8FFF

Crystal structure of Staphylococcus aureus D-alanine D-alanine ligase enzyme in complex with acetate

8FFF の概要

• エントリーDOI: 10.2210/pdb8fff/pdb
• 分子名称: D-alanine--D-alanine ligase, ACETATE ION (3 entities in total)
• 機能のキーワード: d-alanine d-alanie, s.aureus, cell wall biosynthesis, omega loop, ligase
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40161.23

構造登録者

Jayasinghe, Y.P.,Ronning, D.R. (登録日: 2022-12-08, 公開日: 2024-05-08, 最終更新日: 2024-05-15)

主引用文献

Panda, S.,Jayasinghe, Y.P.,Shinde, D.D.,Bueno, E.,Stastny, A.,Bertrand, B.P.,Chaudhari, S.S.,Kielian, T.,Cava, F.,Ronning, D.R.,Thomas, V.C.
Staphylococcus aureus counters organic acid anion-mediated inhibition of peptidoglycan cross-linking through robust alanine racemase activity.
Biorxiv, 2024

PubMed Abstract: Weak organic acids are commonly found in host niches colonized by bacteria, and they can inhibit bacterial growth as the environment becomes acidic. This inhibition is often attributed to the toxicity resulting from the accumulation of high concentrations of organic anions in the cytosol, which disrupts cellular homeostasis. However, the precise cellular targets that organic anions poison and the mechanisms used to counter organic anion intoxication in bacteria have not been elucidated. Here, we utilize acetic acid, a weak organic acid abundantly found in the gut to investigate its impact on the growth of . We demonstrate that acetate anions bind to and inhibit d-alanyl-d-alanine ligase (Ddl) activity in . Ddl inhibition reduces intracellular d-alanyl-d-alanine (d-Ala-d-Ala) levels, compromising staphylococcal peptidoglycan cross-linking and cell wall integrity. To overcome the effects of acetate-mediated Ddl inhibition, maintains a high intracellular d-Ala pool through alanine racemase (Alr1) activity and additionally limits the flux of d-Ala to d-glutamate by controlling d-alanine aminotransferase (Dat) activity. Surprisingly, the of acetate intoxication in is common to multiple biologically relevant weak organic acids indicating that Ddl is a conserved target of small organic anions. These findings suggest that may have evolved to maintain high intracellular d-Ala concentrations, partly to counter organic anion intoxication.

PubMed: 38293037
DOI: 10.1101/2024.01.15.575639

実験手法

X-RAY DIFFRACTION (1.92 Å)