Newton Gerald L, Buchmeier Nancy, Fahey Robert C
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0314, USA.
Microbiol Mol Biol Rev. 2008 Sep;72(3):471-94. doi: 10.1128/MMBR.00008-08.
Mycothiol (MSH; AcCys-GlcN-Ins) is the major thiol found in Actinobacteria and has many of the functions of glutathione, which is the dominant thiol in other bacteria and eukaryotes but is absent in Actinobacteria. MSH functions as a protected reserve of cysteine and in the detoxification of alkylating agents, reactive oxygen and nitrogen species, and antibiotics. MSH also acts as a thiol buffer which is important in maintaining the highly reducing environment within the cell and protecting against disulfide stress. The pathway of MSH biosynthesis involves production of GlcNAc-Ins-P by MSH glycosyltransferase (MshA), dephosphorylation by the MSH phosphatase MshA2 (not yet identified), deacetylation by MshB to produce GlcN-Ins, linkage to Cys by the MSH ligase MshC, and acetylation by MSH synthase (MshD), yielding MSH. Studies of MSH mutants have shown that the MSH glycosyltransferase MshA and the MSH ligase MshC are required for MSH production, whereas mutants in the MSH deacetylase MshB and the acetyltransferase (MSH synthase) MshD produce some MSH and/or a closely related thiol. Current evidence indicates that MSH biosynthesis is controlled by transcriptional regulation mediated by sigma(B) and sigma(R) in Streptomyces coelicolor. Identified enzymes of MSH metabolism include mycothione reductase (disulfide reductase; Mtr), the S-nitrosomycothiol reductase MscR, the MSH S-conjugate amidase Mca, and an MSH-dependent maleylpyruvate isomerase. Mca cleaves MSH S-conjugates to generate mercapturic acids (AcCySR), excreted from the cell, and GlcN-Ins, used for resynthesis of MSH. The phenotypes of MSH-deficient mutants indicate the occurrence of one or more MSH-dependent S-transferases, peroxidases, and mycoredoxins, which are important targets for future studies. Current evidence suggests that several MSH biosynthetic and metabolic enzymes are potential targets for drugs against tuberculosis. The functions of MSH in antibiotic-producing streptomycetes and in bioremediation are areas for future study.
麦硫因（MSH；乙酰半胱氨酸-葡糖胺-肌醇）是放线菌中发现的主要硫醇，具有许多谷胱甘肽的功能，而谷胱甘肽是其他细菌和真核生物中的主要硫醇，但在放线菌中不存在。MSH作为半胱氨酸的储备库，并在烷基化剂、活性氧和氮物种以及抗生素的解毒过程中发挥作用。MSH还作为硫醇缓冲剂，在维持细胞内高度还原的环境以及抵御二硫键应激方面具有重要作用。MSH生物合成途径包括由MSH糖基转移酶（MshA）产生葡糖胺-肌醇磷酸（GlcNAc-Ins-P），由尚未鉴定的MSH磷酸酶MshA2进行去磷酸化，由MshB进行脱乙酰化以产生葡糖胺-肌醇（GlcN-Ins），由MSH连接酶MshC与半胱氨酸连接，以及由MSH合酶（MshD）进行乙酰化，从而产生MSH。对MSH突变体的研究表明，MSH糖基转移酶MshA和MSH连接酶MshC是产生MSH所必需的，而MSH脱乙酰酶MshB和乙酰转移酶（MSH合酶）MshD的突变体则产生一些MSH和/或一种密切相关的硫醇。目前的证据表明，在天蓝色链霉菌中，MSH生物合成受由sigma(B)和sigma(R)介导的转录调控。已鉴定的MSH代谢酶包括麦硫因还原酶（二硫键还原酶；Mtr）、S-亚硝基麦硫因还原酶MscR、MSH S-共轭酰胺酶Mca以及一种依赖MSH的马来酰丙酮酸异构酶。Mca裂解MSH S-共轭物以产生从细胞中排出的巯基尿酸（AcCySR）和用于MSH再合成的葡糖胺-肌醇（GlcN-Ins）。MSH缺陷突变体的表型表明存在一种或多种依赖MSH的S-转移酶、过氧化物酶和麦硫因氧化还原蛋白，这些是未来研究的重要靶点。目前的证据表明，几种MSH生物合成和代谢酶是抗结核药物的潜在靶点。MSH在抗生素产生链霉菌中的功能以及在生物修复中的作用是未来研究的领域。
