Michael-Type Cyclizations in Lantibiotic Biosynthesis Are Reversible
Michael-Type Cyclizations in Lantibiotic Biosynthesis Are Reversible
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DOI：
10.1021/acschembio.5b00007
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发表时间：
2015-05-01
影响因子：
4
通讯作者：
van der Donk, Wilfred A.
中科院分区：
文献类型：
--
作者：
Yang, Xiao;van der Donk, Wilfred A.
羊毛硫肽是核糖体合成和后修饰肽（RIPPs）的成员。它们在两个生物合成步骤中产生：Ser和Thr残基脱水为相应的脱氢氨基酸，随后通过Cys残基的硫醇进行共轭加成，以产生特征性的镧硫基和甲基镧硫基硫醚桥接结构。通常，羊毛硫肽含有多个硫醚交联。最近的研究提出，最终的环拓扑结构可能是热力学控制。如果是这样，那么迈克尔型环化反应将需要是可逆的，但这种可逆性从未被证明过。我们在这里显示I类羊毛硫肽环化酶NisC和II类羊毛硫肽合成酶HalM2，的确，共轭加成反应是可逆的，酶可以打开所有的硫醚环在其产品。我们还建议，一个他的残基之间是保守的羊毛硫肽环化酶作为酸或碱，质子化或产生的烯醇化中间体在硫醚环的形成和开放，分别。
Lanthipeptides are members of the ribosomally synthesized and post-translationally modified peptides (RiPPs). They are generated in two biosynthetic steps: dehydration of Ser and Thr residues to the corresponding dehydroamino acids and subsequent conjugate addition by the thiol of Cys residues to generate the characteristic lanthionine and methyllanthionine thioether-bridged structures. Typically, a lanthipeptide contains multiple thioether cross-links. Recent studies have proposed that the final ring topology may be under thermodynamic control. If so, then the Michael-type cyclization reaction would need to be reversible, but such reversibility has never been demonstrated. We show here for the class I lanthipeptide cyclase NisC and class II lanthipeptide synthetase HalM2 that, indeed, the conjugate addition reactions are reversible and that the enzymes can open up all thioether rings in their products. We also propose that a His residue that is conserved among the lanthipeptide cyclases acts as the acid or base that protonates or generates the enolate intermediate during thioether ring formation and opening, respectively.