Squalene epoxidase ERG1

Function

Squalene epoxidase; part of the third module of ergosterol biosynthesis pathway that includes the late steps of the pathway. ERG1 catalyzes the epoxidation of squalene into 2,3-epoxysqualene. The third module or late pathway involves the ergosterol synthesis itself through consecutive reactions that mainly occur in the endoplasmic reticulum (ER) membrane. Firstly, the squalene synthase ERG9 catalyzes the condensation of 2 farnesyl pyrophosphate moieties to form squalene, which is the precursor of all steroids. Squalene synthase is crucial for balancing the incorporation of farnesyl diphosphate (FPP) into sterol and nonsterol isoprene synthesis. Secondly, the squalene epoxidase ERG1 catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, which is considered to be a rate-limiting enzyme in steroid biosynthesis. Then, the lanosterol synthase ERG7 catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol core. In the next steps, lanosterol is transformed to zymosterol through a complex process involving various demethylation, reduction and desaturation reactions. The lanosterol 14-alpha-demethylase ERG11 (also known as CYP51) catalyzes C14-demethylation of lanosterol to produce 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol, which is critical for ergosterol biosynthesis. The C-14 reductase ERG24 reduces the C14=C15 double bond of 4,4-dimethyl-cholesta-8,14,24-trienol to produce 4,4-dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-cholesta-8,24-dienol is substrate of the C-4 demethylation complex ERG25-ERG26-ERG27 in which ERG25 catalyzes the three-step monooxygenation required for the demethylation of 4,4-dimethyl and 4alpha-methylsterols, ERG26 catalyzes the oxidative decarboxylation that results in a reduction of the 3-beta-hydroxy group at the C-3 carbon to an oxo group, and ERG27 is responsible for the reduction of the keto group on the C-3. ERG28 has a role as a scaffold to help anchor ERG25, ERG26 and ERG27 to the endoplasmic reticulum and ERG29 regulates the activity of the iron-containing C4-methylsterol oxidase ERG25. Then, the sterol 24-C-methyltransferase ERG6 catalyzes the methyl transfer from S-adenosyl-methionine to the C-24 of zymosterol to form fecosterol. The C-8 sterol isomerase ERG2 catalyzes the reaction which results in unsaturation at C-7 in the B ring of sterols and thus converts fecosterol to episterol. The sterol-C5-desaturase ERG3 then catalyzes the introduction of a C-5 double bond in the B ring to produce 5-dehydroepisterol. The C-22 sterol desaturase ERG5 further converts 5-dehydroepisterol into ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23) double bond in the sterol side chain. Finally, ergosta-5,7,22,24(28)-tetraen-3beta-ol is substrate of the C-24(28) sterol reductase ERG4 to produce ergosterol.

Classification

Family (Pfam)

PF08491 SE

InterPro

FAD/NAD-bd_sf, Squalene_epoxidase, Squalene_monox

Functional cluster

Oxidoreductases, Catalases & Peroxidases

Gene Ontology · 6

• GO:0005783 endoplasmic reticulum
• GO:0005789 endoplasmic reticulum membrane
• GO:0005811 lipid droplet
• GO:0050660 flavin adenine dinucleotide binding
• GO:0004506 squalene monooxygenase activity
• GO:0006696 ergosterol biosynthetic process

Drugs targeting this protein · 1

• LIRANAFTATE inhibitor

Related proteins · sequence + function similarity

• Squalene monooxygenase 0.97
• Squalene monooxygenase 0.93
• Squalene epoxidase ERG1 0.92
• Squalene epoxidase ERG1 0.89
• Squalene epoxidase erg1 0.88
• Squalene epoxidase erg1 0.85
• Squalene epoxidase 3 0.82
• Squalene monooxygenase 1,1 0.82
• Squalene epoxidase 6 0.81
• Squalene epoxidase 4 0.79
• Squalene monooxygenase SE1 0.78
• Squalene epoxidase 1 0.77

Co-cited proteins · studied together in the literature

• Putative uncharacterized protein YGR176W 1 shared papers
• C-22 sterol desaturase ERG5 2 shared papers
• Delta(7)-sterol 5(6)-desaturase ERG3 2 shared papers
• Lanosterol 14-alpha demethylase CYP51 2 shared papers
• Sterol-4-alpha-carboxylate 3-dehydrogenase ERG26, decarboxylating 2 shared papers
• C-4 methylsterol oxidase ERG25 3 shared papers
• Ergosterol biosynthetic protein 28 2 shared papers
• 3-keto-steroid reductase ERG27 2 shared papers
• Sterol 24-C-methyltransferase ERG6 2 shared papers
• Mevalonate kinase 1 shared papers
• Phosphomevalonate kinase 1 shared papers
• Hydroxymethylglutaryl-CoA synthase 1 shared papers

Literature · 12 cited papers

• Regulation of ergosterol biosynthesis in Saccharomyces cerevisiae. Genes (Basel) · 2020
• The reference genome sequence of Saccharomyces cerevisiae: Then and now. G3 (Bethesda) · 2014
• Sites of ubiquitin attachment in Saccharomyces cerevisiae. Proteomics · 2012
• A global topology map of the Saccharomyces cerevisiae membrane proteome. Proc. Natl. Acad. Sci. U.S.A. · 2006
• Erg28p is a key protein in the yeast sterol biosynthetic enzyme complex. J. Lipid Res. · 2005
• Global analysis of protein expression in yeast. Nature · 2003
• A subset of membrane-associated proteins is ubiquitinated in response to mutations in the endoplasmic reticulum degradation machinery. Proc. Natl. Acad. Sci. U.S.A. · 2003
• A proteomics approach to understanding protein ubiquitination. Nat. Biotechnol. · 2003
• Dual localization of squalene epoxidase, Erg1p, in yeast reflects a relationship between the endoplasmic reticulum and lipid particles. Mol. Biol. Cell · 1998
• The nucleotide sequence of Saccharomyces cerevisiae chromosome VII. Nature · 1997
• Enzymatic properties of squalene epoxidase from Saccharomyces cerevisiae. Biol. Pharm. Bull. · 1993
• The gene encoding squalene epoxidase from Saccharomyces cerevisiae: cloning and characterization. Gene · 1991