Precursor Supply for Polyketide Biosynthesis: The Role of Crotonyl-CoA Reductase

Liu, Haibin; Reynolds, Kevin A.

doi:10.1006/mben.2000.0169

Cited by 31 publications

(16 citation statements)

References 31 publications

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“…We have grown the wildtype strain and industrial strain C730.1 in both a glucosesoybean medium (Liu & Reynolds, 1999;O'Hagan et al, 1995;Zhang & Reynolds, 2001) and a chemically defined medium (Liu & Reynolds, 2001). The strain has also been grown in glucose-soybean meal supplemented with soybean oil, lard oil and methyl oleate (Reynolds et al, 1988;Zhang & Reynolds, 2001).…”

Section: Resultsmentioning

confidence: 99%

“…Thus it has been argued that in addition to the isomerization of butyryl-CoA (by ICM) and succinyl-CoA (by MCM) another pathway can generate methylmalonylCoA from acetoacetyl-CoA (Liu & Reynolds, 2001;Vrijbloed et al, 1999;Zhang & Reynolds, 2001). The current studies show that such a pathway or pathways cannot be important for S. cinnamonensis grown in the oil-based extended fermentation as both the monensin titres decreased, and there was almost a complete loss of labelling of methylmalonylCoA derived positions by acetoacetyl-CoA in the L1 mutant (in fact, the flux from this intermediate switches towards the formation of acetyl-CoA).…”

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confidence: 99%

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Crotonyl-coenzyme A reductase provides methylmalonyl-CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in an oil-based extended fermentation

2004

Microbiology

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It is demonstrated that crotonyl-CoA reductase (CCR) plays a significant role in providing methylmalonyl-CoA for monensin biosynthesis in oil-based 10-day fermentations of Streptomyces cinnamonensis. Under these conditions S. cinnamonensis L1, a derivative of a high-titre producing industrial strain C730.1 in which ccr has been insertionally inactivated, produces only 15 % of the monensin yield. Labelling of the coenzyme A pools using [ No labelling of the malonyl-CoA-derived positions was observed. The opposite result was observed when the incorporation study was carried out with the L1 strain, demonstrating that ccr insertional inactivation has led to a reversal of carbon flux from an acetoacetyl-CoA intermediate. These results dramatically contrast similar analyses of the L1 mutant in glucose-soybean medium which indicate a role in providing ethylmalonyl-CoA but not methylmalonyl-CoA, thus causing a change in the ratio of monensin A and monensin B analogues, but not the overall monensin titre. These results demonstrate that the relative contributions of different pathways and enzymes to providing polyketide precursors are thus dependent upon the fermentation conditions. Furthermore, the generally accepted pathways for providing methylmalonyl-CoA for polyketide production may not be significant for the S. cinnamonensis high-titre monensin producer in oil-based extended fermentations. An alternative pathway, leading from the fatty acid catabolite acetyl-CoA, via the CCR-catalysed reaction is proposed.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Crotonyl-coenzyme A reductase provides methylmalonyl-CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in an oil-based extended fermentation

2004

Microbiology

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“…The residual biosynthesis of salinosporamide B from ethylmalonyl-CoA in the housekeeping CCR (Strop_3612) deletion mutant may derive from SalG-catalyzed reductive carboxylation of crotonyl-CoA. Alternatively, an orthogonal pathway for acetate assimilation may function in S. tropica (7,20) as suspected in Streptomyces cinnamonensis in which genetic inactivation of its CCR likewise resulted in the reduced production of the ethylmalonyl-CoA-derived polyketide monensin A rather than abolishing it completely (32).…”

Section: Discussionmentioning

confidence: 99%

Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S -adenosyl- l -methionine

Eustáquio

McGlinchey

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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169

201

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Polyketides are among the major classes of bioactive natural products used to treat microbial infections, cancer, and other diseases. Here we describe a pathway to chloroethylmalonyl-CoA as a polyketide synthase building block in the biosynthesis of salinosporamide A, a marine microbial metabolite whose chlorine atom is crucial for potent proteasome inhibition and anticancer activity. S-adenosyl-L-methionine (SAM) is converted to 5-chloro-5-deoxyadenosine (5-ClDA) in a reaction catalyzed by a SAMdependent chlorinase as previously reported. By using a combination of gene deletions, biochemical analyses, and chemical complementation experiments with putative intermediates, we now provide evidence that 5-ClDA is converted to chloroethylmalonyl-CoA in a 7-step route via the penultimate intermediate 4-chlorocrotonyl-CoA. Because halogenation often increases the bioactivity of drugs, the availability of a halogenated polyketide building block may be useful in molecular engineering approaches toward polyketide scaffolds.actinomycete ͉ biological halogenation ͉ marine natural product ͉ proteasome inhibitor ͉ Salinispora tropica

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“…A total of 1,118 genes (15.5%) are involved in regulation. As in S. avermitilis and S. coelicolor, an unusually large number of these (38) Table 2 online). The response to changing environmental conditions and availability of nutrients is mediated by at least 42 sensor kinases, and 113 two-component response regulators.…”

Section: Sequencing and Gene Annotation Of The S Erythraea Genomementioning

confidence: 99%

“…There is a single cluster of the adenosylcobalamin-dependent methylmalonyl-CoA mutase genes (SACE_5638-5640). S. erythraea, unlike many streptomycetes, has no homolog of crotonyl-CoA reductase or of adenosylcobalamin-dependent isobutyryl-CoA mutase, explaining its inability to furnish butyrate units for polyketide biosynthesis 38,39 ; it also has no homolog of meaA in S. coelicolor, which has been implicated in provision of methylmalonyl-CoA from acetoacetyl-CoA 40 . The availability of the complete genome sequence now provides the basis for systematic approaches to identify and manipulate such feeder pathways with the aim of increasing polyketide production.…”

Section: A R T I C L E Smentioning

confidence: 99%

Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338

et al. 2007

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Precursor Supply for Polyketide Biosynthesis: The Role of Crotonyl-CoA Reductase

Cited by 31 publications

References 31 publications

Crotonyl-coenzyme A reductase provides methylmalonyl-CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in an oil-based extended fermentation

Crotonyl-coenzyme A reductase provides methylmalonyl-CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in an oil-based extended fermentation

Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S -adenosyl- l -methionine

Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338

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