Structure and mechanism of MbtI, the salicylate synthase from Mycobacterium tuberculosis

被引:60
作者
Zwahlen, Jacque
Kolappan, Subramaniapillai
Zhou, Rong
Kisker, Caroline [1 ]
Tonge, Peter J.
机构
[1] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA
[2] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA
[3] SUNY Stony Brook, Ctr Struct Biol, Stony Brook, NY 11794 USA
[4] Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, Inst Biol Struct, D-97078 Wurzburg, Germany
关键词
D O I
10.1021/bi060852x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MbtI (rv2386c) from Mycobacterium tuberculosis catalyzes the initial transformation in mycobactin biosynthesis by converting chorismate to salicylate. We report here the structure of MbtI at 2.5 A resolution and demonstrate that isochorismate is a kinetically competent intermediate in the synthesis of salicylate from chorismate. At pH values below 7.5 isochorismate is the dominant product while above this pH value the enzyme converts chorismate to salicylate without the accumulation of isochorismate in solution. The salicylate and isochorismate synthase activities of MbtI are Mg2+-dependent, and in the absence of Mg2+ MbtI has a promiscuous chorismate mutase activity similar to that of the isochorismate pyruvate lyase, PchB, from Pseudomonas aeruginosa. MbtI is part of a larger family of chorismate-binding enzymes descended from a common ancestor (the MST family), that includes the isochorismate synthases and anthranilate synthases. The lack of active site residues unique to pyruvate eliminating members of this family, combined with the observed chorismate mutase activity, suggests that MbtI may exploit a sigmatropic pyruvate elimination mechanism similar to that proposed for PchB. Using a combination of structural, kinetic, and sequence based studies we propose a mechanism for MbtI applicable to all members of the MST enzyme family.
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收藏
页码:954 / 964
页数:11
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