Deconstruction of iterative multidomain polyketide synthase function
Deconstruction of iterative multidomain polyketide synthase function
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DOI：
10.1126/science.1154711
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发表时间：
2008-04-11
期刊：
影响因子：
56.9
通讯作者：
Townsend, Craig A.
中科院分区：
文献类型：
--
作者：
Crawford, Jason M.;Thomas, Paul M.;Townsend, Craig A.
PksA是多结构域迭代聚酮酶（IPKS）的一种，它启动环境致癌物黄曲霉毒素B1的生物合成，IPKS是生物合成酶的一个大的、知之甚少的家族。我们发现，解剖的PksA和它的重建从选定的一组域允许先进的octaketide中间体绑定到酶的积累和表征，允许由单个催化结构域控制的反应被确定。一个产品模板（PT）域与酮合酶和硫酯酶在这个IPKS系统中组装精确的七个丙二酰衍生的积木的己酰起始单元，并介导一个特定的环化级联。由于PT域是常见的非还原IPKS，这些机制的功能应被证明是通用的IPKS催化生产的芳香族聚酮。
PksA, which initiates biosynthesis of the environmental carcinogen aflatoxin B1, is one of the multidomain iterative polyketide synthases (IPKSs), a large, poorly understood family of biosynthetic enzymes. We found that dissection of PksA and its reconstitution from selected sets of domains allows the accumulation and characterization of advanced octaketide intermediates bound to the enzyme, permitting the reactions controlled by individual catalytic domains to be identified. A product template (PT) domain unites with the ketosynthase and thioesterase in this IPKS system to assemble precisely seven malonyl-derived building blocks to a hexanoyl starter unit and mediate a specific cyclization cascade. Because the PT domain is common among nonreducing IPKSs, these mechanistic features should prove to be general for IPKS-catalyzed production of aromatic polyketides.