CLYBL averts methylmalonyl-CoA mutase inhibition and loss of vitamin B12 by eliminating malyl-CoA

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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/614871v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1bd0aa2org.highwire.dtl.DTLVardef@54e11org.highwire.dtl.DTLVardef@48661borg.highwire.dtl.DTLVardef@127968f_HPS_FORMAT_FIGEXP M_FIG C_FIG