Gehring A M, DeMoll E, Fetherston J D, Mori I, Mayhew G F, Blattner F R, Walsh C T, Perry R D
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Chem Biol. 1998 Oct;5(10):573-86. doi: 10.1016/s1074-5521(98)90115-6.
Virulence in the pathogenic bacterium Yersinia pestis, causative agent of bubonic plague, has been correlated with the biosynthesis and transport of an iron-chelating siderophore, yersiniabactin, which is induced under iron-starvation conditions. Initial DNA sequencing suggested that this system is highly conserved among the pathogenic Yersinia. Yersiniabactin contains a phenolic group and three five-membered thiazole heterocycles that serve as iron ligands.
The entire Y. pestis yersiniabactin region has been sequenced. Sequence analysis of yersiniabactin biosynthetic regions (irp2-ybtE and ybtS) reveals a strategy for siderophore production using a mixed polyketide synthase/nonribosomal peptide synthetase complex formed between HMWP1 and HMWP2 (encoded by irp1 and irp2). The complex contains 16 domains, five of them variants of phosphopantetheine-modified peptidyl carrier protein or acyl carrier protein domains. HMWP1 and HMWP2 also contain methyltransferase and heterocyclization domains. Mutating ybtS revealed that this gene encodes a protein essential for yersiniabactin synthesis.
The HMWP1 and HMWP2 domain organization suggests that the yersiniabactin siderophore is assembled in a modular fashion, in which a series of covalent intermediates are passed from the amino terminus of HMWP2 to the carboxyl terminus of HMWP1. Biosynthetic labeling studies indicate that the three yersiniabactin methyl moieties are donated by S-adenosylmethionine and that the linker between the thiazoline and thiazolidine rings is derived from malonyl-CoA. The salicylate moiety is probably synthesized using the aromatic amino-acid biosynthetic pathway, the final step of which converts chorismate to salicylate. YbtS might be necessary for converting chorismate to salicylate.
鼠疫耶尔森氏菌是腺鼠疫的病原体，其毒力与一种铁螯合铁载体耶尔森菌素的生物合成和转运相关，耶尔森菌素在铁饥饿条件下被诱导产生。最初的DNA测序表明，该系统在致病性耶尔森氏菌中高度保守。耶尔森菌素含有一个酚基和三个作为铁配体的五元噻唑杂环。
已对鼠疫耶尔森氏菌的整个耶尔森菌素区域进行了测序。对耶尔森菌素生物合成区域（irp2 - ybtE和ybtS）的序列分析揭示了一种利用HMWP1和HMWP2（由irp1和irp2编码）之间形成的混合聚酮合酶/非核糖体肽合成酶复合物产生铁载体的策略。该复合物包含16个结构域，其中五个是磷酸泛酰巯基乙胺修饰的肽基载体蛋白或酰基载体蛋白结构域的变体。HMWP1和HMWP2还含有甲基转移酶和杂环化结构域。对ybtS进行突变表明，该基因编码一种对耶尔森菌素合成必不可少的蛋白质。
HMWP1和HMWP2的结构域组织表明，耶尔森菌素铁载体是以模块化方式组装的，其中一系列共价中间体从HMWP2的氨基末端传递到HMWP1的羧基末端。生物合成标记研究表明，耶尔森菌素的三个甲基部分由S - 腺苷甲硫氨酸提供，噻唑啉环和噻唑烷环之间的连接基团源自丙二酰辅酶A。水杨酸部分可能是利用芳香族氨基酸生物合成途径合成的，该途径的最后一步将分支酸转化为水杨酸。YbtS可能是将分支酸转化为水杨酸所必需的。
