Molecular basis of the inhibitor selectivity and insights into the feedback inhibition mechanism of citramalate synthase from Leptospira interrogans
文献类型：期刊论文
| 作者 | Zhang, P; Ma, J; Zhang, ZL; Zha, MW; Xu, H; Zhao, GP; Ding, JP |
| 刊名 | BIOCHEMICAL JOURNAL
 |
| 出版日期 | 2009 |
| 卷号 | 421期号:1页码:133-143 |
| 关键词 | allosteric regulation crystal structure feedback inhibition mechanism selectivity |
| 通讯作者 | Ding, JP (reprint author), Chinese Acad Sci, State Key Lab Mol Biol, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,gpzhao@sibs.ac.cn |
| 英文摘要 | LiCMS (Leptospira interrogans citramalate synthase) catalyses the first reaction of the isoleucine biosynthesis pathway in L. interrogans, the pathogen of leptospirosis. The catalytic reaction is regulated through feedback inhibition by its end product isoleucine. To understand the molecular basis of the high selectivity of the inhibitor and the mechanism of feedback inhibition, we determined the crystal structure of LiCMSC (C-terminal regulatory domain of LiCMS) in complex with isoleucine, and performed a biochemical study of the inhibition of LiCMS using mutagenesis and kinetic methods. LiCMSC forms a dimer of dimers in both the crystal structure and solution and the dimeric LiCMSC is the basic functional unit. LiCMSC consists of six-strands forming two anti-parallel beta-sheets and two alpha-helices and assumes a beta alpha beta three-layer sandwich structure. The inhibitor isoleucine is bound in a pocket at the dimer interface and has both hydrophobic and hydrogen-bonding interactions with several conserved residues of both subunits. The high selectivity of LiCMS for isoleucine over leucine is primarily dictated by the residues, Tyr(430), Leu(451), Tyr(454), Ile(458) and Val(468), that form a hydrophobic pocket to accommodate the side chain of the inhibitor. The binding of isoleucine has inhibitory effects on the binding of both the substrate, pyruvate, and coenzyme, acetylCoA, in a typical pattern of K-type inhibition. The structural and biochemical data from the present study together suggest that the binding of isoleucine affects the binding of the substrate and coenzyme at the active site, possibly via conformational change of the dimer interface of the regulatory domain, leading to inhibition of the catalytic reaction. |
| 学科主题 | Biochemistry & Molecular Biology |
| 类目[WOS] | Biochemistry & Molecular Biology |
| 关键词[WOS] | BIOSYNTHETIC THREONINE DEAMINASE ; ALPHA-ISOPROPYLMALATE SYNTHASE ; MYCOBACTERIUM-TUBERCULOSIS ; ESCHERICHIA-COLI ; ISOLEUCINE BIOSYNTHESIS ; CRYSTAL-STRUCTURE ; SPIROCHETE-LEPTOSPIRA ; ASPARTATE KINASE ; ENZYME ; PHOSPHORIBOSYLTRANSFERASE |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000267612200013 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/1312]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Zhang, P,Ma, J,Zhang, ZL,et al. Molecular basis of the inhibitor selectivity and insights into the feedback inhibition mechanism of citramalate synthase from Leptospira interrogans[J]. BIOCHEMICAL JOURNAL,2009,421(1):133-143. |
| APA | Zhang, P.,Ma, J.,Zhang, ZL.,Zha, MW.,Xu, H.,...&Ding, JP.(2009).Molecular basis of the inhibitor selectivity and insights into the feedback inhibition mechanism of citramalate synthase from Leptospira interrogans.BIOCHEMICAL JOURNAL,421(1),133-143. |
| MLA | Zhang, P,et al."Molecular basis of the inhibitor selectivity and insights into the feedback inhibition mechanism of citramalate synthase from Leptospira interrogans".BIOCHEMICAL JOURNAL 421.1(2009):133-143. |
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