5VXO

Crystal Structure Analysis of human CLYBL in complex with propionyl-CoA

5VXO の概要

• エントリーDOI: 10.2210/pdb5vxo/pdb
• 関連するPDBエントリー: 5VXC
• 分子名称: Citrate lyase subunit beta-like protein, mitochondrial, propionyl Coenzyme A, 1,2-ETHANEDIOL, ... (8 entities in total)
• 機能のキーワード: clybl, trimer, propionyl-coa, citrate form, peg form, lyase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 114306.28

構造登録者

Shen, H. (登録日: 2017-05-23, 公開日: 2017-11-01, 最終更新日: 2023-10-04)

主引用文献

Shen, H.,Campanello, G.C.,Flicker, D.,Grabarek, Z.,Hu, J.,Luo, C.,Banerjee, R.,Mootha, V.K.
The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12.
Cell, 171:771-782.e11, 2017

PubMed Abstract: CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator. We report that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B inactivation.

PubMed: 29056341
DOI: 10.1016/j.cell.2017.09.051

実験手法

X-RAY DIFFRACTION (2.266 Å)