Department of Chemical and Biomolecular Engineering, University of California-Berkeley, Berkeley, CA 94270 (USA).
Angew Chem Int Ed Engl. 2015 Feb 16;54(8):2370-3. doi: 10.1002/anie.201410124. Epub 2015 Jan 7.
The gem-dimethyl groups in polyketide-derived natural products add steric bulk and, accordingly, lend increased stability to medicinal compounds, however, our ability to rationally incorporate this functional group in modified natural products is limited. In order to characterize the mechanism of gem-dimethyl group formation, with a goal toward engineering of novel compounds containing this moiety, the gem-dimethyl group producing polyketide synthase (PKS) modules of yersiniabactin and epothilone were characterized using mass spectrometry. The work demonstrated, contrary to the canonical understanding of reaction order in PKSs, that methylation can precede condensation in gem-dimethyl group producing PKS modules. Experiments showed that both PKSs are able to use dimethylmalonyl acyl carrier protein (ACP) as an extender unit. Interestingly, for epothilone module 8, use of dimethylmalonyl-ACP appeared to be the sole route to form a gem-dimethylated product, while the yersiniabactin PKS could methylate before or after ketosynthase condensation.
聚酮衍生天然产物中的宝石二甲基基团增加了空间位阻，因此增加了药物化合物的稳定性，然而，我们将这种官能团合理地引入修饰天然产物的能力是有限的。为了表征宝石二甲基基团形成的机制，以期设计含有该部分的新型化合物，使用质谱法对耶尔森菌素和埃坡霉素的产生宝石二甲基基团的聚酮合酶（PKS）模块进行了表征。这项工作表明，与 PKS 中反应级数的典型理解相反，甲基化可以在产生宝石二甲基基团的 PKS 模块的缩合之前进行。实验表明，两种 PKS 都能够使用二甲基丙二酰酰基载体蛋白（ACP）作为扩展单元。有趣的是，对于埃坡霉素模块 8，使用二甲基丙二酰-ACP 似乎是形成宝石二甲基化产物的唯一途径，而耶尔森菌素 PKS 可以在酮合酶缩合之前或之后进行甲基化。
