Differences in PLP-Dependent Cysteinyl Processing Lead to Diverse S-Functionalization of Lincosamide Antibiotics.
Differences in PLP-Dependent Cysteinyl Processing Lead to Diverse S-Functionalization of Lincosamide Antibiotics.
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DOI：
10.1021/jacs.6b01751
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发表时间：
2016-05
影响因子：
15
通讯作者：
Min Wang;Qunfei Zhao;Qing-lin Zhang;Wen Liu
中科院分区：
文献类型：
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作者：
Min Wang;Qunfei Zhao;Qing-lin Zhang;Wen Liu
吡哆醛-5 '-磷酸（PLP）依赖性蛋白质构成活生物体中最大和最重要的酶家族之一。这些蛋白质参与许多生化过程，其中许多尚未被表征，并通过各种反应转化含有氨基的底物，这些反应将醛亚胺作为共同的中间体。在本文中，我们报告了PLP依赖性酶CcbF和LmbF，这是高度相关的，以不同的方式处理半胱氨酸S-共轭的中间体，并与个别下游酶（S）朝着不同的S-功能化的林可酰胺抗生素celesticlavin和林可霉素A。CcbF催化一种不寻常的转化，该转化涉及在形成二碳醇接头期间半胱氨酰基基团的脱羧偶联氧化脱氨基，而LmbF负责β-消除，随后是S-甲基化以产生甲巯基基团。这两种剪裁途径是可变的，并且彼此可交换，允许体外组合生物合成许多杂合林可酰胺抗生素，包括天然产物Bu-2545。这些发现证明了PLP化学在酶催化中的广泛多样性及其在创造新分子中的有前途的适用性。
Pyridoxal-5'-phosphate (PLP)-dependent proteins constitute one of the largest and most important families of enzymes in living organisms. These proteins participate in numerous biochemical processes, many of which have not been characterized, and transform substrates containing an amino group through various reactions that share aldimine as a common intermediate. Herein, we report that the PLP-dependent enzymes CcbF and LmbF, which are highly related in phylogenesis, process cysteine S-conjugated intermediates in different ways and associate with individual downstream enzyme(s) toward distinct S-functionalization of the lincosamide antibiotics celesticetin and lincomycin A. CcbF catalyzes an unusual conversion that involves decarboxylation-coupled oxidative deamination of the cysteinyl group during the formation of a two-carbon alcohol linker, whereas LmbF is responsible for β-elimination, followed by S-methylation to produce a methylmercapto group. The two tailoring routes are variable and exchangeable with each other, allowing for in vitro combinatorial biosynthesis of a number of hybrid lincosamide antibiotics, including the natural product Bu-2545. These findings demonstrate the wide diversity of PLP chemistry in enzymatic catalysis and its promising applicability in creation of new molecules.