Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22066-71. doi: 10.1073/pnas.1014081107. Epub 2010 Dec 2.
Every polyketide synthase module has an acyl carrier protein (ACP) and a ketosynthase (KS) domain that collaborate to catalyze chain elongation. The same ACP then engages the KS domain of the next module to facilitate chain transfer. Understanding the mechanism for this orderly progress of the growing polyketide chain represents a fundamental challenge in assembly line enzymology. Using both experimental and computational approaches, the molecular basis for KS-ACP interactions in the 6-deoxyerythronolide B synthase has been decoded. Surprisingly, KS-ACP recognition is controlled at different interfaces during chain elongation versus chain transfer. In fact, chain elongation is controlled at a docking site remote from the catalytic center. Not only do our findings reveal a new principle in the modular control of polyketide antibiotic biosynthesis, they also provide a rationale for the mandatory homodimeric structure of polyketide synthases, in contrast to the monomeric nonribosomal peptide synthetases.
每个聚酮合酶模块都有一个酰基载体蛋白 (ACP) 和一个酮合酶 (KS) 结构域，它们协同催化链的延伸。然后，同一个 ACP 与下一个模块的 KS 结构域结合，以促进链转移。理解这种不断增长的聚酮链有序进展的机制是装配线酶学的一个基本挑战。本研究采用实验和计算方法，解码了 6-脱氧赤藓醇 B 合酶中 KS-ACP 相互作用的分子基础。令人惊讶的是，KS-ACP 的识别在链延伸和链转移过程中受到不同界面的控制。事实上，链延伸是在远离催化中心的对接位点控制的。我们的研究结果不仅揭示了聚酮类抗生素生物合成中模块控制的新原则，也为聚酮合酶的必需同源二聚体结构提供了依据，而与单体非核糖体肽合酶相反。
