Piasecki Shawn K, Taylor Clint A, Detelich Joshua F, Liu June, Zheng Jianting, Komsoukaniants Arkady, Siegel Dionicio R, Keatinge-Clay Adrian T
Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
Chem Biol. 2011 Oct 28;18(10):1331-40. doi: 10.1016/j.chembiol.2011.07.021.
Chiral building blocks are valuable intermediates in the syntheses of natural products and pharmaceuticals. A scalable chemoenzymatic route to chiral diketides has been developed that includes the general synthesis of α-substituted, β-ketoacyl N-acetylcysteamine thioesters followed by a biocatalytic cycle in which a glucose-fueled NADPH-regeneration system drives reductions catalyzed by isolated modular polyketide synthase (PKS) ketoreductases (KRs). To identify KRs that operate as active, stereospecific biocatalysts, 11 isolated KRs were incubated with 5 diketides and their products were analyzed by chiral chromatography. KRs that naturally reduce small polyketide intermediates were the most active and stereospecific toward the panel of diketides. Several biocatalytic reactions were scaled up to yield more than 100 mg of product. These syntheses demonstrate the ability of PKS enzymes to economically and greenly generate diverse chiral building blocks on a preparative scale.
手性砌块是天然产物和药物合成中有价值的中间体。已开发出一种可扩展的化学酶法路线来合成手性二酮类化合物，该路线包括α-取代的β-酮酰基N-乙酰半胱氨酸硫酯的常规合成，随后是一个生物催化循环，其中以葡萄糖为燃料的NADPH再生系统驱动由分离的模块化聚酮合酶（PKS）酮还原酶（KRs）催化的还原反应。为了鉴定作为活性立体特异性生物催化剂的KRs，将11种分离的KRs与5种二酮类化合物一起孵育，并通过手性色谱法分析其产物。天然还原小的聚酮中间体的KRs对二酮类化合物组最具活性和立体特异性。扩大了几个生物催化反应的规模，以产生超过100毫克的产物。这些合成证明了PKS酶在制备规模上经济且绿色地生成多种手性砌块的能力。
