D-myo-inosityl 2-N-acetamido-2-deoxy-α-D-glucopyranoside | 526201-68-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: D-myo-inosityl 2-N-acetamido-2-deoxy-α-D-glucopyranoside
• CAS: 526201-68-3
• 化学式: C₁₄H₂₅NO₁₁
• 分子量: 383.353
• InChiKey: MRKTUVZZZRUSQR-JPUVNKLSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.87
• 重原子数：
  26.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  209.4
• 氢给体数：
  9.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  D-myo-inosityl 2-N-acetamido-2-deoxy-α-D-glucopyranoside 在 recombinant protG-AcGI deacetylase 、 三羟甲基氨基甲烷 作用下， 生成 1L-1-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-myo-inositol
  参考文献：
  名称：

  Synthesis of 1-d- and 1-l-myo-inosityl 2-N-acetamido-2-deoxy-α-d-glucopyranoside establishes substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase

  摘要：

  Mycothiol (MSH, 1-D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyrano side) is the principal low molecular weight thiol in actinomycetes. The enzyme 1-D-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase (AcGI deacetylase) is involved in the biosynthesis of MSH and forms the free amine 1-D-niyo-inosityl 2-amino-2-deoxy-alpha-D-glucopyranoside, which is used in the third of four steps of MSH biosynthesis. Here, we report the synthesis of two isomers of AcGL which contain either 1-L-myo-inositol or 1-D-myo-inositol. These synthetic products were used to investigate substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00154-8
• 作为产物：
  描述：

  Acetic acid (1S,2S,3S,4R,5S,6S)-2,3,4-triacetoxy-5-benzyloxy-6-((2R,3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-azido-tetrahydro-pyran-2-yloxy)-cyclohexyl ester 在 palladium on activated charcoal 盐酸 、 氢气 、 magnesium methanolate 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 18.0h， 生成 D-myo-inosityl 2-N-acetamido-2-deoxy-α-D-glucopyranoside
  参考文献：
  名称：

  Synthesis of 1-d- and 1-l-myo-inosityl 2-N-acetamido-2-deoxy-α-d-glucopyranoside establishes substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase

  摘要：

  Mycothiol (MSH, 1-D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyrano side) is the principal low molecular weight thiol in actinomycetes. The enzyme 1-D-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase (AcGI deacetylase) is involved in the biosynthesis of MSH and forms the free amine 1-D-niyo-inosityl 2-amino-2-deoxy-alpha-D-glucopyranoside, which is used in the third of four steps of MSH biosynthesis. Here, we report the synthesis of two isomers of AcGL which contain either 1-L-myo-inositol or 1-D-myo-inositol. These synthetic products were used to investigate substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00154-8

文献信息

• <i>N</i> -Acetyl-1- <scp>d</scp> - <i>myo</i> -Inosityl-2-Amino-2-Deoxy-α- <scp>d</scp> -Glucopyranoside Deacetylase (MshB) Is a Key Enzyme in Mycothiol Biosynthesis
  作者：Gerald L. Newton、Yossef Av-gay、Robert C. Fahey

  DOI：10.1128/jb.182.24.6958-6963.2000

  日期：2000.12.15

  Mycothiol is a novel thiol produced only by actinomycetes and is the major low-molecular-weight thiol in mycobacteria. Mycothiol was previously shown to be synthesized from 1- d - myo -inosityl-2-amino-2-deoxy-α- d -glucopyranoside by ligation with cysteine followed by acetylation. A novel mycothiol-dependent detoxification enzyme, mycothiol conjugate amidase, was recently identified in Mycobacterium smegmatis and shown to have a homolog, Rv1082, in Mycobacterium tuberculosis . In the present study we found that a protein encoded by the M. tuberculosis open reading frame Rv1170, a homolog of Rv1082, possesses weak mycothiol conjugate amidase activity but shows substantial deacetylation activity with 1- d - myo -inosityl-2-acetamido-2-deoxy-α- d -glucopyranoside (GlcNAc-Ins), a hypothetical mycothiol biosynthetic precursor. The availability of this protein enabled us to develop an assay for GlcNAc-Ins, which was used to demonstrate that GlcNAc-Ins is present in M. smegmatis at a level about twice that of mycothiol. It was shown that GlcNAc-Ins is absent in mycothiol-deficient mutant strain 49 of M. smegmatis and that this strain can concentrate GlcNAc-Ins from the medium and convert it to mycothiol. This demonstrates that GlcNAc-Ins is a key intermediate in the pathway of mycothiol biosynthesis. Assignment of Rv1170 as the gene coding the deacetylase in the M. tuberculosis genome represents the first identification of a gene of the mycothiol biosynthesis pathway. The presence of a large cellular pool of substrate for this enzyme suggests that it may be important in regulating mycothiol biosynthesis.

  摘要 霉菌硫醇是一种仅由放线菌产生的新型硫醇，也是霉菌中主要的低分子量硫醇。以前的研究表明，霉菌硫醇是由 1- d - 肌醇 -inosityl-2-amino-2-deoxy-α- d d - myo -inosityl-2-amino-2-deoxy-α- d-吡喃葡萄糖苷。最近在烟曲霉分枝杆菌（Mycobacterium smegmatis）中发现了一种新的依赖于霉硫醇的解毒酶--霉硫醇共轭酰胺酶。 分枝杆菌 的同源物 Rv1082。 结核分枝杆菌 .在本研究中，我们发现由 结核分枝杆菌 开放阅读框 Rv1170 所编码的蛋白质是 Rv1082 的同源物，它具有微弱的霉酚共轭酰胺酶活性，但却显示出大量的去乙酰化活性，其 1- d - 肌 -肌醇-2-乙酰氨基-2-脱氧-α-乙酰基的大量脱乙酰活性。 d -葡萄糖吡喃糖苷（GlcNAc-Ins），这是一种假定的霉菌硫醇生物合成前体。有了这种蛋白质，我们就能开发出一种 GlcNAc-Ins 的检测方法，并用它来证明 GlcNAc-Ins 存在于 M. smegmatis 的水平大约是霉酚的两倍。结果表明，在霉菌硫醇缺乏的突变株 49 中，GlcNAc-Ins 不存在。 M. smegmatis 该菌株能从培养基中浓缩 GlcNAc-Ins 并将其转化为霉菌硫醇。这表明 GlcNAc-Ins 是霉菌硫醇生物合成途径中的一个关键中间体。将 Rv1170 指定为结核杆菌中编码脱乙酰酶的基因。 结核杆菌 基因组中的去乙酰化酶基因，这是首次发现霉菌硫醇生物合成途径的基因。这种酶在细胞中存在大量底物，这表明它可能在调节霉菌硫醇的生物合成中起着重要作用。
• The Crystal Structure of 1-D-myo-Inosityl 2-Acetamido-2-deoxy-α-D-glucopyranoside Deacetylase (MshB) from Mycobacterium tuberculosis Reveals a Zinc Hydrolase with a Lactate Dehydrogenase Fold
  作者：Jason T. Maynes、Craig Garen、Maia M. Cherney、Gerald Newton、Dorit Arad、Yossef Av-Gay、Robert C. Fahey、Michael N.G. James

  DOI：10.1074/jbc.m308914200

  日期：2003.11

  agent in actinomycetes, including Mycobacterium tuberculosis. The biosynthesis of MSH involves a deacetylase that removes the acetyl group from the precursor GlcNAc-Ins to yield GlcN-Ins. The deacetylase (MshB) corresponds to Rv1170 of M. tuberculosis with a molecular mass of 33,400 Da. MshB is a Zn2+ metalloprotein, and the deacetylase activity is completely dependent on the presence of a divalent metal

  麦考硫醇（1-D-肌肌醇2-（N-乙酰基-L-半胱氨酰基）酰胺基-2-脱氧-α-D-吡喃葡萄糖苷，MSH或AcCys-GlcN-肌醇（Ins））是放线菌中的主要还原剂，包括结核分枝杆菌。MSH的生物合成涉及脱乙酰基酶，该脱乙酰基酶从前体GlcNAc-Ins中除去乙酰基，从而生成GlcN-Ins。脱乙酰基酶（MshB）对应于结核分枝杆菌的Rv1170，分子量为33,400 Da。MshB是Zn2 +金属蛋白，脱乙酰酶活性完全取决于二价金属阳离子的存在。我们已经确定了MshB的X射线晶体学结构，该结构揭示了一种蛋白质，其折叠方式类似于N-末端结构域和C-末端结构域中的乳酸脱氢酶，该结构由两个β-折叠和两个α-螺旋组成。锌结合位点在N末端结构域中占据与乳酸脱氢酶的NAD +辅因子的位置相等的位置。Zn2 +是5配位的，带有MshB的3个残基（His-13，Asp-16，His-147）和两个水分
• Biosynthesis and Functions of Mycothiol, the Unique Protective Thiol of <i>Actinobacteria</i>
  作者：Gerald L. Newton、Nancy Buchmeier、Robert C. Fahey

  DOI：10.1128/mmbr.00008-08

  日期：2008.9

  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 σ ^B and σ ^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.

  摘要 霉菌硫醇（MSH；AcCys-GlcN-Ins）是放线菌中发现的主要硫醇。 放线菌 具有谷胱甘肽的许多功能，谷胱甘肽是其他细菌和真核生物中的主要硫醇，但放线菌中却没有。 放线菌 .MSH 可作为受保护的半胱氨酸储备，并在烷化剂、活性氧和氮物种以及抗生素的解毒过程中发挥作用。MSH 还是一种硫醇缓冲剂，对维持细胞内的高还原性环境和抵御二硫压力非常重要。MSH 的生物合成途径包括：MSH 糖基转移酶（MshA）产生 GlcNAc-Ins-P，MSH 磷酸酶 MshA2（尚未确定）进行去磷酸化，MshB 进行去乙酰化以产生 GlcN-Ins，MSH 连接酶 MshC 与 Cys 连接，MSH 合成酶（MshD）进行乙酰化以产生 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 的必要条件，而 MSH 去乙酰化酶 MshB 和乙酰转移酶（MSH 合成酶）MshD 的突变体会产生一些 MSH 和/或一种密切相关的硫醇。目前的证据表明，MSH 的生物合成是由σ B 介导的转录调控控制的。 B 和 σ R 在 链霉菌中 .已确定的 MSH 代谢酶包括霉硫酮还原酶（二硫化物还原酶；Mtr）、σ R S -亚硝基硫醇还原酶 MscR、MSH S -共轭酰胺酶 Mca 以及依赖 MSH 的马来酰丙酮酸异构酶。Mca 可裂解 MSH S -共轭物，生成从细胞中排出的巯基酸（AcCySR）和用于重新合成 MSH 的 GlcN-Ins。MSH缺陷突变体的表型表明存在一种或多种依赖于MSH的 S -转移酶、过氧化物酶和肌红蛋白，这些都是未来研究的重要目标。目前的证据表明，一些 MSH 生物合成和代谢酶是抗结核药物的潜在靶点。MSH 在产生抗生素的链霉菌和生物修复中的功能是未来研究的领域。
• Crystal Structure of MshB from Mycobacterium tuberculosis , a Deacetylase Involved in Mycothiol Biosynthesis
  作者：Andrew A. McCarthy、Neil A. Peterson、Rainer Knijff、Edward N. Baker

  DOI：10.1016/j.jmb.2003.11.034

  日期：2004.1

  All living species require protection against the damaging effects of the reactive oxygen species that are a natural by-product of aerobic life. In most organisms, glutathione is a critical component of these defences, maintaining a reducing environment inside cells. Some bacteria, however, including pathogenic mycobacteria, use an alternative low molecular mass thiol compound called mycothiol (MSH) for this purpose. Enzymes that synthesize MSH are attractive candidates for the design of novel anti-TB drugs because of the importance of MSH for mycobacterial life and the absence of such enzymes in humans. We have determined the three-dimensional structure of MshB (Rv1170), a metal-dependent deacetylase from Mycobacterium tuberculosis that catalyses the second step in MSH biosynthesis. The structure, determined at 1.9A resolution by X-ray crystallography (R=19.0%, R(free)=21.4%), reveals an alpha/beta fold in which helices pack against a seven-stranded mostly parallel beta-sheet. Large loops emanating from the C termini of the beta-strands enclose a deep cavity, which is the location of the putative active site. At the bottom of this cavity is a metal-binding site associated with a sequence motif AHPDDE that is invariant in all homologues. An adventitiously bound beta-octylglucoside molecule, used in crystallization, enables us to model the binding of the true substrate and propose a metal-dependent mechanistic model for deacetylation. Sequence comparisons indicate that MshB is representative of a wider family of enzymes that act on substituted N-acetylglucosamine residues, including a deacetylase involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors in eukaryotes.
• Purification and characterization of Mycobacterium tuberculosis 1d-myo-inosityl-2-acetamido-2-deoxy-α-d-glucopyranoside deacetylase, MshB, a mycothiol biosynthetic enzyme
  作者：Gerald L. Newton、Mary Ko、Philong Ta、Yossef Av-Gay、Robert C. Fahey

  DOI：10.1016/j.pep.2006.03.003

  日期：2006.6

  Mycothiol (MSH, AcCys-GlcN-Ins) is the major low molecular weight thiol in actinomycetes and is essential for growth of Mycobacterium tuberculosis. MshB, the GlcNAc-Ins deacetylase, is a key enzyme in MSH biosynthesis. MshB from M. tuberculosis was cloned, expressed, purified, and its properties characterized. Values of k(cat) and K-m for MshB were determined for the biological substrate, GlcNAc-Ins, and several other good substrates. The substrate specificity of MshB was compared to that of M. tuberculosis mycothiol S-conjugate amidase (Mca), a homologous enzyme having weak GlcNAc-Ins deacetylase activity. Both enzymes are metalloamidases with overlapping amidase activity toward mycothiol S-conjugates (AcCySR-GlcN-Ins). The Ins residue and hydrophobic R groups enhance the activity with both MshB and Mca, but changes in the acyl group attached to GIcN have opposite effects on the two enzymes. (c) 2006 Elsevier Inc. All rights reserved.