CLYBL is a polymorphic human enzyme with malate synthase and β-methylmalate synthase activity

Human Molecular Genetics
Laura StrittmatterVamsi K Mootha

Abstract

CLYBL is a human mitochondrial enzyme of unknown function that is found in multiple eukaryotic taxa and conserved to bacteria. The protein is expressed in the mitochondria of all mammalian organs, with highest expression in brown fat and kidney. Approximately 5% of all humans harbor a premature stop polymorphism in CLYBL that has been associated with reduced levels of circulating vitamin B12. Using comparative genomics, we now show that CLYBL is strongly co-expressed with and co-evolved specifically with other components of the mitochondrial B12 pathway. We confirm that the premature stop polymorphism in CLYBL leads to a loss of protein expression. To elucidate the molecular function of CLYBL, we used comparative operon analysis, structural modeling and enzyme kinetics. We report that CLYBL encodes a malate/β-methylmalate synthase, converting glyoxylate and acetyl-CoA to malate, or glyoxylate and propionyl-CoA to β-methylmalate. Malate synthases are best known for their established role in the glyoxylate shunt of plants and lower organisms and are traditionally described as not occurring in humans. The broader role of a malate/β-methylmalate synthase in human physiology and its mechanistic link to vitamin B12 metabolism remain ...Continue Reading

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Citations

Oct 10, 2015·Nucleic Acids Research·Sarah E CalvoVamsi K Mootha
Oct 24, 2017·Nucleic Acids Research·Kenneth W EllensCarole L Linster
Nov 28, 2017·BMC Systems Biology·Anthony C SmithAlan J Robinson
Feb 16, 2018·Genes & Nutrition·S SurendranK S Vimaleswaran
Nov 22, 2018·Frontiers in Cellular and Infection Microbiology·Garima AroraRamandeep Singh
Jul 30, 2020·Oxidative Medicine and Cellular Longevity·Ruidong LiKaixong Tao
Aug 30, 2020·Disease Models & Mechanisms·Éva SaskőiKrisztina Takács-Vellai
Oct 24, 2017·Cell·Hongying ShenVamsi K Mootha

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