当前位置: X-MOL 学术BBA Gen. Subj. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Comparative structural and mechanistic studies of 4-hydroxy-tetrahydrodipicolinate reductases from Mycobacterium tuberculosis and Vibrio vulnificus
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2020-09-24 , DOI: 10.1016/j.bbagen.2020.129750
Swanandi Pote 1 , Sangita Kachhap 2 , Nicholas J Mank 1 , Leily Daneshian 1 , Vincent Klapper 1 , Sarah Pye 1 , Amy K Arnette 1 , Linda S Shimizu 1 , Tomasz Borowski 2 , Maksymilian Chruszcz 1
Affiliation  

Background

The products of the lysine biosynthesis pathway, meso-diaminopimelate and lysine, are essential for bacterial survival. This paper focuses on the structural and mechanistic characterization of 4-hydroxy-tetrahydrodipicolinate reductase (DapB), which is one of the enzymes from the lysine biosynthesis pathway. DapB catalyzes the conversion of (2S, 4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate (HTPA) to 2,3,4,5-tetrahydrodipicolinate in an NADH/NADPH dependent reaction. Genes coding for DapBs were identified as essential for many pathogenic bacteria, and therefore DapB is an interesting new target for the development of antibiotics.

Methods

We have combined experimental and computational approaches to provide novel insights into mechanism of the DapB catalyzed reaction.

Results

Structures of DapBs originating from Mycobacterium tuberculosis and Vibrio vulnificus in complexes with NAD+, NADP+, as well as with inhibitors, were determined and described. The structures determined by us, as well as currently available structures of DapBs from other bacterial species, were compared and used to elucidate a mechanism of reaction catalyzed by this group of enzymes. Several different computational methods were used to provide a detailed description of a plausible reaction mechanism.

Conclusions

This is the first report presenting the detailed mechanism of reaction catalyzed by DapB.

General significance

Structural data in combination with information on the reaction mechanism provide a background for development of DapB inhibitors, including transition-state analogues.



中文翻译:

结核分枝杆菌和创伤弧菌的 4-羟基四氢吡啶二羧酸还原酶的比较结构和机理研究

背景

赖氨酸生物合成途径的产物,内消旋二氨基庚二酸和赖氨酸,对于细菌的存活是必不可少的。本文重点介绍 4-羟基四氢吡啶二羧酸还原酶 (DapB) 的结构和机理表征,DapB 是赖氨酸生物合成途径中的一种酶。DapB在 NADH/NADPH 依赖性反应中催化 (2 S , 4 S )-4-羟基-2,3,4,5-四氢吡啶二羧酸 (HTPA) 转化为 2,3,4,5-四氢吡啶二羧酸。编码 DapB 的基因被确定为许多致病细菌所必需的,因此 DapB 是开发抗生素的一个有趣的新目标。

方法

我们结合了实验和计算方法,为 DapB 催化反应的机制提供了新的见解。

结果

测定并描述了源自结核分枝杆菌创伤弧菌与 NAD +、NADP +以及抑制剂复合物的 DapB 的结构。我们确定的结构以及来自其他细菌物种的 DapB 目前可用的结构进行了比较,并用于阐明由这组酶催化的反应机制。几种不同的计算方法被用来提供一个合理的反应机制的详细描述。

结论

这是第一份介绍 DapB 催化反应详细机制的报告。

一般意义

结构数据与反应机制信息相结合,为开发 DapB 抑制剂(包括过渡态类似物)提供了背景。

更新日期:2020-09-30
down
wechat
bug