Post-translational Claisen Condensation and Decarboxylation en Route to the Bicyclic Core of Pantocin A
Post-translational Claisen Condensation and Decarboxylation en Route to the Bicyclic Core of Pantocin A
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DOI：
10.1021/jacs.5b13529
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发表时间：
2016-05-04
影响因子：
15
通讯作者：
Bowers, Albert A.
中科院分区：
文献类型：
--
作者：
Ghodge, Swapnil V.;Biernat, Kristen A.;Bowers, Albert A.
催产素A （PA）是核糖体编码和翻译后修饰肽天然产物（RiPPs）家族的一员。PA比大多数已知的RiPPs小得多，RiPPs是一种三肽，具有紧密的双环核心，似乎是从一个更大的30个残基前体肽的中间切割出来的。我们在这里证明了PaaA酶催化30个残基前体PaaP中两个谷氨酸残基的双重脱水和脱羧。PaaP前导肽和跟随肽序列的进一步截断显示了这两个区域对paaa介导的剪裁的不同影响，并描绘了跟随序列在脱羧步骤中的重要作用。载子PaaA的晶体结构被报道，从而使PaaA的结构特征与其他同源酶区分开来，这些酶通常不催化这种扩展的翻译后化学。总之，这些数据揭示了如何从一个普遍存在的酶家族中提取额外的化学物质，用于核糖体衍生的肽天然产物的生物合成，并表明在未开发的基因组空间中可能存在更多此类酶的例子。
Pantocin A (PA) is a member of the growing family of ribosomally encoded and post-translationally modified peptide natural products (RiPPs). PA is much smaller than most known RiPPs, a tripeptide with a tight bicyclic core that appears to be cleaved from the middle of a larger 30-residue precursor peptide. We show here that the enzyme PaaA catalyzes the double dehydration and decarboxylation of two glutamic acid residues in the 30-residue precursor PaaP. Further truncates of PaaP leader and follower peptide sequences demonstrate the different impacts of these two regions on PaaA-mediated tailoring and delineate an essential role for the follower sequence in the decarboxylation step. The crystal structure of apo PaaA is reported, allowing identification of structural features that set PaaA apart from other homologous enzymes that typically do not catalyze such extended post-translational chemistry. Together, these data reveal how additional chemistry can be extracted from a ubiquitous enzyme family toward ribosomally derived peptide natural product biosynthesis and suggest that more examples of such enzymes likely exist in untapped genomic space.