The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B₁₂.

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 B₁₂ 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 B₁₂ metabolism a

SUBMITTER: Shen H 

PROVIDER: S-EPMC5827971 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature