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首页> 外文期刊>Applied Microbiology >Impact of Classical Strain Improvement of Penicillium rubens on Amino Acid Metabolism during β-Lactam Production
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Impact of Classical Strain Improvement of Penicillium rubens on Amino Acid Metabolism during β-Lactam Production

机译：青霉氧化铝对β-内酰胺生产氨基酸代谢的古典应变改善

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摘要

To produce high levels of β-lactams, the filamentous fungus Penicillium rubens (previously named Penicillium chrysogenum ) has been subjected to an extensive classical strain improvement (CSI) program during the last few decades. This has led to the accumulation of many mutations that were spread over the genome. Detailed analysis reveals that several mutations targeted genes that encode enzymes involved in amino acid metabolism, in particular biosynthesis of l-cysteine, one of the amino acids used for β-lactam production. To examine the impact of the mutations on enzyme function, the respective genes with and without the mutations were cloned and expressed in Escherichia coli , purified, and enzymatically analyzed. Mutations severely impaired the activities of a threonine and serine deaminase, and this inactivates metabolic pathways that compete for l-cysteine biosynthesis. Tryptophan synthase, which converts l-serine into l-tryptophan, was inactivated by a mutation, whereas a mutation in 5-aminolevulinate synthase, which utilizes glycine, was without an effect. Importantly, CSI caused increased expression levels of a set of genes directly involved in cysteine biosynthesis. These results suggest that CSI has resulted in improved cysteine biosynthesis by the inactivation of the enzymatic conversions that directly compete for resources with the cysteine biosynthetic pathway, consistent with the notion that cysteine is a key component during penicillin production.IMPORTANCE Penicillium rubens is an important industrial producer of β-lactam antibiotics. High levels of penicillin production were enforced through extensive mutagenesis during a classical strain improvement (CSI) program over 70 years. Several mutations targeted amino acid metabolism and resulted in enhanced l-cysteine biosynthesis. This work provides a molecular explanation for the interrelation between secondary metabolite production and amino acid metabolism and how classical strain improvement has resulted in improved production strains.
机译：为了产生高水平的β-内酰胺，丝状真菌青霉氧化铝（以前命名的Penicillium Chrysogenum）在过去几十年中经过广泛的古典菌株改进（CSI）计划。这导致了许多突变的积聚在基因组上。详细分析表明，几种突变靶向基因，其编码参与氨基酸代谢的酶，特别是L-半胱氨酸的生物合成，用于β-内酰胺产生的氨基酸之一。为了检查酶突变对酶功能的影响，克隆和不突变的各自基因，并在大肠杆菌中纯化并酶促分析。突变严重损害了苏氨酸和丝氨酸脱氨酶的活性，并且这灭活了竞争用于L-半胱氨酸生物合成的代谢途径。将L-丝氨酸转化为L-色氨酸的色氨酸合成酶被突变灭活，而使用甘氨酸的5-氨基纤维素合酶中的突变没有效果。重要的是，CSI导致直接参与半胱氨酸生物合成的一组基因的表达水平增加。这些结果表明，CSI通过酶促转化的灭活导致半胱氨酸生物合成，即直接与半胱氨酸生物合成途径竞争的酶促转换，与半胱氨酸生产过程中的关键组分一致。分析青霉素鲁本质是一个重要的工业β-内酰胺抗生素的生产者。在70年以上的经典菌株改善（CSI）计划期间，通过广泛的诱变强制强制诱变高水平的青霉素生产。几种突变靶向氨基酸代谢并导致增强的L-半胱氨酸生物合成。这项工作为次级代谢产物生产和氨基酸代谢之间的相互关联以及古典应变改善导致改善的生产菌株之间的相互关联提供了分子解释。

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