Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
J Am Chem Soc. 2011 Apr 6;133(13):4746-9. doi: 10.1021/ja2006737. Epub 2011 Mar 10.
The tetramic acid (2,4-pyrrolidinedione) scaffold has been recognized as an important structural feature because of its mycotoxic, antibacterial, antiviral, and antioxidant activities. This important class of natural products is reportedly produced by the type-I polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) hybrid megaenzyme systems. In contrast, the benzalacetone synthase (BAS) from Rheum palmatum is a structurally simple, plant-specific type-III PKS that catalyzes the one-step decarboxylative condensation of malonyl-CoA with 4-coumaroyl-CoA. The type-III PKS exhibits unusually broad substrate specificity and notable catalytic versatility. Here we report that R. palmatum BAS efficiently produces a series of unnatural, novel tetramic acid derivatives by the condensation of malonyl-CoA with aminoacyl-CoA thioesters chemically synthesized from L- and D-amino acids. Remarkably, the novel tetramic acid dimer D-5 formed from D-phenylalanoyl-CoA showed moderate antiproliferative activity against murine leukemia P388 cells.
四氢酸（2,4-吡咯烷二酮）结构因其具有霉菌毒素、抗菌、抗病毒和抗氧化活性而被认为是一个重要的结构特征。据称，这类重要的天然产物是由 I 型聚酮合酶/非核糖体肽合酶（PKS/NRPS）杂合巨型酶系统产生的。相比之下，来自大黄（Rheum palmatum）的苯甲酰丙酮合酶（BAS）是一种结构简单的植物特异性 III 型 PKS，可催化丙二酰辅酶 A 与 4-香豆酰辅酶 A 的一步脱羧缩合反应。III 型 PKS 表现出异常广泛的底物特异性和显著的催化多功能性。在这里，我们报告说，大黄 BAS 通过丙二酰辅酶 A 与化学合成的 L-和 D-氨基酸的酰基辅酶 A 硫酯的缩合，有效地产生了一系列非天然的新型四氢酸衍生物。值得注意的是，由 D-苯丙氨酰辅酶 A 形成的新型四氢酸二聚体 D-5 对小鼠白血病 P388 细胞表现出中等的抗增殖活性。
