A Mononuclear Iron-Dependent Methyltransferase Catalyzes Initial Steps in Assembly of the Apratoxin A Polyketide Starter Unit,ACS Chemical Biology

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A Mononuclear Iron-Dependent Methyltransferase Catalyzes Initial Steps in Assembly of the Apratoxin A Polyketide Starter Unit
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-11-14 00:00:00 , DOI: 10.1021/acschembio.7b00746
Meredith A. Skiba _{1,

2} , Andrew P. Sikkema _{1,

2} , Nathan A. Moss ₃ , Collin L. Tran ₁ , Rebecca M. Sturgis ₁ , Lena Gerwick ₃ , William H. Gerwick _{3,

4} , David H. Sherman _{1,

5,

6,

7} , Janet L. Smith _{1,

2}

Affiliation

Natural product biosynthetic pathways contain a plethora of enzymatic tools to carry out difficult biosynthetic transformations. Here, we discover an unusual mononuclear iron-dependent methyltransferase that acts in the initiation steps of apratoxin A biosynthesis (AprA MT1). Fe³⁺-replete AprA MT1 catalyzes one or two methyl transfer reactions on the substrate malonyl-ACP (acyl carrier protein), whereas Co²⁺, Fe²⁺, Mn²⁺, and Ni²⁺ support only a single methyl transfer. MT1 homologues exist within the “GNAT” (GCN5-related N-acetyltransferase) loading modules of several modular biosynthetic pathways with propionyl, isobutyryl, or pivaloyl starter units. GNAT domains are thought to catalyze decarboxylation of malonyl-CoA and acetyl transfer to a carrier protein. In AprA, the GNAT domain lacks both decarboxylation and acyl transfer activity. A crystal structure of the AprA MT1-GNAT di-domain with bound Mn²⁺, malonate, and the methyl donor S-adenosylmethionine (SAM) reveals that the malonyl substrate is a bidentate metal ligand, indicating that the metal acts as a Lewis acid to promote methylation of the malonyl α-carbon. The GNAT domain is truncated relative to functional homologues. These results afford an expanded understanding of MT1-GNAT structure and activity and permit the functional annotation of homologous GNAT loading modules both with and without methyltransferases, additionally revealing their rapid evolutionary adaptation in different biosynthetic contexts.

中文翻译：

单核铁依赖性甲基转移酶催化Apratoxin A聚酮化合物启动器单元组装的初始步骤。

天然产物的生物合成途径包含大量的酶促工具，可以进行困难的生物合成转化。在这里，我们发现了一种异常的单核铁依赖性甲基转移酶，该酶在pratoxin A生物合成（AprA MT1）的起始步骤中起作用。富含Fe ^3+的AprA MT1催化底物丙二酰ACP（酰基载体蛋白）上的一个或两个甲基转移反应，而Co 2 ⁺，Fe 2 ⁺，Mn ²⁺和Ni ²⁺仅支持一次甲基转移。MT1同源物存在于“ GNAT”（与GCN5相关的N-乙酰转移酶）加载带有丙酰基，异丁酰基或新戊酰基起始剂单元的几种模块化生物合成途径的模块。GNAT结构域被认为可催化丙二酰辅酶A的脱羧反应和乙酰转移到载体蛋白上。在AprA中，GNAT域既缺乏脱羧作用又没有酰基转移活性。结合了Mn ²⁺，丙二酸酯和甲基供体S的AprA MT1-GNAT双结构域的晶体结构-腺苷甲硫氨酸（SAM）揭示丙二酸底物是双齿金属配体，表明该金属充当路易斯酸以促进丙二酸α-碳的甲基化。GNAT域相对于功能同源物被截短。这些结果提供了对MT1-GNAT结构和活性的扩展理解，并允许具有和不具有甲基转移酶的同源GNAT加载模块的功能注释，另外揭示了它们在不同生物合成环境中的快速进化适应性。

更新日期：2017-11-15

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