State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China.
J Biol Chem. 2011 Jun 10;286(23):20648-57. doi: 10.1074/jbc.M110.180000. Epub 2011 Mar 22.
Pyridomycin is a structurally unique antimycobacterial cyclodepsipeptide containing rare 3-(3-pyridyl)-l-alanine and 2-hydroxy-3-methylpent-2-enoic acid moieties. The biosynthetic gene cluster for pyridomycin has been cloned and identified from Streptomyces pyridomyceticus NRRL B-2517. Sequence analysis of a 42.5-kb DNA region revealed 26 putative open reading frames, including two nonribosomal peptide synthetase (NRPS) genes and a polyketide synthase gene. A special feature is the presence of a polyketide synthase-type ketoreductase domain embedded in an NRPS. Furthermore, we showed that PyrA functioned as an NRPS adenylation domain that activates 3-hydroxypicolinic acid and transfers it to a discrete peptidyl carrier protein, PyrU, which functions as a loading module that initiates pyridomycin biosynthesis in vivo and in vitro. PyrA could also activate other aromatic acids, generating three pyridomycin analogues in vivo.
吡啶霉素是一种结构独特的抗分枝杆菌环二肽，含有罕见的 3-(3-吡啶基)-L-丙氨酸和 2-羟基-3-甲基戊-2-烯酸部分。吡啶霉素的生物合成基因簇已从链霉菌属 NRRL B-2517 中克隆和鉴定。对 42.5kb DNA 区域的序列分析揭示了 26 个推定的开放阅读框，包括两个非核糖体肽合成酶 (NRPS) 基因和一个聚酮合酶基因。一个显著特点是存在一个聚酮合酶型酮还原酶结构域嵌入在 NRPS 中。此外，我们表明 PyrA 作为 NRPS 氨酰化结构域发挥作用，激活 3-羟基吡啶酸并将其转移到离散的肽酰载体蛋白 PyrU 上，PyrU 作为加载模块在体内和体外启动吡啶霉素的生物合成。PyrA 还可以激活其他芳香族酸，在体内生成三种吡啶霉素类似物。
