Weill Cornell Medicine, New York, NY.
Texas A&M University, College Station, TX.
J Exp Med. 2021 Jul 5;218(7). doi: 10.1084/jem.20191957. Epub 2021 May 5.
Comparative sequence analysis has enabled the annotation of millions of genes from organisms across the evolutionary tree. However, this approach has inherently biased the annotation of phylogenetically ubiquitous, rather than species-specific, functions. The ecologically unusual pathogen Mycobacterium tuberculosis (Mtb) has evolved in humans as its sole reservoir and emerged as the leading bacterial cause of death worldwide. However, the physiological factors that define Mtb's pathogenicity are poorly understood. Here, we report the structure and function of a protein that is required for optimal in vitro fitness and bears homology to two distinct enzymes, Rv0812. Despite diversification of related orthologues into biochemically distinct enzyme families, rv0812 encodes a single active site with aminodeoxychorismate lyase and D-amino acid transaminase activities. The mutual exclusivity of substrate occupancy in this active site mediates coupling between nucleic acid and cell wall biosynthesis, prioritizing PABA over D-Ala/D-Glu biosynthesis. This bifunctionality reveals a novel, enzymatically encoded fail-safe mechanism that may help Mtb and other bacteria couple replication and division.
比较序列分析使我们能够对来自进化树上各种生物体的数百万个基因进行注释。然而，这种方法本质上偏向于对系统发生上普遍存在的功能进行注释，而不是对物种特异性的功能进行注释。生态上不寻常的病原体结核分枝杆菌（Mtb）在人类中作为其唯一的宿主而进化，并成为全球导致死亡的主要细菌病原体。然而，定义 Mtb 致病性的生理因素仍知之甚少。在这里，我们报告了一种蛋白质的结构和功能，该蛋白质是体外最佳适应性所必需的，并且与两种不同的酶 Rv0812 具有同源性。尽管相关同源物多样化为具有不同生化特性的酶家族，但 rv0812 编码了一个具有氨基脱氧胆质酸盐裂解酶和 D-氨基酸转氨酶活性的单一活性位点。该活性位点中底物占据的相互排斥性介导了核酸和细胞壁生物合成之间的偶联，优先考虑 PABA 而不是 D-Ala/D-Glu 生物合成。这种双功能揭示了一种新的、酶编码的故障安全机制，可能有助于 Mtb 和其他细菌将复制和分裂偶联起来。
