7SMG

Crystal structure of a (p)ppApp hydrolase from Bacteroides caccae

7SMG の概要

• エントリーDOI: 10.2210/pdb7smg/pdb
• 分子名称: (p)ppApp hydrolase, 1,2-ETHANEDIOL, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: (p)ppapp hydrolase, bacteroides caccae, hydrolase
• 由来する生物種: Bacteroides caccae ATCC 43185
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 70960.94

構造登録者

Ahmad, S.,Alexei, A.G.,Tsang, K.K.,Trilesky, S.,Kim, Y.,Whitney, J.C. (登録日: 2021-10-25, 公開日: 2022-11-09, 最終更新日: 2024-10-16)

主引用文献

Ahmad, S.,Gordon, I.J.,Tsang, K.K.,Alexei, A.G.,Sychantha, D.,Colautti, J.,Trilesky, S.L.,Kim, Y.,Wang, B.,Whitney, J.C.
Identification of a broadly conserved family of enzymes that hydrolyze (p)ppApp.
Proc.Natl.Acad.Sci.USA, 120:e2213771120-e2213771120, 2023

PubMed Abstract: Bacteria produce a variety of nucleotide second messengers to adapt to their surroundings. Although chemically similar, the nucleotides guanosine penta- and tetraphosphate [(p)ppGpp] and adenosine penta- and tetraphosphate [(p)ppApp] have distinct functions in bacteria. (p)ppGpp mediates survival under nutrient-limiting conditions and its intracellular levels are regulated by synthetases and hydrolases belonging to the RelA-SpoT homolog (RSH) family of enzymes. By contrast, (p)ppApp is not known to be involved in nutrient stress responses and is synthesized by RSH-resembling toxins that inhibit the growth of bacterial cells. However, it remains unclear whether there exists a family of hydrolases that specifically act on (p)ppApp to reverse its toxic effects. Here, we present the structure and biochemical characterization of adenosine 3'-pyrophosphohydrolase 1 (Aph1), the founding member of a monofunctional (p)ppApp hydrolase family of enzymes. Our work reveals that Aph1 adopts a histidine-aspartate (HD)-domain fold characteristic of phosphohydrolase metalloenzymes and its activity mitigates the growth inhibitory effects of (p)ppApp-synthesizing toxins. Using an informatic approach, we identify over 2,000 putative (p)ppApp hydrolases that are widely distributed across bacterial phyla and found in diverse genomic contexts, and we demonstrate that 12 representative members hydrolyze ppApp. In addition, our in silico analyses reveal a unique molecular signature that is specific to (p)ppApp hydrolases, and we show that mutation of two residues within this signature broadens the specificity of Aph1 to promiscuously hydrolyze (p)ppGpp in vitro. Overall, our findings indicate that like (p)ppGpp hydrolases, (p)ppApp hydrolases are widespread in bacteria and may play important and underappreciated role(s) in bacterial physiology.

PubMed: 36989297
DOI: 10.1073/pnas.2213771120

実験手法

X-RAY DIFFRACTION (2.3 Å)