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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target
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Structural insights into stereochemical inversion by diaminopimelate epimerase: An antibacterial drug target

机译：二氨基庚二酸酯差向异构酶对立体化学转化的结构见解：抗菌药物的靶标

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摘要

D-amino acids are much less common than their L-isomers but are widely distributed in most organisms. Many D-amino acids, including those necessary for bacterial cell wall formation, are synthesized from the corresponding L-isomers by α-amino acid racemases. The important class of pyridoxal phosphate-independent racemases function by an unusual mechanism whose details have been poorly understood. It has been proposed that the stereoinversion involves two active-site cysteine residues acting in concert as a base (thiolate) and an acid (thiol). Although crystallographic structures of several such enzymes are available, with the exception of the recent structures of glutamate racemase from Bacillus subtilis and of proline racemase from Trypanosoma cruzi, the structures either are of inactive forms (e.g., disulfide) or do not allow unambiguous modeling of the substrates in the active sites. Here, we present the crystal structures of diaminopimelate (DAP) epimerase from Haemophilus influenzae with two different isomers of the irreversible inhibitor and substrate mimic aziridino-DAP at 1.35-and 1.70-A resolution. These structures permit a detailed description of this pyridoxal 5′-phosphate-independent amino acid racemase active site and delineate the electrostatic interactions that control the exquisite substrate selectivity of DAP epimerase. Moreover, the active site shows how deprotonation of the substrates' nonacidic hydrogen at the α-carbon (pK_a ≈29) by a seemingly weakly basic cysteine residue (pK_a ≈8-10) is facilitated by interactions with two buried α-helices. Bacterial racemases, including glutamate racemase and DAP epimerase, are potential targets for the development of new agents effective against organisms resistant to conventional antibiotics.
机译：D-氨基酸比其L-异构体少得多，但广泛分布于大多数生物中。许多D-氨基酸，包括细菌细胞壁形成所必需的D-氨基酸，是由相应的L-异构体通过α-氨基酸外消旋体合成的。重要的一类与吡ido醛磷酸盐无关的外消旋体通过不寻常的机理起作用，其机理人们对此知之甚少。已经提出，立体转化涉及两个活性位点的半胱氨酸残基，它们协同作用为碱（硫醇盐）和酸（硫醇）。尽管可以获得几种这样的酶的晶体学结构，除了最近来自枯草芽孢杆菌的谷氨酸消旋酶和来自克氏锥虫的脯氨酸消旋酶的最近结构，这些结构要么是无活性的形式（例如，二硫键），要么不允许对它们进行明确的建模。活性部位的底物。在这里，我们介绍来自流感嗜血杆菌的二氨基庚二酸酯（DAP）差向异构酶的晶体结构，其不可逆抑制剂和底物模拟叠氮基-DAP的两个不同异构体的分离度为1.35和1.70-A。这些结构允许对该吡咯醛不依赖5'-磷酸的氨基酸消旋酶活性位点进行详细描述，并描述控制DAP差向异构酶的底物选择性的静电相互作用。此外，活性位点显示了如何通过与两个掩埋的α-螺旋相互作用，促进看似弱碱性的半胱氨酸残基（pK_a≈8-10）在α-碳上使底物的非酸性氢质子化（pK_a≈8-10）。细菌外消旋酶，包括谷氨酸消旋酶和DAP差向异构酶，是开发新型药物的潜在目标，这些药物可有效抵抗对常规抗生素具有抗性的生物。

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