Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B<sub>12</sub>metabolism

Guéant, Jean‐Louis; Guéant-Rodríguez, Rosa-María; Kosgei, Viola J.; Coelho, David

doi:10.1080/10409238.2021.1979459

Cited by 27 publications

(26 citation statements)

References 143 publications

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“…These SIRTs catalyze deacylation reactions, some with substrate overlap with SIRT5. Moreover, the decrease in SIRT1 has been observed in other disorders of vitamin B12 metabolism ( 71 ). The roles of the other SIRTs as mediators of pathophysiology remain unclear, as we were unable to explore the matter further here.…”

Section: Discussionmentioning

confidence: 96%

Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

et al. 2022

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Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.

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Section: Discussionmentioning

confidence: 96%

Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

et al. 2022

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“…The folate cycle promotes SAM production. MTHFR is a key enzymes for folate metabolism and methyl donor SAM production [ 26 ], and knockdown of MTHFR significantly inhibits GC cell proliferation [ 27 ]. miR-22 overexpression reduces endogenous SAM levels by inhibiting MTHFR and inducing P16, PTEN, and RASSF1A (they are anticancer genes) hypomethylation [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Association of H-Type Hypertension with miR-21, miR-29, and miR-199 in Kazahks of Xinjiang, China

Liu

et al. 2022

International Journal of Hypertension

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Objective. This study aims to analyze the expressions of miR-21, miR-29, and miR-199 in the serum of the patients with H-type hypertension among Kazakhs. Then, we analyzed the effect of MTHFR 677C > T polymorphism on the association between the above miRNA and H-type hypertension. Method. In this study, the expression of miR-21, miR-29, and miR-199 was quantitatively measured in 120 serum samples and then stratified according to the C677T polymorphism to analyze the relationship between target miRNAs and HHcy. Results. The expression of miR-21/-29 in the hypertension group was higher than the normal group ( P < 0.001 ). And the expression of miR-199 was higher in the hcy group than in the normal group ( P < 0.001 ). In the CC and CT genotypes of MTHFR 677C > T, the expression of miR-21 was lower in the HHcy patients than in the normal individuals ( P = 0.005 and P = 0.001 ) and miR-199 was significantly higher in the HHcy patients than in the normal ones ( P = 0.002 and P = 0.048 ). No such difference was found in the TT genotype. Logistic regression analysis showed that after adjusting for sex, age, BMI, systolic blood pressure, diastolic blood pressure, and MTHFRC677 T gene polymorphism, miR-21 was negatively correlated with hcy (OR = 0.222, 95% CI (0.101–0.485), P < 0.001 ) and miR-199 was positively correlated with hcy (OR = 1.823,95%CI (1.272∼2.614), P = 0.001 ). Conclusion. miR-21, miR-29, and miR-199 are associated with H-type hypertension in the Kazakhs, especially hyperhomocysteinemia. And these three miRNAs may serve as biomarkers to provide clues to the potential pathogenesis of H-type hypertension.

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“…It catalyzes histone and non-histone lysine deacetylation in a NAD+-dependent manner [ 14 , 40 , 41 ]. Previous work in our lab showed the role of SIRT1 in regulating energy metabolism through PPAR-α and PGC-1α in a methyl-deficient diet [ 14 , 40 , 41 , 42 , 43 ]. PGC-1α is a master regulator of lipid metabolism and fatty acid oxidation.…”

Section: Methionine and Stemnessmentioning

confidence: 99%

Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players

Siblini

Namour

Oussalah

et al. 2022

Cells

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Stem cells are a population of undifferentiated cells with self-renewal and differentiation capacities. Normal and cancer stem cells share similar characteristics in relation to their stemness properties. One-carbon metabolism (OCM), a network of interconnected reactions, plays an important role in this dependence through its role in the endogenous synthesis of methionine and S-adenosylmethionine (SAM), the universal donor of methyl groups in eukaryotic cells. OCM genes are differentially expressed in stem cells, compared to their differentiated counterparts. Furthermore, cultivating stem cells in methionine-restricted conditions hinders their stemness capacities through decreased SAM levels with a subsequent decrease in histone methylation, notably H3K4me3, with a decrease in stem cell markers. Stem cells’ reliance on methionine is linked to several mechanisms, including high methionine flux or low endogenous methionine biosynthesis. In this review, we provide an overview of the recent discoveries concerning this metabolic dependence and we discuss the mechanisms behind them. We highlight the influence of SIRT1 on SAM synthesis and suggest a role of PGC-1α/PPAR-α in impaired stemness produced by methionine deprivation. In addition, we discuss the potential interest of methionine restriction in regenerative medicine and cancer treatment.

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Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B₁₂metabolism

Cited by 27 publications

References 143 publications

Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

Association of H-Type Hypertension with miR-21, miR-29, and miR-199 in Kazahks of Xinjiang, China

Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players

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Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B12metabolism

Cited by 27 publications

References 143 publications

Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

Association of H-Type Hypertension with miR-21, miR-29, and miR-199 in Kazahks of Xinjiang, China

Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players

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Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B₁₂metabolism