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<p>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 <i>CLYBL</i> loss of function with reduced circulating vitamin B<sub>12</sub> levels was proposed to result from inhibition of the B<sub>12</sub>-dependent enzyme methylmalonyl-CoA mutase by itaconyl-CoA. The discrepancy between the highly inducible and locally confined production of itaconate and the broad expression profile of <i>CLYBL</i> across tissues suggested a role for this enzyme beyond itaconate catabolism. Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. We found that <i>CLYBL</i> knockout cells, accumulating malyl-CoA but not itaconyl-CoA, show decreased levels of adenosylcobalamin and that malyl-CoA is a more potent inhibitor of methylmalonyl-CoA mutase than itaconyl-CoA. Our work thus suggests that malyl-CoA plays a role in the B<sub>12</sub> deficiency observed in individuals with <i>CLYBL</i> loss of function.</p><p></p>

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CLYBL averts vitamin B12 depletion by repairing malyl-CoA

  • 期刊论文

  • 发表日期：

    2025年3月19日

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  • Corey M. Griffith,
  • Jean-François Conrotte,
  • Parisa Paydar,
  • Xinqiang Xie,
  • Ursula Heins-Marroquin,
  • Floriane Gavotto,
  • Christian Jäger,
  • Kenneth W. Ellens,
  • Carole L. Linster

摘要

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 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. Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid 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 methylmalonyl-CoA mutase 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.