MVD is human diphosphomevalonate decarboxylase (mevalonate-5-diphosphate decarboxylase; EC 4.1.1.33), the enzyme that catalyses the final step of the mevalonate pathway. It performs the ATP-dependent decarboxylation of (R)-5-diphosphomevalonate (mevalonate-5-diphosphate) to isopentenyl diphosphate (IPP), releasing CO2, ADP and inorganic phosphate. IPP is the fundamental five-carbon (C5) isoprenoid building block from which all downstream isoprenoids are assembled, so MVD sits at the point where the mevalonate pathway delivers activated isoprene units for sterol (cholesterol) biosynthesis and for the non-sterol isoprenoid branches (dolichol, ubiquinone, and the prenyl groups used in protein prenylation). The protein is a member of the GHMP kinase superfamily, binds ATP, and functions as a homodimer of ~43-kDa subunits. It is a soluble cytosolic enzyme. In humans, loss-of-function and missense variants in MVD (together with MVK, the two principal porokeratosis genes) cause porokeratosis (POROK7), a disorder of faulty epidermal keratinization characterised by the cornoid lamella.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004163 diphosphomevalonate decarboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core catalytic molecular function of MVD, propagated by phylogenetic inference across the diphosphomevalonate decarboxylase family and strongly corroborated by direct human experimental evidence. Reason: This is the defining molecular function of MVD (EC 4.1.1.33): ATP-dependent decarboxylation of (R)-5-diphosphomevalonate to isopentenyl diphosphate. The IBA is consistent with human biochemical and structural characterization. Supporting Evidence: PMID:18823933 Mevalonate diphosphate decarboxyase (MDD1; EC 4.1.1.33) catalyzes the ATP dependent decarboxylation of mevalonate 5-diphosphate (MVAPP) to form isopentenyl 5-diphosphate file:human/MVD/MVD-uniprot.txt Catalyzes the ATP dependent decarboxylation of (R)-5- |
| GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Precise biological process for MVD: it produces isopentenyl diphosphate (IPP) as the final step of the mevalonate pathway. Reason: MVD's product is IPP, and the enzyme catalyses the terminal mevalonate-pathway step that generates it. This term captures the direct biological process at the correct level of specificity and is the best core BP term. Supporting Evidence: PMID:18823933 catalyzes the ATP dependent decarboxylation of mevalonate 5-diphosphate (MVAPP) to form isopentenyl 5-diphosphate file:human/MVD/MVD-uniprot.txt Functions in CC the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP) |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: MVD is a soluble cytosolic enzyme; the phylogenetically inferred cytosolic localization matches direct human experimental evidence. Reason: Direct subcellular fractionation, immunofluorescence and immunoelectron microscopy established a cytosolic localization for human MVD, with no peroxisomal signal. Supporting Evidence: PMID:14972328 We found a cytosolic localization for both endogenous human mevalonate pyrophosphate decarboxylase |
| GO:0004163 diphosphomevalonate decarboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/InterPro/RHEA/EC) assignment of the core catalytic function, redundant with the experimental and IBA annotations. Reason: Correctly maps the specific diphosphomevalonate decarboxylase activity (EC 4.1.1.33, RHEA:23732) to MVD; concordant with experimental evidence. Supporting Evidence: file:human/MVD/MVD-uniprot.txt EC=4.1.1.33 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Broader cytoplasmic localization from the UniProt subcellular-location mapping; correct but less specific than cytosol. Reason: UniProt annotates MVD as cytoplasmic, consistent with its established cytosolic localization. This parent term is correct though the more specific GO:0005829 (cytosol) is preferred. Supporting Evidence: file:human/MVD/MVD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Automated cytosol localization consistent with experimental evidence. Reason: Correct; MVD is cytosolic (established experimentally in PMID:14972328). Supporting Evidence: PMID:14972328 but no indication for a peroxisomal localization |
| GO:0008299 isoprenoid biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Broader isoprenoid biosynthesis framing; MVD produces IPP, the universal isoprenoid precursor. Reason: True but general parent of the more precise GO:0019287. Retained as an accurate higher-level BP: MVD's product IPP is the substrate for all isoprenoid biosynthesis. Supporting Evidence: PMID:18823933 The reaction is required for production of polyisoprenoids and sterols from acetyl-CoA. |
| GO:0016831 carboxy-lyase activity | IEA GO_REF:0000002 | MODIFY | Summary: Broad InterPro2GO molecular-function parent of the specific diphosphomevalonate decarboxylase activity. Reason: MVD is a decarboxylase (carboxy-lyase), so this term is not wrong, but it is an uninformative parent of the specific GO:0004163 diphosphomevalonate decarboxylase activity which is experimentally established. Replace with the specific term. Proposed replacements: diphosphomevalonate decarboxylase activity Supporting Evidence: PMID:18823933 catalyzes the ATP dependent decarboxylation of mevalonate 5-diphosphate (MVAPP) to form isopentenyl 5-diphosphate |
| GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Automated (InterPro2GO) assignment of the precise mevalonate-pathway IPP biosynthesis process, redundant with the IBA. Reason: Correct and specific; MVD produces IPP as the terminal mevalonate-pathway step. Supporting Evidence: file:human/MVD/MVD-uniprot.txt Functions in CC the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP) |
| GO:0006695 cholesterol biosynthetic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived link to cholesterol biosynthesis. MVD feeds the sterol branch but its direct product is IPP, upstream of the sterol/non-sterol branch point. Reason: Cholesterol biosynthesis is a downstream consequence of MVD activity rather than its direct process: MVD makes IPP, which supplies both sterol (cholesterol) and many non-sterol isoprenoid branches (dolichol, ubiquinone, prenyl groups). The accurate direct BP is the mevalonate-pathway IPP biosynthesis (GO:0019287). Retain as a valid non-core downstream pathway association. Supporting Evidence: file:human/MVD/MVD-uniprot.txt a key precursor for the biosynthesis of isoprenoids and sterol file:human/MVD/MVD-uniprot.txt PATHWAY: Steroid biosynthesis; cholesterol biosynthesis. |
| GO:0005737 cytoplasm | IDA PMID:14972328 Human mevalonate pyrophosphate decarboxylase is localized in... | ACCEPT | Summary: Experimental cytoplasmic/cytosolic localization of human MVD. Reason: Directly supported by the localization study; MVD is active in the cytosol (cytoplasm). GO:0005829 (cytosol) is the more specific form of the same finding. Supporting Evidence: PMID:14972328 We found a cytosolic localization for both endogenous human mevalonate pyrophosphate decarboxylase |
| GO:0004163 diphosphomevalonate decarboxylase activity | EXP PMID:18823933 Human mevalonate diphosphate decarboxylase: characterization... | ACCEPT | Summary: Direct experimental characterization of recombinant human MVD's diphosphomevalonate decarboxylase activity, including kinetics and active-site mutagenesis, backed by a crystal structure. Reason: Gold-standard experimental support for the core catalytic function. Kinetic parameters were measured and active-site residues (R161, N17) validated; R161Q causes ~1000-fold loss of activity. Supporting Evidence: PMID:18823933 Mevalonate diphosphate decarboxyase (MDD1; EC 4.1.1.33) catalyzes the ATP dependent decarboxylation of mevalonate 5-diphosphate (MVAPP) to form isopentenyl 5-diphosphate PMID:18823933 R161Q exhibits a approximately 1000-fold diminution in specific activity |
| GO:0004163 diphosphomevalonate decarboxylase activity | EXP PMID:8626466 Molecular cloning and expression of the cDNAs encoding human... | ACCEPT | Summary: Cloning/expression paper showing recombinant human MVD has decarboxylase activity (2.4 units/mg). Reason: Experimental confirmation of the core catalytic function; duplicate of the other GO:0004163 catalytic annotations. Supporting Evidence: PMID:8626466 The recombinant human enzyme is a homodimer of 43-kDa subunits with a specific activity of 2.4 units/mg. |
| GO:0004163 diphosphomevalonate decarboxylase activity | EXP PMID:9392419 Post-translational regulation of mevalonate kinase by interm... | ACCEPT | Summary: Recombinant human MDDase (MVD) was expressed, purified and assayed as part of a mevalonate-pathway feedback-inhibition study. Reason: Experimental support for the decarboxylase activity; MVD's KM for (R)-5-diphosphomevalonate was determined. Duplicate of the core catalytic annotation. Supporting Evidence: PMID:9392419 mevalonate diphosphate decarboxylase (MDDase) file:human/MVD/MVD-uniprot.txt KM=7.4 uM for (R)-5-diphosphomevalonate {ECO:0000269|PubMed:9392419} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655836 | ACCEPT | Summary: Reactome traceable assertion placing MVD in the cytosol. Reason: Consistent with the experimentally established cytosolic localization of MVD. Supporting Evidence: PMID:14972328 Human mevalonate pyrophosphate decarboxylase is localized in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-191414 | ACCEPT | Summary: Reactome traceable assertion (MVD decarboxylates MVA5PP to IPPP reaction) placing MVD in the cytosol. Reason: Consistent with the experimentally established cytosolic localization; the cited Reactome reaction is exactly the MVD decarboxylation of mevalonate-5-diphosphate to IPP. Supporting Evidence: PMID:14972328 Human mevalonate pyrophosphate decarboxylase is localized in the cytosol. |
| GO:0004163 diphosphomevalonate decarboxylase activity | IDA PMID:11792727 Absence of functional peroxisomes does not lead to deficienc... | ACCEPT | Summary: MVD (MPD) decarboxylase activity measured directly in human/mouse tissue in a study of MVA-pathway enzyme activities. Reason: Direct activity measurement of MVD supports the core catalytic function (duplicate of the other GO:0004163 annotations). Supporting Evidence: PMID:11792727 mislocalization of enzymes to the cytosol does not lead to decreased activity or |
| GO:0004163 diphosphomevalonate decarboxylase activity | IDA PMID:14680974 Cholesterol biosynthesis is not defective in peroxisome biog... | ACCEPT | Summary: MVD (mevalonate pyrophosphate decarboxylase) activity measured directly among presqualene MVA/isoprenoid enzymes in PBD fibroblasts. Reason: Direct activity measurement supports the core catalytic function (duplicate of the other GO:0004163 annotations). Supporting Evidence: PMID:14680974 mevalonate pyrophosphate decarboxylase |
| GO:0006695 cholesterol biosynthetic process | NAS PMID:14680974 Cholesterol biosynthesis is not defective in peroxisome biog... | KEEP AS NON CORE | Summary: Author-stated (NAS) placement of MVD in the cholesterol/isoprenoid biosynthetic pathway. Reason: MVD is one of the presqualene enzymes of the cholesterol/isoprenoid pathway, but cholesterol synthesis is downstream of MVD's direct product IPP (which also feeds non-sterol branches). Accurate as a non-core downstream pathway association; the precise direct BP is the mevalonate-pathway IPP biosynthesis. Supporting Evidence: PMID:14680974 five different enzymes of the presqualene segment of the cholesterol/isoprenoid biosynthetic pathway |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:9270019 Regulation of proliferation and Ras localization in transfor... | KEEP AS NON CORE | Summary: Inhibiting MVD with 6-fluoromevalonate (Fmev) blocks production of downstream mevalonate products, prevents Ras prenylation/membrane localization, and suppresses proliferation of transformed cells. Reason: This is a pathway-level, indirect effect: MVD activity is required to make IPP and hence the prenyl groups that drive Ras-dependent proliferation. It reflects a physiological consequence of MVD's metabolic role rather than a distinct signalling function of the protein. Retain as a non-core process rather than a core molecular function. Per curation policy this experimental (IMP) annotation is not removed. Supporting Evidence: PMID:9270019 6-fluoromevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase PMID:9270019 completely prevented the proliferation of U-937 cells |
| GO:0008299 isoprenoid biosynthetic process | IDA PMID:11792727 Absence of functional peroxisomes does not lead to deficienc... | ACCEPT | Summary: Experimental support for MVD participation in isoprenoid/cholesterol biosynthesis (MVA-pathway enzyme activities measured). Reason: Broad but accurate: MVD produces IPP, the universal isoprenoid precursor. GO:0019287 is the more precise BP; this parent is retained as correct. Supporting Evidence: PMID:11792727 enzymes involved in cholesterol biosynthesis |
| GO:0008299 isoprenoid biosynthetic process | IDA PMID:14680974 Cholesterol biosynthesis is not defective in peroxisome biog... | ACCEPT | Summary: Experimental support for MVD participation in the cholesterol/isoprenoid biosynthetic pathway. Reason: Accurate higher-level BP; MVD's product IPP is the isoprenoid building block. GO:0019287 is the precise process; this parent is retained as correct. Supporting Evidence: PMID:14680974 cholesterol/isoprenoid biosynthetic pathway |
| GO:0030544 Hsp70 protein binding | IPI PMID:12646231 Mortalin-MPD (mevalonate pyrophosphate decarboxylase) intera... | MARK AS OVER ANNOTATED | Summary: MVD (MPD) was identified in a yeast two-hybrid screen and co-IP as an interactor of mortalin (mot-2/GRP75), a member of the HSP70 family, in a study of proliferation control. Reason: A physical interaction with an HSP70-family chaperone (mortalin) is a protein-binding-type annotation that does not describe MVD's core catalytic molecular function; it is peripheral to why MVD exists (isoprenoid synthesis). Per curation policy this experimental (IPI) annotation is not removed but is flagged as an over-annotation relative to the enzyme's function. Supporting Evidence: PMID:12646231 Mevalonate pyrophosphate decarboxylase (MPD) was identified as one of the mortalin binding partners |
| GO:0042803 protein homodimerization activity | IDA PMID:8626466 Molecular cloning and expression of the cDNAs encoding human... | KEEP AS NON CORE | Summary: Recombinant human MVD is a homodimer of ~43-kDa subunits. Reason: Homodimerization is an experimentally supported structural property of the enzyme (also stated as SUBUNIT: Homodimer in UniProt), but it is a quaternary structure feature rather than MVD's core catalytic function. Retain as non-core. Supporting Evidence: PMID:8626466 The recombinant human enzyme is a homodimer of 43-kDa subunits file:human/MVD/MVD-uniprot.txt SUBUNIT: Homodimer. |
| GO:0005777 peroxisome | IDA NOT PMID:14972328 Human mevalonate pyrophosphate decarboxylase is localized in... | ACCEPT | Summary: MVD is explicitly NOT located in the peroxisome; earlier peroxisomal claims were refuted by direct localization studies. Reason: The negated annotation is correct and important: careful subcellular fractionation and microscopy found no peroxisomal MVD, overturning earlier reports of a peroxisomal targeting signal. UniProt records the same correction in its CAUTION note. Supporting Evidence: PMID:14972328 but no indication for a peroxisomal localization file:human/MVD/MVD-uniprot.txt However, was later shown to be cytosolic |
| GO:0005829 cytosol | IDA PMID:14972328 Human mevalonate pyrophosphate decarboxylase is localized in... | ACCEPT | Summary: Direct experimental evidence that human MVD is a cytosolic protein. Reason: The definitive localization study; MVD is cytosolic in fibroblasts, liver, CV1 and HEK293 cells by fractionation, immunofluorescence and immunoelectron microscopy. Supporting Evidence: PMID:14972328 We found a cytosolic localization for both endogenous human mevalonate pyrophosphate decarboxylase |
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Experiment: Structure-guided kinetic characterization of the full panel of POROK7 missense variants to quantify how each affects diphosphomevalonate decarboxylase activity and homodimer stability, correlating biochemical severity with clinical presentation.
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