The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Oct 24

PMID 29056341

Citations 60

Authors

Hongying Shen

Gregory C Campanello

Daniel Flicker

Zenon Grabarek

Junchi Hu

Cheng Luo

Ruma Banerjee

Vamsi K Mootha

Affiliations

Soon will be listed here.

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.

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