Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B metabolism.
Fiche publication
Date publication
octobre 2021
Journal
Critical reviews in biochemistry and molecular biology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GUEANT Jean-Louis
Tous les auteurs :
Guéant JL, Guéant-Rodriguez RM, Kosgei VJ, Coelho D
Lien Pubmed
Résumé
Methyl-Cobalamin (Cbl) derives from dietary vitamin B and acts as a cofactor of methionine synthase (MS) in mammals. MS encoded by catalyzes the remethylation of homocysteine to generate methionine and tetrahydrofolate, which fuel methionine and cytoplasmic folate cycles, respectively. Methionine is the precursor of S-adenosyl methionine (SAM), the universal methyl donor of transmethylation reactions. Impaired MS activity results from inadequate dietary intake or malabsorption of B and inborn errors of Cbl metabolism (IECM). The mechanisms at the origin of the high variability of clinical presentation of impaired MS activity are classically considered as the consequence of the disruption of the folate cycle and related synthesis of purines and pyrimidines and the decreased synthesis of endogenous methionine and SAM. For one decade, data on cellular and animal models of B deficiency and IECM have highlighted other key pathomechanisms, including altered interactome of MS with methionine synthase reductase, MMACHC, and MMADHC, endoplasmic reticulum stress, altered cell signaling, and genomic/epigenomic dysregulations. Decreased MS activity increases catalytic protein phosphatase 2A (PP2A) and produces imbalanced phosphorylation/methylation of nucleocytoplasmic RNA binding proteins, including ELAVL1/HuR protein, with subsequent nuclear sequestration of mRNAs and dramatic alteration of gene expression, including . Decreased SAM and SIRT1 activity induce ER stress through impaired SIRT1-deacetylation of HSF1 and hypomethylation/hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC1), which deactivate nuclear receptors and lead to impaired energy metabolism and neuroplasticity. The reversibility of these pathomechanisms by SIRT1 agonists opens promising perspectives in the treatment of IECM outcomes resistant to conventional supplementation therapies.
Mots clés
Methionine synthase, cobalamin, fetal programming, inborn errors of metabolism, peroxisome proliferator-activated receptor-γ coactivator-1α, sirtuin 1, vitamin B12 deficiency
Référence
Crit Rev Biochem Mol Biol. 2021 Oct 5;:1-23