Shen Ben, Kwon Hyung-Jin
Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave., Madison, WI 53705-2222.
Chem Rec. 2002;2(6):389-96. doi: 10.1002/tcr.10042.
Polyketide biosynthesis is catalyzed by polyketide synthase (PKS) and three types of bacterial PKS are known to date. Feeding experiments with isotope-labeled precursors established the polyketide origin of the macrotetrolides, but the labeling pattern cannot be rationalized according to the established PKS paradigm. Genetic analysis of the macrotetrolide biosynthesis unveiled an unprecedented organization for a polyketide gene cluster that features five genes encoding discrete ketoacyl synthase (KS) and four genes encoding discrete ketoreductase (KR) but lacking an acyl carrier protein (ACP). Macrotetrolide biosynthesis is proposed to involve a novel type II PKS that acts directly on acyl CoA substrates, functions noniteratively, and catalyzes both C-C and C-O bond formation. These findings demonstrate once again Nature's versatility in making complex molecules and suggests new strategies for PKS engineering to further expand the scope and diversity of polyketide library. They also should serve as an inspiration in searching for PKS with novel chemistry for combinatorial biosynthesis.
聚酮化合物的生物合成由聚酮合酶（PKS）催化，迄今为止已知三种类型的细菌PKS。用同位素标记前体进行的饲喂实验确定了大环四醇类化合物的聚酮起源，但根据已确立的PKS范式，标记模式无法得到合理解释。大环四醇类化合物生物合成的遗传分析揭示了一种前所未有的聚酮基因簇组织形式，其特征是有五个编码离散酮酰基合成酶（KS）的基因和四个编码离散酮还原酶（KR）的基因，但缺乏酰基载体蛋白（ACP）。有人提出大环四醇类化合物的生物合成涉及一种新型的II型PKS，它直接作用于酰基辅酶A底物，非迭代发挥功能，并催化碳-碳键和碳-氧键的形成。这些发现再次证明了大自然在制造复杂分子方面的多样性，并为PKS工程提出了新策略，以进一步扩大聚酮化合物文库的范围和多样性。它们也应该为寻找具有新型化学性质的PKS用于组合生物合成提供灵感。
