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A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus.

ABSTRACT: The stereochemical course of the cyclisation reaction catalysed by the bacterial 1,8-cineol synthase from Streptomyces clavuligerus was investigated using stereospecifically deuterated substrates. In contrast to the well investigated plant enzyme from Salvia officinalis, the reaction proceeds via (S)-linalyl diphosphate and the (S)-terpinyl cation, while the final cyclisation reaction is in both cases a syn addition, as could be shown by incubation of (2-¹³C)geranyl diphosphate in deuterium oxide.

SUBMITTER: Rinkel J

PROVIDER: S-EPMC5238540 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus.

Rinkel Jan J Rabe Patrick P Zur Horst Laura L Dickschat Jeroen S JS

Beilstein journal of organic chemistry 20161104

The stereochemical course of the cyclisation reaction catalysed by the bacterial 1,8-cineol synthase from Streptomyces clavuligerus was investigated using stereospecifically deuterated substrates. In contrast to the well investigated plant enzyme from Salvia officinalis, the reaction proceeds via (S)-linalyl diphosphate and the (S)-terpinyl cation, while the final cyclisation reaction is in both cases a syn addition, as could be shown by incubation of (2-1 ...[more]

PMID: 28144299

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Project description:Clavulanic acid (CA) is the preferred clinical drug for the treatment of infections by β-lactam antibiotic-resistant bacteria. CA is produced by Streptomyces clavuligerus, and although there have been many reports on the effects of carbon and nitrogen sources on CA production, the mechanisms involved remain unclear. In this study, we found that CA accumulation in S. clavuligerus F613-1 was increased significantly in MH medium, which is rich in organic nitrogen, compared with that in ML medium, which contains half the amount of organic nitrogen present in MH medium. Transcriptome analysis revealed that genes involved in CA biosynthesis, such as ceas1, ceas2, bls1, bls2, cas2, pah2, gcaS, and cad, and arginine biosynthesis, such as argB, argC, argD, argG, argH, argJ, and argR, were upregulated under rich organic nitrogen. Metabolome data revealed notable differences between cultures of F613-1 grown in MH and ML media with regard to levels of key intracellular metabolites, most of which are involved in arginine metabolic pathways, including arginine, glutamine, and glutamic acid. Additionally, supplementation of ML medium with arginine, glutamine, or glutamic acid resulted in increased CA production by S. clavuligerus F613-1. Our results indicate that rich organic nitrogen mainly affects CA biosynthesis by increasing the levels of amino acids associated with the arginine metabolic pathway and activating the expression of the CA biosynthetic gene cluster. These findings provide important insights for improving medium optimization and engineering of S. clavuligerus F613-1 for high-yield production of CA. IMPORTANCE The bacterium Streptomyces clavuligerus is used for the industrial production of the broad-spectrum β-lactamase inhibitor clavulanic acid (CA). However, much remains unknown about the factors which affect CA yields. We investigated the effects of different levels of organic nitrogen on CA production. Our analyses indicate that higher organic nitrogen levels were associated with increased CA yields and increased levels of arginine biosynthesis. Further analyses supported the relationship between arginine metabolism and CA production and demonstrated that increasing the levels of arginine or associated amino acids could boost CA yields. These findings suggest approaches for improving the production of this clinically important antibiotic.

Dataset Information

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus.

Publications

A detailed view on 1,8-cineol biosynthesis by <i>Streptomyces clavuligerus</i>.

Similar Datasets

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