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Repurposing the GNAT Fold in the Initiation of Polyketide Biosynthesis.
Structure ( IF 4.4 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.str.2019.11.004
Meredith A Skiba 1 , Collin L Tran 2 , Qingyun Dan 2 , Andrew P Sikkema 1 , Zachary Klaver 2 , William H Gerwick 3 , David H Sherman 4 , Janet L Smith 1
Affiliation  

Natural product biosynthetic pathways are replete with enzymes repurposed for new catalytic functions. In some modular polyketide synthase (PKS) pathways, a GCN5-related N-acetyltransferase (GNAT)-like enzyme with an additional decarboxylation function initiates biosynthesis. Here, we probe two PKS GNAT-like domains for the dual activities of S-acyl transfer from coenzyme A (CoA) to an acyl carrier protein (ACP) and decarboxylation. The GphF and CurA GNAT-like domains selectively decarboxylate substrates that yield the anticipated pathway starter units. The GphF enzyme lacks detectable acyl transfer activity, and a crystal structure with an isobutyryl-CoA product analog reveals a partially occluded acyltransfer acceptor site. Further analysis indicates that the CurA GNAT-like domain also catalyzes only decarboxylation, and the initial acyl transfer is catalyzed by an unidentified enzyme. Thus, PKS GNAT-like domains are re-classified as GNAT-like decarboxylases. Two other decarboxylases, malonyl-CoA decarboxylase and EryM, reside on distant nodes of the superfamily, illustrating the adaptability of the GNAT fold.

中文翻译:

在聚酮化合物生物合成的起始中重新利用 GNAT 折叠。

天然产物生物合成途径充满了重新用于新催化功能的酶。在一些模块化聚酮合酶 (PKS) 途径中,具有附加脱羧功能的 GCN5 相关 N-乙酰转移酶 (GNAT) 样酶启动生物合成。在这里,我们探测了两个 PKS GNAT 样结构域,以了解从辅酶 A (CoA) 到酰基载体蛋白 (ACP) 的 S-酰基转移和脱羧的双重活性。GphF 和 CurA GNAT 样结构域选择性地使底物脱羧,产生预期的途径起始单元。GphF 酶缺乏可检测的酰基转移活性,并且异丁酰辅酶 A 产物类似物的晶体结构揭示了部分封闭的酰基转移受体位点。进一步分析表明,CurA GNAT 样结构域也只催化脱羧,最初的酰基转移是由一种未鉴定的酶催化的。因此,PKS GNAT 样结构域被重新分类为 GNAT 样脱羧酶。另外两种脱羧酶,丙二酰辅酶A脱羧酶和EryM,位于该超家族的远距离节点上,说明了GNAT折叠的适应性。
更新日期:2019-11-28
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