| 1326706-26-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• CAS: 1326706-26-6
• 化学式: C₁₆H₂₉N₂O₁₄PS
• 分子量: 536.451
• InChiKey: FVQZBHDUDWCYPF-GNNCMFTNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.2
• 重原子数：
  34.0
• 可旋转键数：
  13.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  286.63
• 氢给体数：
  10.0
• 氢受体数：
  12.0

反应信息

• 作为产物：
  描述：

  在 FosB from Staphylococcus aureus 、 三氟乙酸 、 nickel dichloride 、 4-羟乙基哌嗪乙磺酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 3.5h， 生成
  参考文献：
  名称：

  Synthesis of Bacillithiol and the Catalytic Selectivity of FosB-Type Fosfomycin Resistance Proteins

  摘要：

  Bacillithiol (BSH) has been prepared on the gram scale from the inexpensive starting material, D-glucosamine hydrochloride, in 11 steps and 8-9% overall yield. The BSH was used to survey the substrate and metal-ion selectivity of FosB enzymes from four Gram-positive microorganisms associated with the deactivation of the antibiotic fosfomycin. The in vitro results indicate that the preferred thiol substrate and metal ion for the FosB from Staphylococcus aureus are BSH and Ni(II), respectively. However, the metal-ion selectivity is less distinct with FosB from Bacillus subtilis, Bacillus anthracis, or Bacillus cereus.

  DOI：

  10.1021/ol302327t

文献信息

• Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in <i>Staphylococcus aureus</i>
  作者：Alexandra A. Roberts、Sunil V. Sharma、Andrew W. Strankman、Shayla R. Duran、Mamta Rawat、Chris J. Hamilton

  DOI：10.1042/bj20121541

  日期：2013.4.1

  FosB is a divalent-metal-dependent thiol-S-transferase implicated in fosfomycin resistance among many pathogenic Gram-positive bacteria. In the present paper, we describe detailed kinetic studies of FosB from Staphylococcus aureus (SaFosB) that confirm that bacillithiol (BSH) is its preferred physiological thiol substrate. SaFosB is the first to be characterized among a new class of enzyme (bacillithiol-S-transferases), which, unlike glutathione transferases, are distributed among many low-G+C Gram-positive bacteria that use BSH instead of glutathione as their major low-molecular-mass thiol. The Km values for BSH and fosfomycin are 4.2 and 17.8 mM respectively. Substrate specificity assays revealed that the thiol and amino groups of BSH are essential for activity, whereas malate is important for SaFosB recognition and catalytic efficiency. Metal activity assays indicated that Mn2+ and Mg2+ are likely to be the relevant cofactors under physiological conditions. The serine analogue of BSH (BOH) is an effective competitive inhibitor of SaFosB with respect to BSH, but uncompetitive with respect to fosfomycin. Coupled with NMR characterization of the reaction product (BS–fosfomycin), this demonstrates that the SaFosB-catalysed reaction pathway involves a compulsory ordered binding mechanism with fosfomycin binding first followed by BSH which then attacks the more sterically hindered C-1 carbon of the fosfomycin epoxide. Disruption of BSH biosynthesis in S. aureus increases sensitivity to fosfomycin. Together, these results indicate that SaFosB is a divalent-metal-dependent bacillithiol-S-transferase that confers fosfomycin resistance on S. aureus.

  FosB 是一种依赖二价金属的硫醇-S-转移酶，与许多致病性革兰氏阳性细菌的磷霉素耐药性有关。在本文中，我们描述了对金黄色葡萄球菌（SaFosB）中的 FosB 的详细动力学研究，研究结果证实，杆菌硫醇（BSH）是其首选的生理硫醇底物。与谷胱甘肽转移酶不同，SaFosB分布在许多低G+C革兰氏阳性细菌中，它们使用BSH代替谷胱甘肽作为主要的低分子量硫醇。BSH 和磷霉素的 Km 值分别为 4.2 和 17.8 mM。底物特异性测定显示，BSH 的硫醇和氨基对活性至关重要，而苹果酸盐对 SaFosB 的识别和催化效率至关重要。金属活性测定表明，在生理条件下，Mn2+ 和 Mg2+ 可能是相关的辅助因子。相对于 BSH，BSH 的丝氨酸类似物（BOH）是一种有效的 SaFosB 竞争性抑制剂，但相对于磷霉素则不具竞争性。结合反应产物（BS-磷霉素）的核磁共振特征，这表明 SaFosB 催化反应途径涉及一种强制性有序结合机制，先是磷霉素结合，然后是 BSH 结合，BSH 然后攻击磷霉素环氧化物中立体阻碍较大的 C-1 碳。破坏金黄色葡萄球菌的 BSH 生物合成会增加其对磷霉素的敏感性。这些结果表明，SaFosB 是一种依赖于二价金属的碱性硫醇-S-转移酶，它能使金黄色葡萄球菌对磷霉素产生抗性。