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

Lum, Pek Yee; Edwards, Scott V.; Wright, Robin

doi:10.1002/(sici)1097-0061(19960915)12:11<1107::aid-yea992>3.0.co;2-e

Cited by 32 publications

(21 citation statements)

References 65 publications

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“…HMG-CoA reductase is the rate-limiting enzyme in sterol biosynthesis in fungi. Though mammals are thought to have only one HMG-CoA reductase gene, more than two HMG-CoA reductase genes have been found to exist in fungi and plants (Liscum et al 1985;Basson et al 1986Basson et al , 1988Choi et al 1992;Burmester and Czempinski 1994;Lum et al 1996). It is not clear how many HMG-CoA reductase genes there are in P. citrinum, but, interestingly, one of them, mlcD, is located in the ML-236B biosynthetic gene cluster, and the expression of mlcD appears to be related to ML-236B production.…”

Section: Discussionmentioning

confidence: 99%

“…mlcD contains two introns and encodes a putative HMG-CoA reductase of 1173 amino acids (126 kDa). MlcD has the characteristic eight transmembrane-spanning domains in the N-terminal region, predicted by the Kyte-Doolittle method, and the conserved catalytic domains in the C-terminal segment, like other HMG-CoA reductases (data not shown) (Liscum et al 1985;Basson et al 1986Basson et al , 1988Choi et al 1992;Burmester and Czempinski 1994;Lum et al 1996). MlcD is 63% identical to a putative polypeptide encoded by orf8 in the lovastatin gene cluster from A. terreus (Kennedy et al 1999).…”

Section: Resistance and Secretionmentioning

confidence: 94%

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Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum

Abe¹,

Suzuki²,

Ono³

et al. 2002

Mol Gen Genomics

138

119

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Cloning of genes encoding polyketide synthases (PKSs) has allowed us to identify a gene cluster for ML-236B biosynthesis in Penicillium citrinum. Like lovastatin, which is produced by Aspergillus terreus, ML-236B (compactin) inhibits the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Genomic sequencing and Northern analysis showed that nine predicted genes for ML-236B biosynthesis were located within a 38-kb region and were transcribed when ML-236B was produced. The predicted amino acid sequences encoded by these nine genes, designated mlcA- mlcH and mlcR, were similar to those encoded by the genes for lovastatin synthesis, and were therefore assumed to be involved either directly or indirectly in ML-236B biosynthesis. Targeted disruption experiments provided evidence that two PKS genes in the cluster, mlcA and mlcB, are required for the biosynthesis of the nonaketide and the diketide moieties, respectively, of ML-236B, suggesting that the gene cluster as a whole is responsible for ML-236B biosynthesis in P. citrinum. Bioconversion of some of the predicted intermediates by an mlcA-disrupted mutant was also investigated in order to analyze the ML-236B biosynthetic pathway. The molecular organization of the gene cluster and proposed functions for the ML-236B biosynthetic genes in P. citrinum are described.

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Section: Discussionmentioning

confidence: 99%

Section: Resistance and Secretionmentioning

confidence: 94%

Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum

Abe¹,

Suzuki²,

Ono³

et al. 2002

Mol Gen Genomics

138

119

View full text Add to dashboard Cite

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“…In plants, the membrane domain contains two transmembrane helices (Denbow et al, 1996;Re et al, 1997), whereas in animals and fungi, it contains of a series of seven or eight transmembrane helices (Liscum et al, 1985;Basson et al, 1988;Sengstag et al, 1990;Olender and Simon, 1992;Roitelman et al, 1992). Although there is little obvious primary sequence conservation, the structural conservation of this complex membrane domain over the 1 billion years of evolution since divergence of fungi and animals (Doolittle et al, 1996;Lum et al, 1996;Feng et al, 1997) suggests that the structure has an important functional role. However, the molecular logic of tethering the catalytic activity to a membrane appears enigmatic, because prokaryotic HMG-CoA reductase proteins are soluble (Beach and Rodwell, 1989;Bischoff and Rodwell, 1996;Baltscheffsky et al, 1997;Bochar et al, 1997;Takahashi et al, 1999), and the catalytic domain of eukaryotic HMG-CoA reductase can support apparently normal growth of cells when it is freed from the membrane domain (Gil et al, 1985;Donald et al, 1997).…”

Section: Discussionmentioning

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). The membrane domain is essential for both the proliferation of ER membranes (Jingami et al, 1987;Parrish et al, 1995) and the regulated degradation of both the mammalian and yeast HMG-CoA reductases (Gil et al, 1985;Skalnik et al, 1988;Hampton et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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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“…A ␥ shape parameter of 0.578 was estimated using the maximum likelihood method in PAUP, and a linearized NJ tree was constructed. A nucleotide substitution rate of 1.156 ‫ן‬ 10 ‫9מ‬ substitutions per site per year was estimated from the NJ tree using 420 million years ago for the divergence of S. cerevisiae from S. pombe (Lum et al 1996). This tRNA nucleotide substitution rate was used to estimate the divergence times of key genes within the linearized tRNA trees displayed in Figures 2 and 4.…”

Section: Tree Calibration and Estimates Of Divergence Timesmentioning

confidence: 99%

Comparative Evolutionary Genomics Unveils the Molecular Mechanism of Reassignment of the CTG Codon inCandidaspp.

Massey¹,

Moura²,

Beltrão³

et al. 2003

Genome Res.

113

111

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Using the (near) complete genome sequences of the yeasts Candida albicans, Saccharomyces cerevisiae, and Schizosaccharomyces pombe, we address the evolution of a unique genetic code change, which involves decoding of the standard leucine-CTG codon as serine in Candida spp. By using two complementary comparative genomics approaches, we have been able to shed new light on both the origin of the novel Candida spp. Ser-tRNA CAG , which has mediated CTG reassignment, and on the evolution of the CTG codon in the genomes of C. albicans, S. cerevisiae, and S. pombe. Sequence analyses of newly identified tRNAs from the C. albicans genome demonstrate that the Ser-tRNA CAG is derived from a serine and not a leucine tRNA in the ancestor yeast species and that this codon reassignment occurred ∼170 million years ago, but the origin of the Ser-tRNA CAG is more ancient, implying that the ancestral Leu-tRNA that decoded the CTG codon was lost after the appearance of the Ser-tRNA CAG . Ambiguous CTG decoding by the Ser-tRNA CAG combined with biased AT pressure forced the evolution of CTG into TTR codons and have been major forces driving evolution of the CTN codon family in C. albicans. Remarkably, most of the CTG codons present in extant C. albicans genes are encoded by serine and not leucine codons in homologous S. cerevisiae and S. pombe genes, indicating that a significant number of serine TCN and AGY codons evolved into CTG codons either directly by simultaneous double mutations or indirectly through an intermediary codon. In either case, CTG reassignment had a major impact on the evolution of the coding component of the Candida spp. genome.

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

Cited by 32 publications

References 65 publications

Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum

Molecular cloning and characterization of an ML-236B (compactin) biosynthetic gene cluster in Penicillium citrinum

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

Comparative Evolutionary Genomics Unveils the Molecular Mechanism of Reassignment of the CTG Codon inCandidaspp.

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