Walsh Christopher T
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Science. 2004 Mar 19;303(5665):1805-10. doi: 10.1126/science.1094318.
Polyketide (PK) and nonribosomal peptides (NRP), constructed on multimodular enzymatic assembly lines, often attain the conformations that establish biological activity by cyclization constraints introduced by tailoring enzymes. The dedicated tailoring enzymes are encoded by genes clustered with the assembly line genes for coordinated regulation. NRP heterocyclizations to thiazoles and oxazoles can occur on the elongating framework of acyl-S enzyme intermediates, whereas tandem cyclic PK polyether formation of furans and pyrans can be initiated by post-assembly line epoxidases. Macrocyclizations of NRP, PK, and hybrid NRP-PK scaffolds occur in assembly line chain termination steps. Post-assembly line cascades of enzymatic oxidations also create cross-linked and cyclized architectures that generate the mature scaffolds of natural product antibiotics. The modularity of the natural product assembly lines and permissivity of tailoring enzymes offer prospects for reprogramming to create novel antibiotics with optimized properties.
聚酮化合物（PK）和非核糖体肽（NRP）由多模块酶组装线构建而成，它们常常通过修饰酶引入的环化限制来获得能确立生物活性的构象。专门的修饰酶由与组装线基因成簇的基因编码，以进行协调调控。NRP向噻唑和恶唑的杂环化可在酰基-S酶中间体的延伸骨架上发生，而呋喃和吡喃的串联环状PK聚醚形成可由组装线后环氧酶引发。NRP、PK以及NRP-PK杂合支架的大环化发生在组装线链终止步骤中。组装线后酶促氧化级联反应还会产生交联和环化结构，从而生成天然产物抗生素的成熟支架。天然产物组装线的模块化以及修饰酶的允许性为重新编程以创造具有优化特性的新型抗生素提供了前景。
