Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin
Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin
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DOI：
10.1016/s1074-5521(98)90291-5
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发表时间：
1998-11-01
影响因子：
--
通讯作者：
Walsh, CT
中科院分区：
文献类型：
--
作者：
Quadri, LEN;Sello, J;Walsh, CT
背景资料：许多病原菌分泌铁螯合铁载体作为毒力因子，在脊椎动物宿主的铁限制环境中竞争三价铁。结核分枝杆菌分枝杆菌素是一种混合的聚酮/非核糖体肽，含有一个羟基芳基恶唑啉帽和两个N-羟基酰胺，它们共同产生对铁离子的高亲和力位点。该菌素结构与鼠疫菌的耶尔森氏杆菌素和霍乱菌的弧菌杆菌素铁载体结构相似。结核病基因组，命名为mbtA-J，含有分枝杆菌素生物合成所必需的核心组分。基因产物MbtB、MbtE和MbtF被认为是肽合成酶、MbtC和MbtD聚酮脱氢酶、Mbt 1是提供由MbtA激活的水杨酸的异分支酸合酶，并且MbtG是必需的羟化酶。一个芳基载体蛋白（ArCP）结构域编码的mbtB，可能是铁载体链起始的网站。mbtB ArCP结构域和MbtA在大肠杆菌中的过量产生和纯化允许验证分枝杆菌素起始假说，因为PptT（磷酸泛酰巯基乙胺基转移酶）和MbtA（水杨酰-AMP连接酶）的顺序作用导致mbtB ArCP结构域被激活为水杨酰-S-ArCP。结核病使用聚酮合酶/非核糖体肽合成酶策略。分枝杆菌素基因簇与耶尔森氏杆菌素和肠杆菌素合成酶基因具有组织同源性。在分枝杆菌、耶尔森氏菌和大肠杆菌的铁载体中使用类似的铁离子连接策略，提示了抑制剂设计和治疗干预的酶靶点。称为病原体。
Background: Many pathogenic bacteria secrete iron-chelating siderophores as virulence factors in the iron-limiting environments of their vertebrate hosts to compete for ferric iron. Mycobacterium tuberculosis mycobactins are mi,ted polyketide/nonribosomal peptides that contain a hydroxyaryloxazoline cap and two N-hydroxyamides that together create a high-affinity site for ferric ion. The mycobactin structure is analogous to that of the yersiniabactin and vibriobactin siderophores from the bacteria that cause plague and cholera, respectively.Results: A ten-gene cluster spanning 24 kilobases of the M. tuberculosis genome, designated mbtA-J, contains the core components necessary for mycobactin biogenesis. The gene products MbtB, MbtE and MbtF are proposed to be peptide synthetases, MbtC and MbtD polyketide synthases, Mbtl an isochorismate synthase that provides a salicylate activated by MbtA, and MbtG a required hydroxylase. An aryl carrier protein (ArCP) domain is encoded in mbtB, and is probably the site of siderophore chain initiation. Overproduction and purification of the mbtB ArCP domain and MbtA in Escherichia coli allowed validation of the mycobactin initiation hypothesis, as sequential action of PptT (a phosphopantetheinyl transferase) and MbtA (a salicyl-AMP ligase) resulted in the mbtB ArCP domain being activated as salicyl-S-ArCP.Conclusions: Mycobactins are produced in M. tuberculosis using a polyketide synthase/nonribosomal peptide synthetase strategy. The mycobactin gene cluster has organizational homologies to the yersiniabactin and enterobactin synthetase genes. Enzymatic targets for inhibitor design and therapeutic intervention are suggested by the similar ferric-ion ligation strategies used in the siderophores from Mycobacteria, Yersinia and E. call pathogens.