南海极端微生物Streptomyces drozdowiczii SCSIO 10141来源的极端脂肪酶在手性beta-羟基酸制备中的应用

Chiral beta-hydroxy acids are important intermediates of many drugs. With the expirations of those drug patents, the costs and production techniques of chiral beta-hydroxy acids are the crucial reasons for the competitions of drugs. Lipases have been widely used in the enzymatic synthesis of many important drug intermediates like chiral beta-hydroxy acids. Microorganisms from deep sea can yield many extreme lipases, which behave relatively high activities at low temperatures. Through whole genome sequencing, we can identify a large number of completely new coding genes of lipases. From the genome of extremophile Streptomyces drozwiczii SCSIO 10141, we could identify as many as 56 coding genes for extreme lipases. We are trying to characterize the biochemical properties of those extreme lipases in the enzymatic preparation of chiral beta-hydroxy acids, and trying to improve their activities, stabilities, stereoselectivities and tolerance to organic solvents through directed evolution and rational design. We are expecting to obtain highly-efficient extreme lipases for the enzymatic synthesis of optically pure beta-hydroxy acids, and to replace present chemical industries yielding high pollutions and improve our living environments.

手性beta-羟基酸是重要的药物中间体。随着药物专利的到期，手性beta-羟基酸等中间体的制备成本和工艺技术已经成为药物产品竞争的重要因素。脂肪酶被广泛应用于手性beta-羟基酸等重要药物中间体的拆分制备。深海极端微生物可以产生众多在低温条件下仍具较高活性的极端脂肪酶。通过对微生物基因组测序，可以找到大量全新的脂肪酶编码基因。我们从测序的深海极端链霉菌Streptomyces drozwiczii SCSIO 10141的基因组中，找寻到多至56个极端脂肪酶的编码基因。鉴定这些极端脂肪酶拆分制备手性beta-羟基酸中间体的酶学性质，并通过定向进化和理性设计等酶工程手段，提高极端脂肪酶的活性、稳定性、光学选择性和对有机溶剂的耐受性等重要工业应用指标。可望获得我国具有自主知识产权并用于光学纯beta-羟基酸高效制备的极端脂肪酶，并替代现有的高污染化学工业体系，改善我国国民的生活环境。

以手性beta-羟基酸为代表的手性羟基酸是众多药物的中间体，手性beta-羟基酸等中间体的制备成本和工艺技术已经成为产品竞争的重要因素。脂肪酶/酯酶被广泛应用于手性beta-羟基酸等重要药物中间体的拆分制备。我们通过对深海极端链霉菌Streptomyces drozwiczii SCSIO 10141等微生物基因组测序，找到大量全新的脂肪酶编/酯酶码基因。我们克隆、表达并鉴定这些极端脂肪酶/酯酶拆分制备手性S-3-羟基丁酸乙酯等手性beta-羟基酸的酶学性质，并通过反应过程优化等工程技术手段，提高极端脂肪酶/酯酶的光学选择性和产率等重要工业应用指标。同时我们还获得多个能拆分制备手性扁桃酸甲酯等手性羟基酸的深海微生物脂肪酶/酯酶。本项目获得多个可用于光学纯beta-羟基酸高效制备的深海极端微生物脂肪酶/酯酶，并有望替代现有的高污染化学工业体系，改善我国国民的生活环境。