ERG19 (MVD1; ORF YNR043W) encodes diphosphomevalonate decarboxylase (mevalonate-5-diphosphate decarboxylase, MDD/MVD; EC 4.1.1.33), a cytosolic homodimeric enzyme that catalyzes the third and final step of the mevalonate module of isoprenoid biosynthesis. It performs the ATP-dependent decarboxylation of (R)-5-diphosphomevalonate to isopentenyl diphosphate (IPP), releasing CO2, ADP and inorganic phosphate. IPP is the universal C5 building block of all isoprenoids, and in yeast feeds the downstream synthesis of farnesyl diphosphate and thence ergosterol, dolichol, ubiquinone, heme A and prenylated proteins. Mechanistically the enzyme couples an ATP-dependent phosphorylation of the substrate 3-hydroxyl to elimination/decarboxylation, and it belongs to the GHMP kinase superfamily; its two-domain fold is known from the crystal structure (PDB 1FI4). ERG19 is essential for viability, and loss-of-function mutants are ergosterol auxotrophs.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred cytosolic localization, consistent with the experimental GFP localization of the yeast protein to the cytoplasm. Reason: MDD is a soluble cytosolic enzyme of the mevalonate pathway. The IBA call agrees with the HDA cytoplasm annotation for this protein and with the general localization of mevalonate-module enzymes; this is the appropriate compartment annotation. Supporting Evidence: PMID:14562095 Here we describe the construction and analysis of a collection of yeast strains expressing full-length, chromosomally tagged green fluorescent protein fusion proteins. |
| GO:0004163 diphosphomevalonate decarboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function. Electronic mapping from InterPro/RHEA/EC:4.1.1.33, and it is directly confirmed by enzymatic assay of the cloned yeast enzyme. Reason: The EC/RHEA-backed electronic annotation matches the experimentally demonstrated activity (the recombinant yeast enzyme catalyzes diphosphomevalonate decarboxylation). This is the central, correct molecular function of ERG19. Supporting Evidence: PMID:8626466 We also cloned and expressed the yeast homolog using the human enzyme's similarity to a previously unidentified and incomplete genomic sequence. |
| GO:0005829 cytosol | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-to-GO electronic localization to cytosol, consistent with the experimental and phylogenetic localization of this enzyme. Reason: Redundant with the IBA and HDA cytosol/cytoplasm annotations but correct; MDD is a cytosolic enzyme. Supporting Evidence: PMID:14562095 we classify these proteins, representing 75% of the yeast proteome, into 22 distinct subcellular localization categories |
| GO:0008299 isoprenoid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: Broad but correct grouping term; the IPP made by ERG19 is the universal precursor of all isoprenoids. Reason: This is a true high-level parent of the enzyme's specific role (IPP biosynthesis via the mevalonate pathway). An IEA annotation broader than the IBA/experimental terms is acceptable here and provides useful pathway context. Supporting Evidence: PMID:8626466 Because mevalonate pyrophosphate decarboxylase is a unique enzyme in the cholesterol biosynthetic pathway it is a potential therapeutic target |
| GO:0016831 carboxy-lyase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic parent molecular-function term (carboxy-lyase) that is subsumed by the specific, experimentally supported GO:0004163. Reason: GO:0016831 is a direct parent of diphosphomevalonate decarboxylase activity and is uninformatively general for a single-function enzyme whose specific activity is well established. Replace with the specific child term, which is already present with experimental (IDA/IMP) support. Proposed replacements: diphosphomevalonate decarboxylase activity Supporting Evidence: PMID:15169949 Identification of active site residues in mevalonate diphosphate decarboxylase: implications for a family of phosphotransferases. |
| GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Most precise biological-process term for ERG19 - it catalyzes the final, committed step that produces IPP in the mevalonate pathway. Reason: This term exactly captures the direct biological role of the enzyme (IPP from mevalonate, step 3/3 of UniPathway UPA00057). Strongly supported by the catalytic reaction and pathway placement. Supporting Evidence: PMID:8626466 We also cloned and expressed the yeast homolog using the human enzyme's similarity to a previously unidentified and incomplete genomic sequence. |
| GO:0004163 diphosphomevalonate decarboxylase activity | RCA GO_REF:0000123 | ACCEPT | Summary: Core molecular function, derived computationally from YeastPathways; identical to the experimentally validated activity. Reason: Correct and central function; duplicate of the IDA/IMP/IEA annotations to the same term. Duplicates across evidence codes are acceptable. Supporting Evidence: PMID:8626466 We also cloned and expressed the yeast homolog using the human enzyme's similarity to a previously unidentified and incomplete genomic sequence. |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: Computationally inferred cytosolic site of action, consistent with experimental localization. Reason: Agrees with the IBA/IEA/HDA cytosol-cytoplasm annotations; MDD acts in the cytosol. Supporting Evidence: PMID:14562095 Here we describe the construction and analysis of a collection of yeast strains expressing full-length, chromosomally tagged green fluorescent protein fusion proteins. |
| GO:0006696 ergosterol biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: Pathway-level process annotation; ERG19 is an essential, named (ERG) enzyme required for ergosterol biosynthesis. Reason: ERG19 is genetically required for ergosterol production (erg19 mutants are ergosterol auxotrophs and the gene is essential), so involvement in ergosterol biosynthetic process is well supported. It is a downstream end-product pathway relative to the enzyme's direct IPP-producing step, but is the defining physiological process for this gene. Supporting Evidence: PMID:1779710 Yeast mutant strains auxotrophic for ergosterol and blocked in mevalonate diphosphate decarboxylase (erg19) PMID:9244250 the ERG19 gene, which was shown to be an essential gene for yeast, was disrupted |
| GO:0008299 isoprenoid biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: Broad grouping process term; correct as the enzyme produces the universal isoprenoid precursor IPP. Reason: True parent process. Duplicate of the IEA isoprenoid biosynthetic process annotation; retained as informative pathway context. Supporting Evidence: PMID:8626466 Because mevalonate pyrophosphate decarboxylase is a unique enzyme in the cholesterol biosynthetic pathway it is a potential therapeutic target |
| GO:0010142 farnesyl diphosphate biosynthetic process, mevalonate pathway | RCA GO_REF:0000123 | REMOVE | Summary: Downstream pathway-membership term derived from the FPP biosynthesis YeastPathway (PWY-922). ERG19's direct product is IPP, which is consumed several steps later to make farnesyl diphosphate. Reason: The enzyme does not itself synthesize farnesyl diphosphate; FPP is produced downstream by the isomerase (IDI1) and FPP synthase (ERG20) acting on the IPP that ERG19 makes. GO:0010142 is obsolete in the GO release 2026-07-26 (consider GO:0019287 or GO:0045337). Of the two, only GO:0019287 isopentenyl diphosphate biosynthetic process, mevalonate pathway describes a step ERG19 performs (the final decarboxylation to IPP); GO:0045337 covers the downstream IDI1/ERG20 steps. GO:0019287 is already annotated to ERG19 (IEA row, ACCEPTed with independent support), so remapping this obsolete RCA row would only duplicate it; the row is removed. Supporting Evidence: PMID:1779710 the isolation of the functional ERG20 gene allowed us to show that farnesyl diphosphate synthetase could be a rate limiting enzyme in ergosterol biosynthesis |
| GO:0004163 diphosphomevalonate decarboxylase activity | IDA PMID:8626466 Molecular cloning and expression of the cDNAs encoding human... | ACCEPT | Summary: Direct biochemical demonstration of diphosphomevalonate decarboxylase activity for the cloned, expressed yeast enzyme. Reason: Experimental (IDA) confirmation of the core molecular function. The recombinant enzyme has measurable specific activity and is a homodimer, matching the curated EC 4.1.1.33 assignment. Supporting Evidence: PMID:8626466 We also cloned and expressed the yeast homolog using the human enzyme's similarity to a previously unidentified and incomplete genomic sequence. |
| GO:0005773 vacuole | NAS PMID:28904410 Recent Advances in Ergosterol Biosynthesis and Regulation Me... | MARK AS OVER ANNOTATED | Summary: Non-traceable author statement (from a review) placing the farnesyl-PP/"second module" of ergosterol biosynthesis in the vacuole. This conflicts with the experimental cytoplasmic/cytosolic localization of MDD. Reason: The vacuole annotation rests on a review-level compartmentalization statement (NAS), not on a direct localization assay of MDD, whereas the genome-wide GFP study (HDA) and the phylogenetic/InterPro annotations all place the protein in the cytoplasm/cytosol. MDD is a soluble cytosolic mevalonate-module enzyme; a vacuolar site of action is not supported by direct evidence and is likely an over-annotation. Retained (not removed) because a published source asserts it, but flagged as weakly supported and contradicted by experimental localization. Supporting Evidence: PMID:14562095 we classify these proteins, representing 75% of the yeast proteome, into 22 distinct subcellular localization categories, and provide localization information for 70% of previously unlocalized proteins file:yeast/ERG19/ERG19-deep-research-falcon.md The relevant mevalonate/IPP-producing enzymes, including the second module, are described as predominantly cytoplasmic, supporting cytosolic localization for Mvd1/Erg19 in yeast. Garay also describes fungal MDD as a cytosolic homodimer. |
| GO:0006696 ergosterol biosynthetic process | IDA PMID:8626466 Molecular cloning and expression of the cDNAs encoding human... | ACCEPT | Summary: Involvement in ergosterol biosynthesis, supported by the enzyme's demonstrated activity in this branch of the pathway. Reason: ERG19 catalyzes an essential, non-bypassable step required for ergosterol production; its involvement in ergosterol biosynthetic process is well established by both biochemistry and the ergosterol-auxotroph mutant phenotype. This is the defining physiological process for the gene (hence the ERG nomenclature). Supporting Evidence: PMID:8626466 We also cloned and expressed the yeast homolog using the human enzyme's similarity to a previously unidentified and incomplete genomic sequence. PMID:1779710 Yeast mutant strains auxotrophic for ergosterol and blocked in mevalonate diphosphate decarboxylase (erg19) |
| GO:0005737 cytoplasm | HDA PMID:14562095 Global analysis of protein localization in budding yeast. | ACCEPT | Summary: High-throughput GFP-fusion localization of MVD1/ERG19 to the cytoplasm. Reason: Experimental (HDA) localization evidence consistent with the cytosol annotations. Cytoplasm is a broader but correct compartment for this soluble enzyme. Supporting Evidence: PMID:14562095 provide localization information for 70% of previously unlocalized proteins |
| GO:0004163 diphosphomevalonate decarboxylase activity | IDA PMID:15169949 Identification of active site residues in mevalonate diphosp... | ACCEPT | Summary: Direct assay of diphosphomevalonate decarboxylase activity in the context of active-site residue characterization (Asp302, Lys18). Reason: Experimental confirmation of the core molecular function; kinetic analysis of wild-type and active-site mutants directly measures MDD activity and ATP utilization. Supporting Evidence: PMID:15169949 The 10(3) and 10(5)-fold decreases in k(cat) observed for the Asp 302 mutants (D302N and D302A, respectively) support assignment of a crucial catalytic role to Asp 302. |
| GO:0004163 diphosphomevalonate decarboxylase activity | IMP PMID:15169949 Identification of active site residues in mevalonate diphosp... | ACCEPT | Summary: Mutant-phenotype evidence (active-site mutants with reduced kcat) supporting the diphosphomevalonate decarboxylase activity assignment. Reason: The functional importance of active-site residues was established by site-directed mutagenesis and kinetic loss of activity, supporting the core MF by IMP. Supporting Evidence: PMID:15169949 A 30-fold decrease in activity and a 16-fold inflation of the K(m) for ATP is documented for the K18M mutant |
| GO:0004163 diphosphomevalonate decarboxylase activity | IMP PMID:1779710 Sterol pathway in yeast. Identification and properties of mu... | ACCEPT | Summary: Classic erg19 mutants are blocked in mevalonate diphosphate decarboxylase activity, linking the gene to this enzymatic function by mutant phenotype. Reason: The founding genetic characterization isolated erg19 strains specifically defective in MDD activity, supporting the molecular function assignment by IMP. Supporting Evidence: PMID:1779710 Yeast mutant strains auxotrophic for ergosterol and blocked in mevalonate diphosphate decarboxylase (erg19) and farnesyl diphosphate (FPP) synthetase (erg20) were isolated |
| GO:0016126 sterol biosynthetic process | IMP PMID:9244250 The Saccharomyces cerevisiae mevalonate diphosphate decarbox... | ACCEPT | Summary: Mutant-phenotype evidence that ERG19 is required for sterol biosynthesis; the gene is essential and overexpression alters sterol steady-state levels. Reason: Sterol biosynthetic process is a parent of ergosterol biosynthetic process and is directly supported by the essentiality and sterol phenotypes of ERG19 mutants. A correct, experimentally grounded pathway-process annotation. Supporting Evidence: PMID:9244250 a high level of expression of the wild-type ERG19 gene led to a lower sterol steady-state accumulation compared to that of a wild-type strain, suggesting that this enzyme may be a key enzyme in mevalonate pathway regulation |
| GO:0005524 ATP binding | IDA PMID:15169949 Identification of active site residues in mevalonate diphosp... | NEW | Summary: ATP is an obligatory co-substrate of the decarboxylase reaction; nucleotide (TNP-ATP) binding and ATP-dependent kinetics were directly measured, and ATP binding is captured by UniProt (keyword/feature) but is missing from the GOA set. Reason: The enzyme uses ATP to phosphorylate the substrate 3-hydroxyl prior to decarboxylation; active-site mutant studies measured stoichiometric nucleotide binding and ATP Km, and the GHMP-kinase-superfamily structure (PDB 1FI4) shows the small-molecule-kinase fold that binds ATP. UniProt annotates ATP-binding (GO:0005524). Adding this molecular function makes the ATP-dependent mechanism explicit. Supporting Evidence: PMID:15169949 these mutant enzymes (D302A, D302N, K18M) retain the ability to stoichiometrically bind nucleotide triphosphates at the active site PMID:15169949 A 30-fold decrease in activity and a 16-fold inflation of the K(m) for ATP is documented for the K18M mutant PMID:11698677 Mevalonate-5-diphosphate decarboxylase (MDD) is a single-domain alpha/beta protein that catalyzes the last of three sequential ATP-dependent reactions which convert mevalonate to isopentenyl diphosphate PMID:11698677 MDD is a member of the GHMP superfamily of small-molecule kinases |
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Download this section (compressed HTML)Q: Does ERG19/MDD have any moonlighting or regulatory role beyond catalysis, given that ERG19 overexpression lowers steady-state sterol levels?
Q: Is there any genuine non-cytosolic (e.g. vacuolar or peroxisomal) pool of MDD in yeast, or is the vacuole assignment purely a review-level pathway-compartment inference?
Experiment: Determine the high-resolution structure of MDD in complex with substrate and an ATP analog to confirm the proposed catalytic roles of Asp302 and Lys18 and the phosphorylation-then-decarboxylation mechanism.
Experiment: Use high-resolution / quantitative imaging (e.g. endogenous tagging plus organelle markers) to test whether any fraction of MDD localizes outside the cytosol, resolving the cytosol-versus-vacuole annotation discrepancy.
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