Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed mammalian enzyme known for its role in the degradation of itaconate, a bactericidal immunometabolite produced in activated macrophages. The association of CLYBL loss-of-function with reduced circulating vitamin B12 levels was proposed to result from inhibition of the B12-dependent enzyme methylmalonyl-CoA mutase (MCM) by itaconyl-CoA. The discrepancy between the highly inducible and locally confined production of itaconate and the broad expression profile of CLYBL across tissues, suggested a role for this enzyme beyond itaconate catabolism. We discovered that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side-product of promiscuous TCA cycle enzymes. We found that CLYBL knockout cells, accumulating malyl-CoA but not itaconyl-CoA, show decreased levels of adenosylcobalamin and that malyl-CoA is a more potent inhibitor of MCM than itaconyl-CoA. Our work thus suggests that malyl-CoA plays a role in the B12 deficiency observed in individuals with CLYBL loss-of-function. Data deposited herein corresponds to the untargeted LC-HRMS/MS acyl-CoA ester and HILIC analyses conducted for this study.
[doi:10.25345/C5G44J284]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: CLYBL ; acyl-CoA ; metabolite repair ; 3T3-L1 adipocytes ; vitamin B12
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Carole Linster, Luxembourg Centre for Systems Biomedicine, Luxembourg |
Submitting User: | coreymgriffith |
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