Disease relevance of ERG1

• Recombinant SPF produced in Escherichia coli enhances microsomal squalene epoxidase activity and promotes intermembrane transfer of squalene in vitro [1].
• On the basis of functional homologies to p-hydroxybenzoate hydroxylase (PHBH) from Pseudomonas fluorescens, the Erg1 protein contains two flavin adenine dinucleotide (FAD) domains and one nucleotide binding (NB) site [2].

High impact information on ERG1

• Squalene epoxidase, a membrane-associated enzyme that converts squalene to squalene 2,3-oxide, plays an important role in the maintenance of cholesterol homeostasis [1].
• Introduction of the erg26 mutation into an erg1 (squalene epoxidase) strain also was viable in ergosterol-supplemented media [3].
• Thus, ETS1 and ETS2 are allelic to ERG1 and ERG7, respectively [4].
• The quadruple mutant, however, was more sensitive to terbinafine, an inhibitor of Erg1p, than the are1are2 strain suggesting that the presence of TAG and/or intact lipid particles has an additional protective effect [5].
• Most interestingly, the amount of the squalene epoxidase Erg1p, which is dually located in lipid particles and endoplasmic reticulum of wild type, is decreased in the quadruple mutant, whereas amounts of other lipid particle proteins tested were not reduced [5].

Biological context of ERG1

• Physical and genetic mapping data reveal that ERG1 is located on the right arm of chromosome VII proximal to QCR9 at a distance of 14.6 cM from ADE3 [6].
• Deletion analysis of the ERG1 promoter identified a novel regulatory DNA sequence element [7].
• ERG1 is an essential gene [6].
• Two 6-bp direct repeats, separated by 4 bp, AGCTCGGCCGAGCTCG, are unique to the ERG1 promoter [7].
• By random PCR mutagenesis of the ERG1 gene, one erg1 allele was isolated that carries a mutation leading to a single amino acid exchange in the FAD I domain close to the N-terminus of Erg1p [8].

Anatomical context of ERG1

• The relative distribution of Erg1p between the endoplasmic reticulum and lipid particles changes during growth [9].
• Analysis of subcellular fractions revealed that squalene epoxidase was present in the microsomal fraction (30,000 x g) and also cofractionated with lipid particles [9].
• When lipid particles of the wild-type strain and microsomes of an erg1 disruptant were mixed, squalene epoxidase activity was partially restored [9].
• Squalene epoxidase inhibition results in ergosterol-depleted fungal cell membranes (fungistatic effect) and the toxic accumulation of intracellular squalene (fungicidal effect) [10].

Associations of ERG1 with chemical compounds

• Squalene epoxidase, encoded by the ERG1 gene in yeast, is a key enzyme of sterol biosynthesis [9].
• Chromosomal integration of ERG1 ERG7 at their loci in erg26-1ts ets1-1 and erg26-1ts and ets2-1 mutants, respectively, results in the loss of accumulation of squalene and squalene epoxide, re-accumulation of 4-carboxysterols and cell inviability at high temperature [4].
• Inhibition of ergosterol biosynthesis with terbinafine increases the expression of ERG1 in a concentration-dependent manner to a maximum of sevenfold [7].
• The ERG1 gene of Saccharomyces cerevisiae encodes squalene epoxidase, a key enzyme in the ergosterol pathway [6].
• Inhibition of later steps in the ergosterol-biosynthetic pathway by ketoconazole, an inhibitor of the lanosterol-14alpha-demethylase, and U18666A, an inhibitor of the squalene-2,3-epoxide-lanosterol cyclase, also induce expression of ERG1, suggesting that ERG1 expression is positively regulated by diminished intracellular ergosterol levels [7].

Regulatory relationships of ERG1

• Evidence was obtained suggesting that Triton X-100 apparently activated squalene synthetase (EC 2.5.1.21) but inhibited squalene epoxidase (EC 1.14.99.7) and delta 24-sterol methyltransferase (EC 2.1.1.41) [11].

Other interactions of ERG1

• In the yeast Saccharomyces cerevisiae, three enzymes of the sterol biosynthetic pathway, namely Erg1p, Erg6p and Erg7p, are located in lipid particles [12].
• Both antifungals induced to various levels the expression of ERG1, ERG11, CDR1, and CDR2; addition of TSA reduced this upregulation 50 to 100% [13].
• A comparison between planktonic and biofilm populations of transcript abundance for genes coding for enzymes in the ergosterol (ERG1, -3, -5, -6, -9, -11, and -25) and beta-1,6-glucan (SKN and KRE1, -5, -6, and -9) pathways was performed by quantitative RT-PCR [14].
• As de novo lipid synthesis may be involved in ethanol tolerance, we studied the effect of oxygen addition on sterol and UFA auxotrophs (erg1 and ole1 mutants, respectively) [15].
• Squalene synthetase (EC 2.5.1.21) and squalene epoxidase (EC 1.14 99.7) activities have been measured in cell-free extracts of wild type yeast grown in aerobic and semi-anaerobic conditions as well as in sterol-auxotrophic mutant strains grown aerobically [16].

Analytical, diagnostic and therapeutic context of ERG1

• A dual localization of Erg1p was confirmed by immunofluorescence microscopy [9].
• Genetic manipulation of oxidosqualene-lanosterol cyclase did result in the buildup of detectable levels of 24,25-oxidolanosterol by gas chromatography, gas chromatography-mass spectroscopy, and NMR analyses, whereas no detectable amounts were observed in wild-type cells or cells with squalene epoxidase down-regulated [17].
• Polyclonal antibodies, raised against an internal peptide of C. albicans SE, recognized a protein associated with the particulate fraction of M(r) 55000 on Western blots of C. albicans extracts [18].

References