Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Basson, M E; Thorsness, Mary K.; Rine, Jasper

doi:10.1073/pnas.83.15.5563

Cited by 225 publications

(178 citation statements)

References 33 publications

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“…JRY527, hmgl, and hmg2 are isogenic strains. HMG1 encodes the major isoform of HMG CoA reductase in yeast contributing 83% of enzymatic activity in a vegetatively growing cell [16].…”

Section: Quantitative Stero! Analysismentioning

confidence: 99%

“…The erg2 mutation in S. cerevisiae is non-auxotrophic for sterol and results in an accumulation of sterol intermediates such as ergosta-5,8,22-313-ol, and ergosta-8-en-313-ol [15] and the erg3 mutation leads to an accumulation of ergosta-7,22-dien-313-ol [3]. Similarly, a mutation in the HMG1 gene encoding the major isoform of HMG-CoA reductase [16] results in a 4-fold increase in ERG3 expression. Loss of the HMG2 gene results in no increase in ERG3 expression, hmgl and hmg2 mutants show a 50 and 20% decrease, respectively, in end product ergosterol (data not shown).…”

Section: A Block In the Ergosterol Biosynthetic Pathway Up-regulatmentioning

confidence: 99%

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Positive and negative regulation of a sterol biosynthetic gene (ERG3) in the post‐squalene portion of the yeast ergosterol pathway

et al. 1996

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Regulation of sterol biosynthesis in the terminal portion of the pathway represents an efficient mechanism by which the cell can control the production of sterol without disturbing the production of other essential mevaionate pathway products. We demonstrate that mutations affecting early and late steps in sterol homeostasis modulate the expression of the ERG3 gene: a late step in sterol biosynthesis in yeast. Expression of ERG3 is increased in response to a mutation in the major isoform of HMG CoA reductase which catalyzes the rate-limiting step of sterol biosynthesis. Likewise, mutations in non-auxotrophic ergosterol biosynthetic genes downstream of squalene production (erg2, erg3, erg4, ergS, and ergO') result in an up-regulation of ERG3 expression. Deletion analysis of the ERG3 promoter identified two upstream activation sequences: UAS1, which when deleted reduces ERG3 gene expression 3-4-fuld but maintains sterol regulation and UAS2, which when deleted further reduces ERG3 expression and abolishes sterol regulation. The recent isolation of two yeast genes responsible for the esterification of intracellular sterol (ARE1 and ARE2) has enabled us to directly analyze the relationship between sterol esterification and de novo biosynthesis. Our results demonstrate that the absence of sterol esterification leads to a decrease in total intracellular sterol and ERG3 is a target of this negative regulation.

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“…JRY527, hmgl, and hmg2 are isogenic strains. HMG1 encodes the major isoform of HMG CoA reductase in yeast contributing 83% of enzymatic activity in a vegetatively growing cell [16].…”

Section: Quantitative Stero! Analysismentioning

confidence: 99%

Section: A Block In the Ergosterol Biosynthetic Pathway Up-regulatmentioning

confidence: 99%

Positive and negative regulation of a sterol biosynthetic gene (ERG3) in the post‐squalene portion of the yeast ergosterol pathway

et al. 1996

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“…These plasmids contain Syrian hamster HMG-CoA reductase fused to ␤-gal or a truncated ␤-gal missing the last 20 amino acids needed for tetramerization (Cheng et al, 1999). Both Basson et al (1986). b Koning et al (1996).…”

Section: Plasmidsmentioning

confidence: 99%

“…Unlike mammalian cells, which have one HMG-CoA reductase, yeast express two functional HMG-CoA reductase isozymes, Hmg1p and Hmg2p (Basson et al, 1986). Each isozyme triggers the proliferation of distinct sets of membrane arrays that reflect the localization of the particular isozyme .…”

Section: Introductionmentioning

confidence: 99%

“…The structure of HMG-CoA reductase can be divided into two domains: a complex membrane-spanning domain at the amino terminus followed by a cytosolic catalytic domain (Liscum et al, 1985;Basson et al, 1986;Roitelman et al, 1991). The membrane domain of mammalian and yeast HMG-CoA reductases spans the membrane seven or eight times and is connected to the catalytic domain through a flexible linker sequence (Liscum et al, 1985;Lum et al, 1996;Roitelman et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis

Profant¹,

Roberts

Koning

et al. 1999

MBoC

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In all cells examined, specific endoplasmic reticulum (ER) membrane arrays are induced in response to increased levels of the ER membrane protein 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase. In yeast, expression of Hmg1p, one of two yeast HMG-CoA reductase isozymes, induces assembly of nuclear-associated ER stacks called karmellae. Understanding the features of HMG-CoA reductase that signal karmellae biogenesis would provide useful insights into the regulation of membrane biogenesis. The HMG-CoA reductase protein consists of two domains, a multitopic membrane domain and a cytosolic catalytic domain. Previous studies had indicated that the HMG-CoA reductase membrane domain was exclusively responsible for generation of ER membrane proliferations. Surprisingly, we discovered that this conclusion was incorrect: sequences at the carboxyl terminus of HMG-CoA reductase can profoundly affect karmellae biogenesis. Specifically, truncations of Hmg1p that removed or shortened the carboxyl terminus were unable to induce karmellae assembly. This result indicated that the membrane domain of Hmg1p was not sufficient to signal for karmellae assembly. Using β-galactosidase fusions, we demonstrated that the carboxyl terminus was unlikely to simply serve as an oligomerization domain. Our working hypothesis is that a truncated or misfolded cytosolic domain prevents proper signaling for karmellae by interfering with the required tertiary structure of the membrane domain.

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Molecular, functional and evolutionary characterization of the gene encoding HMG-CoA reductase in the fission yeast,Schizosaccharomyces pombe

Lum

Edwards

Wright

1996

Yeast

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The synthesis of mevalonate, a molecule required for both sterol and isoprene biosynthesis in eukaryotes, is catalysed by 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase. Using a gene dosage approach, we have isolated the gene encoding HMG‐CoA reductase, hmg1+, from the fission yeast Schizosaccharomyces pombe (Accession Number L76979). Specifically, hmg1+ was isolated on the basis of its ability to confer resistance to lovastatin, a competitive inhibitor of HMG‐CoA reductase. Gene disruption analysis showed that hmg1+ was an essential gene. This result provided evidence that, unlike Saccharomyces cerevisiae, S. pombe contained only a single functional HMG‐CoA reductase gene. The presence of a single HMG‐CoA reductase gene was confirmed by genomic hybridization analysis. As observed for the S. cerevisiae HMG1p, the hmg1+ protein induced membrane proliferations known as karmellae. A previously undescribed ‘feed‐forward’ regulation was observed in which elevated levels of HMG‐CoA synthase, the enzyme catalysing the synthesis of the HMG‐CoA reductase substrate, induced elevated levels of hmg1+ protein in the cell and conferred partial resistance to lovastatin. The amino acid sequences of yeast and human HMG‐CoA reductase were highly divergent in the membrane domains, but were extensively conserved in the catalytic domains. We tested whether the gene duplication that produced the two functional genes in S. cerevisiae occurred before or after S. pombe and S. cerevisiae diverged by comparing the log likelihoods of trees specified by these hypotheses. We found that the tree specifying post‐divergence duplication had significantly higher likelihood. Moreover, phylogenetic analyses of available HMG‐CoA reductase sequences also suggested that the lineages of S. pombe and S. cerevisiae diverged approximately 420 million years ago but that the duplication event that produced two HMG‐CoA reductase genes in the budding yeast occurred only approximately 56 million years ago. To date, S. pombe is the only unicellular eukaryote that has been found to contain a single HMG‐CoA reductase gene. Consequently, S. pombe may provide important opportunities to study aspects of the regulation of sterol biosynthesis that have been difficult to address in other organisms and serve as a test organism to identify novel therapies for modulating cholesterol synthesis.

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Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Cited by 225 publications

References 33 publications

Positive and negative regulation of a sterol biosynthetic gene (ERG3) in the post‐squalene portion of the yeast ergosterol pathway

Positive and negative regulation of a sterol biosynthetic gene (ERG3) in the post‐squalene portion of the yeast ergosterol pathway

The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis

Molecular, functional and evolutionary characterization of the gene encoding HMG-CoA reductase in the fission yeast,Schizosaccharomyces pombe

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