6OXD

Structure of Mycobacterium tuberculosis methylmalonyl-CoA mutase with adenosyl cobalamin

6OXD の概要

• エントリーDOI: 10.2210/pdb6oxd/pdb
• 関連するPDBエントリー: 6OXC
• 分子名称: Methylmalonyl-CoA mutase large subunit, Methylmalonyl-CoA mutase small subunit, COBALAMIN, ... (7 entities in total)
• 機能のキーワード: methylmalonyl coa mutase, methylmalonyl coa mutase deficiency, metabolic disease, cobalamin, cobalt, disease mutation, isomerase, metal-binding, itaconyl coa, radical, mycobacterium tuberculosis, immunometabolite, b12, methylmalonic aciduria
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 148063.54

構造登録者

Purchal, M.,Ruetz, M.,Banerjee, R.,Koutmos, M. (登録日: 2019-05-13, 公開日: 2019-11-13, 最終更新日: 2023-10-11)

主引用文献

Ruetz, M.,Campanello, G.C.,Purchal, M.,Shen, H.,McDevitt, L.,Gouda, H.,Wakabayashi, S.,Zhu, J.,Rubin, E.J.,Warncke, K.,Mootha, V.K.,Koutmos, M.,Banerjee, R.
Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair.
Science, 366:589-593, 2019

PubMed Abstract: Itaconate is an immunometabolite with both anti-inflammatory and bactericidal effects. Its coenzyme A (CoA) derivative, itaconyl-CoA, inhibits B-dependent methylmalonyl-CoA mutase (MCM) by an unknown mechanism. We demonstrate that itaconyl-CoA is a suicide inactivator of human and MCM, which forms a markedly air-stable biradical adduct with the 5'-deoxyadenosyl moiety of the B coenzyme. Termination of the catalytic cycle in this way impairs communication between MCM and its auxiliary repair proteins. Crystallography and spectroscopy of the inhibited enzyme are consistent with a metal-centered cobalt radical ~6 angstroms away from the tertiary carbon-centered radical and suggest a means of controlling radical trajectories during MCM catalysis. Mycobacterial MCM thus joins enzymes in the glyoxylate shunt and the methylcitrate cycle as targets of itaconate in pathogen propionate metabolism.

PubMed: 31672889
DOI: 10.1126/science.aay0934

実験手法

X-RAY DIFFRACTION (2 Å)