MVK

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004496 mevalonate kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred core molecular function. Mevalonate kinase activity is the defining, experimentally established activity of this protein. 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. Supporting Evidence: PMID:9325256 cDNA encoding human mevalonate kinase has been overexpressed and the recombinant enzyme isolated. This stable enzyme is a dimer of 42-kDa subunits
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosolic localization, confirmed directly for the human enzyme by multiple biochemical and microscopy methods. Reason: Human MK was shown to be exclusively cytosolic; the IBA cytosol call is consistent with the direct experimental data (PMID:14730012). Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0006695 cholesterol biosynthetic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: MK catalyses an early committed step of the mevalonate pathway that ultimately supplies cholesterol biosynthesis. 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. Supporting Evidence: PMID:1377680 Mevalonic aciduria is the first proposed inherited disorder of the
GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:18302342 catalyzes a key reaction in polyisoprenoid and
GO:0004496 mevalonate kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of the core mevalonate kinase activity (ARBA/InterPro, EC 2.7.1.36, RHEA:17065). Reason: Consistent with the experimentally verified core activity; IEA mapping to the correct EC/RHEA reaction. Supporting Evidence: file:human/MVK/MVK-uniprot.txt Reaction=(R)-mevalonate + ATP = (R)-5-phosphomevalonate + ADP + H(+)
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	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. 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. Supporting Evidence: file:human/MVK/MVK-uniprot.txt KM=74 uM for ATP
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Cytoplasmic localization (parent of cytosol); consistent with the direct cytosolic evidence for human MK. Reason: Correct but less specific than the experimentally supported cytosol term; retained as a valid broader location. Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0008299 isoprenoid biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: MK acts within the mevalonate arm of isoprenoid biosynthesis; a valid but broad biological process. 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. Supporting Evidence: PMID:14680974 cholesterol/isoprenoid biosynthetic
GO:0016125 sterol metabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: MK contributes to sterol (cholesterol) metabolism as an upstream pathway enzyme. 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. Supporting Evidence: file:human/MVK/MVK-uniprot.txt Cholesterol metabolism
GO:0005515 protein binding	IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi...	MARK AS OVER ANNOTATED	Summary: Bare protein-binding IPI from a large-scale YFP protein-complementation screen (interaction with POT1/Q9NUX5). 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. Supporting Evidence: PMID:21044950 a large-scale screen for regulators of telomeres
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare protein-binding IPI from a systematic binary interactome map (interaction with RNF141/Q8WVD5). 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. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0042802 identical protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	ACCEPT	Summary: Self-interaction (Q03426–Q03426), consistent with the enzyme being a homodimer. 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). Supporting Evidence: PMID:9325256 This stable enzyme is a dimer of 42-kDa subunits
GO:0042802 identical protein binding	IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam...	ACCEPT	Summary: Self-interaction detected in a high-throughput variant-clone interactome pipeline; consistent with homodimerization. Reason: Corroborates the homodimeric state of MK; informative self-association term. Supporting Evidence: PMID:9325256 This stable enzyme is a dimer of 42-kDa subunits
GO:0042802 identical protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	ACCEPT	Summary: Self-interaction from an alternative-splicing interactome study; consistent with homodimerization. Reason: Corroborates MK homodimer formation. Supporting Evidence: PMID:9325256 This stable enzyme is a dimer of 42-kDa subunits
GO:0042802 identical protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	ACCEPT	Summary: Self-interaction from a population-variant interaction-disruption study; consistent with homodimerization. Reason: Corroborates MK homodimer formation. Supporting Evidence: PMID:9325256 This stable enzyme is a dimer of 42-kDa subunits
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	ACCEPT	Summary: Self-interaction (Q03426–Q03426) in the HuRI binary interactome; consistent with homodimerization. Reason: Corroborates MK homodimer formation; informative self-association term. Supporting Evidence: PMID:9325256 This stable enzyme is a dimer of 42-kDa subunits
GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway	IEA GO_REF:0000041	ACCEPT	Summary: UniPathway-based electronic assignment of the mevalonate-pathway isopentenyl diphosphate biosynthetic process. Reason: Matches the UniProt PATHWAY statement (step 1/3, isopentenyl diphosphate from (R)-mevalonate); duplicate of the IBA core BP call and equally valid. Supporting Evidence: file:human/MVK/MVK-uniprot.txt isopentenyl diphosphate from (R)-mevalonate
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence (HPA) supports cytosolic localization. Reason: Consistent with the definitive human cytosolic localization data (PMID:14730012). Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0004496 mevalonate kinase activity	EXP PMID:11278915 Investigation of invariant serine/threonine residues in meva...	ACCEPT	Summary: Experimentally verified mevalonate kinase activity via mutagenesis of invariant serine/threonine residues affecting KM(mevalonate) and Vmax. Reason: Direct experimental characterization of the human enzyme's kinase activity, including the catalytic Ser-146 and the disease-relevant T243. Supporting Evidence: PMID:11278915 V(max) for S146A is diminished by 4000-fold
GO:0004496 mevalonate kinase activity	EXP PMID:9392419 Post-translational regulation of mevalonate kinase by interm...	ACCEPT	Summary: Experimentally verified mevalonate kinase activity; recombinant human MK assayed and shown to be feedback-inhibited at the ATP site. Reason: Direct enzymatic assay of human MK confirms the core catalytic activity and its competitive inhibition by isoprenoid diphosphates. Supporting Evidence: PMID:9392419 only MKase was inhibited through competitive interaction at the ATP-binding site
GO:0005737 cytoplasm	EXP PMID:14730012 Mevalonate kinase is a cytosolic enzyme in humans.	ACCEPT	Summary: Experimental subcellular localization: human MK is cytoplasmic/cytosolic. Reason: Direct experimental evidence (fractionation, digitonin permeabilization, immunofluorescence, immunocytochemistry) for cytoplasmic localization. Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0005777 peroxisome	ISS GO_REF:0000024	REMOVE	Summary: Peroxisomal localization transferred by similarity from rat P17256. 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. Supporting Evidence: PMID:14730012 No indication of a peroxisomal localisation was obtained
GO:0000287 magnesium ion binding	ISS GO_REF:0000024	ACCEPT	Summary: Mg2+ binding, required cofactor for the kinase reaction (Mg-ATP), mapped to binding residues by similarity. 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. Supporting Evidence: file:human/MVK/MVK-uniprot.txt Name=Mg(2+); Xref=ChEBI:CHEBI:18420
GO:0004496 mevalonate kinase activity	IDA PMID:18302342 Biochemical and structural basis for feedback inhibition of ...	ACCEPT	Summary: Direct assay and crystal structure (PDB 2R3V) of human MK, confirming kinase activity and defining feedback inhibition by farnesyl thiodiphosphate. Reason: Structural/biochemical demonstration of the core catalytic activity and its regulation. Supporting Evidence: PMID:18302342 Farnesyl thiodiphosphate competes
GO:0005524 ATP binding	ISS GO_REF:0000024	ACCEPT	Summary: ATP binding transferred by similarity; ATP is the phosphate donor for the kinase reaction. Reason: Correct and directly supported by human kinetics and structure (KM(ATP), competitive feedback inhibition at the ATP site). Supporting Evidence: file:human/MVK/MVK-uniprot.txt KM=74 uM for ATP
GO:0004496 mevalonate kinase activity	IDA PMID:9325256 Identification of catalytic residues in human mevalonate kin...	ACCEPT	Summary: Direct assay of recombinant human MK; catalytic residues (Asp-204 base; Glu-193) identified by mutagenesis. Reason: Foundational direct characterization of the human enzyme's core kinase activity and catalytic mechanism. Supporting Evidence: PMID:9325256 support assignment of a crucial catalytic role to
GO:0042802 identical protein binding	IDA PMID:9325256 Identification of catalytic residues in human mevalonate kin...	ACCEPT	Summary: Homodimerization directly demonstrated: MK is a dimer of 42-kDa subunits. Reason: Informative self-association term directly supported by the biochemical demonstration that the enzyme is a homodimer. Supporting Evidence: PMID:9325256 This stable enzyme is a dimer of 42-kDa subunits
GO:0005829 cytosol	TAS Reactome:R-HSA-1655846	ACCEPT	Summary: Reactome curator assertion of cytosolic localization. Reason: Consistent with the definitive human cytosolic localization evidence. Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0005829 cytosol	TAS Reactome:R-HSA-191380	ACCEPT	Summary: Reactome curator assertion of cytosolic localization for the mevalonate-to-mevalonate-5-phosphate reaction. Reason: Consistent with the definitive human cytosolic localization evidence, and the Reactome reaction is the MK-catalysed step. Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0005777 peroxisome	IDA NOT PMID:14730012 Mevalonate kinase is a cytosolic enzyme in humans.	ACCEPT	Summary: NOT\|located_in peroxisome — direct experimental evidence that human MK is not peroxisomal. 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. Supporting Evidence: PMID:14730012 No indication of a peroxisomal localisation was obtained
GO:0050728 negative regulation of inflammatory response	IMP PMID:16732551 AA amyloidosis complicating hyperimmunoglobulinemia D with p...	MARK AS OVER ANNOTATED	Summary: Inferred anti-inflammatory role from the autoinflammatory phenotype of mevalonate kinase deficiency (HIDS), cited via an AA amyloidosis case report. 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. Supporting Evidence: PMID:16732551 hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
GO:0004496 mevalonate kinase activity	IMP PMID:10369261 Mutations in MVK, encoding mevalonate kinase, cause hyperimm...	ACCEPT	Summary: Reduced MK activity in HIDS patient cells demonstrates the enzyme's mevalonate kinase activity via mutational phenotype. Reason: HIDS mutations reduce MK enzymatic activity, confirming MVK encodes the mevalonate kinase activity; the IMP is well supported. Supporting Evidence: PMID:10369261 revealed reduced activities of mevalonate kinase
GO:0005829 cytosol	IDA PMID:14730012 Mevalonate kinase is a cytosolic enzyme in humans.	ACCEPT	Summary: Direct experimental cytosolic localization of human MK. Reason: Definitive direct evidence for cytosolic localization; the preferred, specific cellular-component annotation for this protein. Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0004496 mevalonate kinase activity	IDA PMID:1377680 Molecular cloning of human mevalonate kinase and identificat...	ACCEPT	Summary: Molecular cloning of human MVK and functional expression confirming mevalonate kinase activity; MEVA missense mutation reduces activity. Reason: Cloning + functional expression established the human enzyme's kinase activity and linked it to mevalonic aciduria. Supporting Evidence: PMID:1377680 confirmed that the mutation produced an
GO:0004496 mevalonate kinase activity	IDA PMID:14730012 Mevalonate kinase is a cytosolic enzyme in humans.	ACCEPT	Summary: Direct measurement of endogenous human MK enzymatic activity in the subcellular-localization study. Reason: Endogenous human MK activity was assayed (fractionation/permeabilization), confirming the core mevalonate kinase activity in a cytosolic context. Supporting Evidence: PMID:14730012 We exclusively found a cytosolic localisation of both endogenous human MK
GO:0006695 cholesterol biosynthetic process	IDA PMID:1377680 Molecular cloning of human mevalonate kinase and identificat...	KEEP AS NON CORE	Summary: MK function within the cholesterol/isoprene biosynthetic pathway, inferred from the mevalonic aciduria metabolic defect. 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). Supporting Evidence: PMID:1377680 Mevalonic aciduria is the first proposed inherited disorder of the
GO:0008299 isoprenoid biosynthetic process	IDA PMID:14730012 Mevalonate kinase is a cytosolic enzyme in humans.	ACCEPT	Summary: MK participates in isoprenoid biosynthesis; localization study frames MK within the isoprenoid/cholesterol pathway. Reason: Valid (broad) biological process for MK; the isoprenoid pathway role is well established. Supporting Evidence: PMID:14730012 isoprenoid/cholesterol biosynthesis
GO:0004496 mevalonate kinase activity	IDA PMID:14680974 Cholesterol biosynthesis is not defective in peroxisome biog...	ACCEPT	Summary: MK enzymatic activity measured directly in fibroblasts (activity present and peroxisome-independent). Reason: Direct activity measurement of human MK; supports the core kinase function and confirms it does not require peroxisomes. Supporting Evidence: PMID:14680974 all enzymes measured are at least as active in
GO:0008299 isoprenoid biosynthetic process	IDA PMID:14680974 Cholesterol biosynthesis is not defective in peroxisome biog...	ACCEPT	Summary: MK operates in the cholesterol/isoprenoid biosynthetic pathway, independent of peroxisomes. Reason: Valid biological process; the study measured MK as one of the presqualene-segment cholesterol/isoprenoid enzymes. Supporting Evidence: PMID:14680974 cholesterol/isoprenoid biosynthetic

Gene Description

Existing Annotations Review

Core Functions

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.

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.

Magnesium ion binding: Mg2+ is the required cofactor coordinated with ATP for phosphoryl transfer.

Mevalonate kinase is a cytosolic enzyme in humans.

References

📚 Additional Documentation

Notes

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