  to be peroxisomal, multiple biochemical and microscopy studies establish that human PMVK
  is a cytosolic protein. Loss-of-function variants cause autosomal-dominant porokeratosis.
existing_annotations:
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of the defining molecular function. This is
      the correct, experimentally corroborated core catalytic activity of PMVK.
    action: ACCEPT
    reason: PMVK is the human phosphomevalonate kinase; the activity is directly
      demonstrated for the recombinant human enzyme and encoded by UniProt EC 2.7.4.2.
    supported_by:
      - reference_id: PMID:16519518
        supporting_text: Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment placing PMVK in cholesterol biosynthesis. This is
      correct but represents a downstream branch of the pathway; the enzymatic step feeds
      the whole isoprenoid program, of which cholesterol is one output.
    action: KEEP_AS_NON_CORE
    reason: Cholesterol is a downstream product of the mevalonate pathway; the more precise
      pathway role of PMVK is IPP biosynthesis (GO:0019287, step 2/3 to IPP), from which
      the sterol and nonsterol isoprenoid branches diverge. Keep as a valid but non-core
      (broader downstream) process annotation.
    supported_by:
      - reference_id: PMID:27052676
        supporting_text: PMVK catalyzes the fifth reaction of the cholesterol/isoprenoid
          biosynthetic pathway
- 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: Phylogenetic assignment to IPP biosynthesis via the mevalonate pathway. This
      is the most precise biological-process term for PMVK and matches the UniProt PATHWAY
      statement (IPP from (R)-mevalonate, step 2/3).
    action: ACCEPT
    reason: PMVK catalyses the direct precursor step to IPP; the UniProt PATHWAY line
      places it at "isopentenyl diphosphate from (R)-mevalonate, step 2/3", making this
      the core process annotation.
    supported_by:
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "isopentenyl diphosphate from (R)-mevalonate:"
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of the phosphomevalonate kinase activity via ARBA/InterPro
      (IPR005919, RHEA:16341, EC 2.7.4.2). Correct and consistent with the experimental
      evidence.
    action: ACCEPT
    reason: Correctly captures the core molecular function (duplicate of the EXP/IDA/IBA
      GO:0004631 annotations); the electronic mapping is accurate.
    supported_by:
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "Reaction=(R)-5-phosphomevalonate + ATP = (R)-5-diphosphomevalonate +"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro2GO electronic mapping to cytoplasm. Consistent with the established
      cytosolic localization, but less precise than the cytosol (GO:0005829) IDA/TAS terms.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasm is a broader parent of the more precise, experimentally supported
      cytosol term; correct but non-core given the specific cytosol annotations.
    supported_by:
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Cytoplasm, cytosol"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt Subcellular-Location keyword mapping to cytosol. Correct; matches the
      experimental IDA cytosol annotations.
    action: ACCEPT
    reason: Correctly captures the core cytosolic location (duplicate of the experimental
      IDA GO:0005829 annotations).
    supported_by:
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Cytoplasm, cytosol"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic (ARBA/InterPro) assignment to cholesterol biosynthesis. Correct
      but a downstream branch rather than the most precise pathway role.
    action: KEEP_AS_NON_CORE
    reason: Duplicate of the cholesterol biosynthetic process annotation; correct but
      downstream/broad relative to the core IPP biosynthesis role (GO:0019287).
    supported_by:
      - reference_id: PMID:27052676
        supporting_text: PMVK catalyzes the fifth reaction of the cholesterol/isoprenoid
          biosynthetic pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare "protein binding" from the HuRI high-throughput yeast-two-hybrid binary
      interactome map (interactors ZNF177 Q13360-2 and DDIT4L Q96D03). Uninformative and
      not connected to a characterised biological function of PMVK.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 (protein binding) is uninformative and per curation guidelines
      should not be used as a stand-in for a specific molecular function. The interactors
      (a zinc-finger protein and a DDIT4-like protein) come from a proteome-wide binary
      screen with no follow-up establishing a physiological complex or function for PMVK.
      Marked as over-annotated rather than removed (experimental IPI, full text not read).
    supported_by:
      - reference_id: PMID:32296183
        supporting_text: Here we present a human 'all-by-all' reference interactome map of
          human binary protein interactions, or 'HuRI'.
- term:
    id: GO:0019287
    label: isopentenyl diphosphate biosynthetic process, mevalonate pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic (ARBA/UniPathway UPA00057) assignment to IPP biosynthesis via the
      mevalonate pathway. Correct and matches the core pathway role.
    action: ACCEPT
    reason: Correctly captures the core pathway role (duplicate of the IBA GO:0019287
      annotation); matches the UniProt PATHWAY statement (IPP from (R)-mevalonate, step 2/3).
    supported_by:
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "isopentenyl diphosphate from (R)-mevalonate:"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9969896
  qualifier: involved_in
  review:
    summary: Reactome (Lanosterol biosynthesis) traceable-author annotation to cholesterol
      biosynthesis. Correct but a downstream branch relative to the core IPP-precursor role.
    action: KEEP_AS_NON_CORE
    reason: Correct pathway membership but downstream/broad; duplicate of the cholesterol
      biosynthetic process annotations kept as non-core (core process is GO:0019287).
    supported_by:
      - reference_id: PMID:27052676
        supporting_text: PMVK catalyzes the fifth reaction of the cholesterol/isoprenoid
          biosynthetic pathway
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191422
  qualifier: enables
  review:
    summary: Reactome reaction "Mevalonate-5-phosphate is further phosphorylated" attributes
      the phosphomevalonate kinase activity to PMVK. Correct core molecular function.
    action: ACCEPT
    reason: Correctly captures the core molecular function (duplicate of the experimental
      GO:0004631 annotations).
    supported_by:
      - reference_id: PMID:16519518
        supporting_text: Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655839
  qualifier: located_in
  review:
    summary: Reactome (Expression of PMVK) traceable-author cytosol location. Consistent
      with the experimental IDA cytosol annotations.
    action: ACCEPT
    reason: Correctly captures the core cytosolic location (duplicate of the experimental
      IDA GO:0005829 annotations).
    supported_by:
      - reference_id: PMID:14729858
        supporting_text: exclusive cytosolic localization of both endogenously expressed human
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191422
  qualifier: located_in
  review:
    summary: Reactome (mevalonate-5-phosphate phosphorylation reaction) traceable-author
      cytosol location. Consistent with the established cytosolic localization.
    action: ACCEPT
    reason: Correctly captures the core cytosolic location (duplicate of the experimental
      IDA GO:0005829 annotations).
    supported_by:
      - reference_id: PMID:14729858
        supporting_text: exclusive cytosolic localization of both endogenously expressed human
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: EXP
  original_reference_id: PMID:17902708
  qualifier: enables
  review:
    summary: Experimental demonstration of phosphomevalonate kinase activity for human PMVK
      via kinetic and mutagenesis analysis of conserved active-site basic residues.
    action: ACCEPT
    reason: Direct experimental evidence for the core catalytic activity; identifies
      catalytic (R110, K48, R73) and substrate/ATP-binding (R111, R84, R141) residues.
    supported_by:
      - reference_id: PMID:17902708
        supporting_text: Phosphomevalonate kinase (PMK) catalyzes the cation-dependent reaction
          of
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: EXP
  original_reference_id: PMID:9392419
  qualifier: enables
  review:
    summary: Experimental study expressing and assaying recombinant human PMKase (alongside
      MKase and MDDase); confirms phosphomevalonate kinase activity for PMVK.
    action: ACCEPT
    reason: Direct experimental evidence for the core catalytic activity (the enzyme was
      purified and assayed spectrophotometrically); underpins UniProt EC 2.7.4.2.
    supported_by:
      - reference_id: PMID:9392419
        supporting_text: 'phosphomevalonate kinase (PMKase), and'
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:14729858
  qualifier: located_in
  negated: true
  review:
    summary: Correct NOT annotation. Multiple techniques (subcellular fractionation,
      digitonin permeabilization, immunofluorescence, immunoelectron microscopy) found no
      peroxisomal PMVK, overturning the earlier peroxisomal claim.
    action: ACCEPT
    reason: This negated annotation captures the definitive finding that human PMVK is not
      peroxisomal; it is corroborated by PMID:27052676 (no co-localization with PEX14) and
      by the UniProt CAUTION note.
    supported_by:
      - reference_id: PMID:14729858
        supporting_text: No indication of a peroxisomal localization was obtained.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:27052676
  qualifier: located_in
  review:
    summary: Direct assay (immunofluorescence in HaCaT/ARPE-19 cells) showing wild-type
      PMVK has a dispersed cytoplasmic (cytosolic) distribution that does not co-localize
      with the peroxisomal marker PEX14.
    action: ACCEPT
    reason: Experimental confirmation of the core cytosolic localization of PMVK.
    supported_by:
      - reference_id: PMID:27052676
        supporting_text: The wild-type PMVK exhibited dispersed cytoplasmic localization and
          showed little co-localization with the peroxisomal marker PEX14
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput detection of PMVK in an NK-cell "membrane proteome"
      preparation. This is a soluble cytosolic kinase; membrane co-purification in a
      large-scale MS dataset is not a functional membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: PMVK is an established soluble, cytosolic enzyme with no transmembrane domain
      or lipid anchor (UniProt). Its appearance in a bulk membrane-enriched MS dataset most
      likely reflects incomplete fractionation/contamination rather than a physiological
      membrane location.
    supported_by:
      - reference_id: PMID:19946888
        supporting_text: define the composition of the membrane
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Cytoplasm, cytosol"
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput MS identification of PMVK in a urinary-exosome proteome. This
      is a bulk proteomic catalogue rather than evidence of a functional exosomal role for
      this cytosolic kinase.
    action: MARK_AS_OVER_ANNOTATED
    reason: Detection in a large-scale exosome proteomics survey is a common finding for
      abundant cytosolic proteins and does not indicate a biological function of PMVK in
      exosomes; the enzyme's characterised location is the cytosol.
    supported_by:
      - reference_id: PMID:19056867
        supporting_text: LC-MS/MS to profile the proteome of human urinary exosomes
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Cytoplasm, cytosol"
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:17180682
  qualifier: located_in
  review:
    summary: Minority-view IDA reporting peroxisomal localization of presqualene enzymes
      (including PMVK) using isotopomer and immunofluorescence methods. This conclusion has
      been rejected by the field; the consensus (and UniProt) is that human PMVK is cytosolic.
    action: MARK_AS_OVER_ANNOTATED
    reason: Directly contradicted by PMID:14729858 (exclusive cytosolic localization; NOT
      peroxisome) and PMID:27052676 (no PEX14 co-localization), and by the UniProt CAUTION
      note stating PMVK "was later shown to be cytosolic". Retained rather than removed
      because it is an experimental IDA whose full text was not read, but flagged as an
      over-annotation superseded by stronger, concordant evidence.
    supported_by:
      - reference_id: PMID:17180682
        supporting_text: segment of the cholesterol biosynthetic pathway is localized to peroxisomes
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: "Was originally thought to be located in the peroxisome"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:14729858
  qualifier: located_in
  review:
    summary: Direct experimental determination (subcellular fractionation, digitonin
      permeabilization, immunofluorescence, immunoelectron microscopy) that endogenous and
      overexpressed human PMVK localize exclusively to the cytosol.
    action: ACCEPT
    reason: Definitive experimental evidence for the core cytosolic localization; this is
      the study that established PMVK as cytosolic and underlies the UniProt annotation.
    supported_by:
      - reference_id: PMID:14729858
        supporting_text: exclusive cytosolic localization of both endogenously expressed human
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:16519518
  qualifier: enables
  review:
    summary: Direct assay of recombinant His-tagged human PMVK confirming phosphomevalonate
      kinase activity; kinetic constants determined for both forward and reverse reactions.
    action: ACCEPT
    reason: Primary experimental evidence for the core catalytic activity of the human
      enzyme, with determined KM and Vmax values.
    supported_by:
      - reference_id: PMID:16519518
        supporting_text: Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:16519518
  qualifier: enables
  review:
    summary: ATP is the phosphoryl donor for the kinase reaction; the study identifies an
      N-terminal Walker-A-like basic-residue motif and demonstrates ATP binding via
      mutagenesis (e.g. K22M abolishes activity).
    action: ACCEPT
    reason: ATP binding is directly supported and mechanistically integral to the core
      phosphotransferase function (ATP + mevalonate-5-P -> mevalonate-5-PP + ADP).
    supported_by:
      - reference_id: PMID:16519518
        supporting_text: an N-terminal basic
      - reference_id: file:human/PMVK/PMVK-uniprot.txt
        supporting_text: 'ligand="ATP"'
- term:
    id: GO:0016126
    label: sterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16519518
  qualifier: involved_in
  review:
    summary: Places PMVK in sterol biosynthesis. Correct at a broad level but downstream of
      the direct enzymatic step; the more precise process is IPP biosynthesis (GO:0019287).
    action: KEEP_AS_NON_CORE
    reason: Sterol biosynthesis is a downstream/broad process relative to the direct
      IPP-precursor role; retained as a valid but non-core process annotation.
    supported_by:
      - reference_id: PMID:16519518
        supporting_text: catalyzes a key step in isoprenoid/sterol
- term:
    id: GO:0070723
    label: response to cholesterol
  evidence_type: IEP
  original_reference_id: PMID:10191291
  qualifier: involved_in
  review:
    summary: Expression-pattern evidence that PMVK message and activity are regulated in
      response to dietary/cellular sterol levels, coordinately with HMG-CoA reductase. This
      reflects transcriptional (SREBP-type) regulation of the gene, not a core enzymatic
      function.
    action: KEEP_AS_NON_CORE
    reason: The sterol-responsive regulation of PMVK is a genuine, documented property but
      is a regulatory/response process distinct from the enzyme's molecular function; kept
      as a valid non-core annotation.
    supported_by:
      - reference_id: PMID:10191291
        supporting_text: activity of rat liver phosphomevalonate kinase are regulated in response
          to
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:8663599
  qualifier: enables
  review:
    summary: Original molecular cloning of human liver PMKase with expression of PMKase
      catalytic activity in bacteria from the cloned cDNA, establishing the enzyme's
      identity and activity.
    action: ACCEPT
    reason: Foundational experimental evidence for the core phosphomevalonate kinase
      activity of human PMVK.
    supported_by:
      - reference_id: PMID:8663599
        supporting_text: expression of PMKase activity in bacteria
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8663599
  qualifier: involved_in
  review:
    summary: Assigns PMVK to cholesterol biosynthesis. Correct membership but a
      downstream/broad process relative to the direct IPP-precursor step.
    action: KEEP_AS_NON_CORE
    reason: Cholesterol biosynthesis is downstream of PMVK's direct reaction; duplicate of
      the cholesterol biosynthetic process annotations, kept as non-core (core process is
      GO:0019287 IPP biosynthesis).
    supported_by:
      - reference_id: PMID:8663599
        supporting_text: cholesterol biosynthetic protein which contains a consensus PTS-1
- term:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:14680974
  qualifier: enables
  review:
    summary: Directly measured phosphomevalonate kinase protein level and enzymatic
      activity in fibroblasts (among five presqualene-pathway enzymes) while assessing
      peroxisomal involvement in cholesterol biosynthesis.
    action: ACCEPT
    reason: Provides direct experimental measurement of PMVK activity, supporting the core
      catalytic function; also shows the activity is retained in peroxisome-deficient cells.
    supported_by:
      - reference_id: PMID:14680974
        supporting_text: determined the protein levels and activities of five different
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10191291
  title: 'Characterization of phosphomevalonate kinase: chromosomal localization,
    regulation, and subcellular targeting.'
  findings: []
- id: PMID:14680974
  title: Cholesterol biosynthesis is not defective in peroxisome biogenesis defective
    fibroblasts.
  findings: []
- id: PMID:14729858
  title: Phosphomevalonate kinase is a cytosolic protein in humans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; definitive multi-technique demonstration that human PMVK
      is exclusively cytosolic, the basis for the NOT|peroxisome and cytosol annotations.
- id: PMID:16519518
  title: 'Phosphomevalonate kinase: functional investigation of the recombinant human
    enzyme.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; primary characterization of recombinant human PMVK
      establishing the phosphomevalonate kinase activity, ATP binding, and monomeric state.
- id: PMID:17180682
  title: Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway
    in mammalian peroxisomes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: DISPUTED
    review_notes: PubMed-verified citation, but its conclusion of peroxisomal localization
      of presqualene enzymes (including PMVK) is contradicted by PMID:14729858 and
      PMID:27052676 and by the UniProt CAUTION note; the field consensus is cytosolic.
- id: PMID:17902708
  title: Functional evaluation of conserved basic residues in human phosphomevalonate
    kinase.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:27052676
  title: Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated
    Superficial Porokeratosis.
  findings: []
- 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 interactome map. The PMVK interactors it reports are
      high-throughput Y2H hits with no functional follow-up; supports only a bare, and
      uninformative, protein-binding annotation.
- id: PMID:8663599
  title: Molecular cloning of human phosphomevalonate kinase and identification of
    a consensus peroxisomal targeting sequence.
  findings: []
- id: PMID:9392419
  title: Post-translational regulation of mevalonate kinase by intermediates of the
    cholesterol and nonsterol isoprene biosynthetic pathways.
  findings: []
- id: Reactome:R-HSA-1655839
  title: Expression of Phosphomevalonate Kinase (PMVK)
  findings: []
- id: Reactome:R-HSA-191422
  title: Mevalonate-5-phosphate is further phosphorylated
  findings: []
- id: Reactome:R-HSA-9969896
  title: Lanosterol biosynthesis
  findings: []
- id: file:human/PMVK/PMVK-uniprot.txt
  title: UniProtKB Q15126 (PMVK_HUMAN) record
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt entry; source for the EC 2.7.4.2 catalytic activity, the
      isoprenoid/IPP PATHWAY statement, the cytosolic subcellular location, the ATP-binding
      features, and the CAUTION note reconciling the peroxisome-vs-cytosol history.
core_functions:
- description: Phosphomevalonate kinase activity - ATP-dependent phosphorylation of
    (R)-mevalonate 5-phosphate to (R)-mevalonate 5-diphosphate, the direct precursor step
    to isopentenyl diphosphate in the mevalonate pathway.
  molecular_function:
    id: GO:0004631
    label: phosphomevalonate kinase activity
  directly_involved_in:
    - id: GO:0019287
      label: isopentenyl diphosphate biosynthetic process, mevalonate pathway
  supported_by:
    - reference_id: PMID:16519518
      supporting_text: Phosphomevalonate kinase (PMK) catalyzes a key step in isoprenoid/sterol
    - reference_id: file:human/PMVK/PMVK-uniprot.txt
      supporting_text: "isopentenyl diphosphate from (R)-mevalonate:"
  locations:
    - id: GO:0005829
      label: cytosol
- description: ATP binding required for phosphoryl transfer; ATP is the phosphate donor
    consumed in the phosphomevalonate kinase reaction, coordinated by an N-terminal
    Walker-A-like basic-residue motif.
  molecular_function:
    id: GO:0005524
    label: ATP binding
  directly_involved_in:
    - id: GO:0019287
      label: isopentenyl diphosphate biosynthetic process, mevalonate pathway
  supported_by:
    - reference_id: PMID:16519518
      supporting_text: an N-terminal basic
    - reference_id: file:human/PMVK/PMVK-uniprot.txt
      supporting_text: 'ligand="ATP"'
  locations:
    - id: GO:0005829
      label: cytosol