ERG1 (YGR175C) encodes squalene epoxidase (squalene monooxygenase, EC 1.14.14.17), which converts squalene to (3S)-2,3-epoxysqualene (2,3-oxidosqualene), the first oxygen-dependent step of the sterol branch and the substrate for lanosterol synthase Erg7. The enzyme is a membrane-bound flavoprotein of the squalene monooxygenase family that draws electrons from NADPH via NADPH-cytochrome P450 reductase; it is a rate-limiting step of ergosterol synthesis and the target of allylamine antifungals such as terbinafine. Erg1p is distributed between the ER membrane and lipid droplets, but catalytic activity is detected only in the ER, the LD pool requiring an ER factor for activity. erg1 mutants are ergosterol auxotrophs. Erg1p is anchored in the ER membrane by a hairpin that is recognised by Get3, so its targeting, especially its rapid upregulation under low-sterol conditions, depends on the GET pathway. Its abundance is also controlled by ER-associated degradation through the Doa10-Ubc7 ubiquitin ligase, which is triggered when membrane lipids become saturated.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004506 squalene monooxygenase activity | EXP PMID:1743514 The gene encoding squalene epoxidase from Saccharomyces cere... | ACCEPT | Summary: Jandrositz et al. 1991 cloned ERG1 from an allylamine-resistant mutant and showed that squalene epoxidase activity in cell-free extracts of the transformant was terbinafine-resistant, tying the epoxidase activity to the ERG1 gene product. Squalene epoxidation is the core catalytic activity of Erg1. Supporting Evidence: PMID:1743514 The ERG tested in a cell-free extract from one of these transformants proved to be resistant to the Al derivative, terbinafine. file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0004506 squalene monooxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the squalene monooxygenase clade (PTN000089417), with human SQLE, mouse/rat Sqle, C. albicans ERG1 and Erg1 itself among the experimentally annotated descendants. Erg1 is a clear member of this family and its own activity is experimentally established, so the inherited assertion is sound. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt SIMILARITY: Belongs to the squalene monooxygenase family. file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0004506 squalene monooxygenase activity | IDA PMID:8358382 Enzymatic properties of squalene epoxidase from Saccharomyce... | ACCEPT | Summary: Satoh et al. 1993 characterised squalene epoxidase from S. cerevisiae microsomes (NADPH-dependent, Km 13.5 uM for squalene, terbinafine-sensitive). Direct assay of the activity attributed to Erg1. Supporting Evidence: PMID:8358382 S. cerevisiae squalene epoxidase required NADPH for enzyme reaction |
| GO:0004506 squalene monooxygenase activity | IDA PMID:9450962 Dual localization of squalene epoxidase, Erg1p, in yeast ref... | ACCEPT | Summary: Leber et al. 1998 measured squalene epoxidase activity in subcellular fractions: Erg1p was absent from an erg1 disruptant, and the activity was present in ER membranes. Direct evidence for the activity of the ERG1 product. Supporting Evidence: PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0004506 squalene monooxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA from InterPro squalene epoxidase signatures (IPR013698, IPR040125), RHEA:25282 and EC 1.14.14.17. Correct for Erg1; redundant with the experimental annotations. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- file:yeast/ERG1/ERG1-uniprot.txt SIMILARITY: Belongs to the squalene monooxygenase family. |
| GO:0004506 squalene monooxygenase activity | IMP PMID:200835 Ertosterol biosynthesis in Saccharomyces cerevisiae: mutants... | ACCEPT | Summary: Karst and Lacroute 1977 isolated thermosensitive ergosterol auxotrophs; the erg1 complementation group lacked squalene epoxidase activity. Loss-of-function evidence for the activity. Supporting Evidence: PMID:200835 Thermosensitive mutants, auxotrophic for ergosterol synthesis, have been isolated |
| GO:0004506 squalene monooxygenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (SGD_PWY:ERGOSTEROL-SYN-PWY-1, 'ergosterol biosynthesis') assigns squalene + reduced NADPH-hemoprotein reductase + O2 -> (3S)-2,3-epoxysqualene (EC 1.14.14.17) to Erg1. This is the correct reaction and electron donor for the yeast enzyme, which needs NADPH and the P450 reductase rather than free FAD. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0004506 squalene monooxygenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (SGD_PWY:PWY-5670-1, 'epoxysqualene biosynthesis') assigns squalene + reduced NADPH-hemoprotein reductase + O2 -> (3S)-2,3-epoxysqualene (EC 1.14.14.17) to Erg1. This is the correct reaction and electron donor for the yeast enzyme, which needs NADPH and the P450 reductase rather than free FAD. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0004506 squalene monooxygenase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (SGD_PWY:PWY3O-31704, 'superpathway of ergosterol biosynthesis I') assigns squalene + reduced NADPH-hemoprotein reductase + O2 -> (3S)-2,3-epoxysqualene (EC 1.14.14.17) to Erg1. This is the correct reaction and electron donor for the yeast enzyme, which needs NADPH and the P450 reductase rather than free FAD. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0005783 endoplasmic reticulum | HDA PMID:26928762 One library to make them all: streamlining the creation of y... | ACCEPT | Summary: Genome-wide N-terminal SWAT-GFP imaging (Yofe et al. 2016) placed Erg1 in the ER, consistent with the fractionation and immunofluorescence data. Supporting Evidence: PMID:26928762 we were able to uncover the sub-cellular localization of hundreds of proteins never visualized before PMID:9450962 62% of cellular Erg1p could be assigned to the endoplasmic reticulum and 38% to lipid particles in late logarithmic-phase cells |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: IBA is_active_in ER from the squalene monooxygenase clade (human SQLE, mouse Sqle, S. japonicus and trypanosome orthologs). Erg1 activity is ER-restricted, so the inference holds. Supporting Evidence: PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0005783 endoplasmic reticulum | IDA PMID:9450962 Dual localization of squalene epoxidase, Erg1p, in yeast ref... | ACCEPT | Summary: Leber et al. 1998 fractionation and immunofluorescence assigned 62% of Erg1p to the ER; enzymatic activity was found only in ER membranes. Supporting Evidence: PMID:9450962 62% of cellular Erg1p could be assigned to the endoplasmic reticulum and 38% to lipid particles in late logarithmic-phase cells PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:9450962 Dual localization of squalene epoxidase, Erg1p, in yeast ref... | ACCEPT | Summary: Same study (Leber et al. 1998); Erg1 is an integral membrane protein (two predicted TM segments) of microsomal/ER membranes, which is where the activity resides. Supporting Evidence: PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles file:yeast/ERG1/ERG1-uniprot.txt SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:9450962}; |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (SL-0097) to ER membrane; correct for Erg1. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:9450962}; |
| GO:0005811 lipid droplet | IDA PMID:24868093 High confidence proteomic analysis of yeast LDs identifies a... | ACCEPT | Summary: Currie et al. 2014 high-confidence lipid droplet proteome found Erg1 in their own and all previously reported LD proteomes, classing it as a constitutive LD protein. Erg1 is genuinely located on LDs, although the LD pool is enzymatically inactive. Supporting Evidence: PMID:24868093 Twelve proteins (Ayr1, Eht1, Erg1, Erg6, Erg7, Faa1, Faa4, Fat1, Pet10, Slc1, Tgl1, and Tgl3) were detected in the current work and all reported proteomes |
| GO:0005811 lipid droplet | IDA PMID:9450962 Dual localization of squalene epoxidase, Erg1p, in yeast ref... | ACCEPT | Summary: Leber et al. 1998 found ~38% of Erg1p cofractionating with lipid particles and confirmed dual localisation by immunofluorescence; the LD-associated pool lacked activity unless mixed with ER membranes. Supporting Evidence: PMID:9450962 62% of cellular Erg1p could be assigned to the endoplasmic reticulum and 38% to lipid particles in late logarithmic-phase cells PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0005811 lipid droplet | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (SL-0154) to lipid droplet; consistent with the experimental LD data for Erg1. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Lipid droplet {ECO:0000269|PubMed:9450962} |
| GO:0005829 cytosol | RCA GO_REF:0000123 | MODIFY | Summary: YeastPathways-to-GO-CAM conversion (GO_REF:0000123, SGD_PWY:ERGOSTEROL-SYN-PWY-1, 'ergosterol biosynthesis') places every pathway reaction "is_active_in cytosol" by default. Erg1 is an integral ER membrane protein (also on lipid droplets) whose activity is detectable only in the ER fraction; its sterol/squalene substrate is embedded in the ER bilayer and the activity is measured in the microsomal (ER) membrane fraction, not in the soluble cytosol. Reason: Converter compartment default; the site of activity is the ER membrane. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0005829 cytosol | RCA GO_REF:0000123 | MODIFY | Summary: YeastPathways-to-GO-CAM conversion (GO_REF:0000123, SGD_PWY:PWY-5670-1, 'epoxysqualene biosynthesis') places every pathway reaction "is_active_in cytosol" by default. Erg1 is an integral ER membrane protein (also on lipid droplets) whose activity is detectable only in the ER fraction; its sterol/squalene substrate is embedded in the ER bilayer and the activity is measured in the microsomal (ER) membrane fraction, not in the soluble cytosol. Reason: Converter compartment default; the site of activity is the ER membrane. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0005829 cytosol | RCA GO_REF:0000123 | MODIFY | Summary: YeastPathways-to-GO-CAM conversion (GO_REF:0000123, SGD_PWY:PWY3O-31704, 'superpathway of ergosterol biosynthesis I') places every pathway reaction "is_active_in cytosol" by default. Erg1 is an integral ER membrane protein (also on lipid droplets) whose activity is detectable only in the ER fraction; its sterol/squalene substrate is embedded in the ER bilayer and the activity is measured in the microsomal (ER) membrane fraction, not in the soluble cytosol. Reason: Converter compartment default; the site of activity is the ER membrane. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0006696 ergosterol biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from a fungal node (PTN000851137) seeded by S. cerevisiae ERG1 and C. albicans ERG1. Erg1 performs the second step of the sterol branch (squalene to 2,3-oxidosqualene); erg1 mutants are ergosterol auxotrophs. Supporting Evidence: PMID:200835 Thermosensitive mutants, auxotrophic for ergosterol synthesis, have been isolated |
| GO:0006696 ergosterol biosynthetic process | IDA PMID:8358382 Enzymatic properties of squalene epoxidase from Saccharomyce... | ACCEPT | Summary: Direct assay of microsomal squalene epoxidase (Satoh et al. 1993); the enzyme catalyses a step of ergosterol synthesis. Supporting Evidence: PMID:8358382 S. cerevisiae squalene epoxidase required NADPH for enzyme reaction |
| GO:0006696 ergosterol biosynthetic process | IMP PMID:200835 Ertosterol biosynthesis in Saccharomyces cerevisiae: mutants... | ACCEPT | Summary: erg1 thermosensitive mutants are ergosterol auxotrophs lacking squalene epoxidase (Karst and Lacroute 1977). Supporting Evidence: PMID:200835 Thermosensitive mutants, auxotrophic for ergosterol synthesis, have been isolated |
| GO:0006696 ergosterol biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (SGD_PWY:ERGOSTEROL-SYN-PWY-1, 'ergosterol biosynthesis') places Erg1 in ergosterol biosynthesis via the squalene epoxidase step; correct. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0006696 ergosterol biosynthetic process | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (SGD_PWY:PWY3O-31704, 'superpathway of ergosterol biosynthesis I') places Erg1 in ergosterol biosynthesis via the squalene epoxidase step; correct. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0008204 ergosterol metabolic process | IEA GO_REF:0000117 | MODIFY | Summary: ARBA rule ARBA00092291 assigns the broad "ergosterol metabolic process". Erg1 acts only in the biosynthetic direction, which is already annotated experimentally; the biosynthetic child term is the accurate one. Reason: Too general; Erg1 participates specifically in ergosterol biosynthesis. Proposed replacements: ergosterol biosynthetic process Supporting Evidence: PMID:200835 Thermosensitive mutants, auxotrophic for ergosterol synthesis, have been isolated |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR013698 (squalene epoxidase) mapping to generic "membrane". True but uninformative; the experimentally supported location is the ER membrane. Reason: Generic membrane; replace with the specific compartment. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:9450962 enzymatic activity of squalene epoxidase was only detectable in the endoplasmic reticulum but was absent from isolated lipid particles |
| GO:0016104 triterpenoid biosynthetic process | RCA GO_REF:0000123 | KEEP AS NON CORE | Summary: YeastPathways RCA (SGD_PWY:PWY-5670-1, 'epoxysqualene biosynthesis') gives "triterpenoid biosynthetic process" because 2,3-oxidosqualene is a C30 triterpenoid. Technically true, but in yeast the product is committed to sterol (lanosterol) synthesis; the informative process is ergosterol biosynthesis. Reason: Correct by chemistry of the product, but a superpathway-derived grouping rather than the biological role. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Reaction=squalene + reduced [NADPH--hemoprotein reductase] + O2 = (S)- |
| GO:0016126 sterol biosynthetic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR040125 maps the conserved squalene monooxygenase family to sterol biosynthesis; in yeast, Erg1 participates specifically in the ergosterol pathway already supported by the fungal PTN000851137 IBA, direct assays and YeastPathways RCA rows. Reason: Correct but general; ergosterol biosynthetic process is the specific sterol biosynthetic process for S. cerevisiae Erg1. Proposed replacements: ergosterol biosynthetic process Supporting Evidence: PMID:200835 Thermosensitive mutants, auxotrophic for ergosterol synthesis, have been isolated |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro IPR013698 mapping to FAD binding. Squalene monooxygenases are FAD-containing flavoproteins and UniProt assigns FAD by similarity to human SQLE. Satoh et al. 1993 found no requirement for added FAD with the yeast microsomal enzyme, which is consistent with tightly bound flavin but means FAD binding has not been demonstrated directly for Erg1. Reason: Cofactor binding inferred by homology; supports catalysis but is not the core function itself. Supporting Evidence: file:yeast/ERG1/ERG1-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692; PMID:8358382 S. cerevisiae enzyme reaction did not require FAD or autologous S105 fraction |
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Download this section (compressed HTML)Q: What ER-resident factor (e.g. NADPH-cytochrome P450 reductase Ncp1) is missing from lipid droplets and accounts for the inactivity of the LD-associated Erg1 pool?
Q: Is the LD pool of Erg1 a storage/degradation pool or does it become active at ER-LD contact sites in vivo?
Squalene epoxidase; catalyzes epoxidation of squalene to 2,3-oxidosqualene; plays essential role in ergosterol-biosynthesis pathway and is specific target of antifungal drug terbinafine; directed to ER via guided entry of tail-anchored proteins (GET) pathway; degradation by ERAD triggered by membrane lipid saturation; human SQLE functionally complements the lethality of the erg1 null mutation
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