![]() Methionine is used in many methyl transfer reactions. The methyl group is donated to Hcy and in the presence of methionine synthase (encoded by Mtr), and B 12 is converted to methionine. In the remethylation pathway, THF is converted to N 5, N 10-methylenetetrahydrofolate and then to MTHF by methylenetetrahydrofolate reductase (encoded by the gene Mthfr). Homocysteine sits at the intersection of the remethylation and transsulfuration pathways. 1 Heterozygous mutations in these enzymes or nutritional deficiency of cofactors lead to moderate increase in plasma Hcy known as hyperhomocysteinemia (Hhcy). Homozygous mutations in Cbs and Mthfr lead to homocystinuria characterized by exceedingly high levels of plasma Hcy, severe mental and skeletal abnormalities, premature thromboembolism, and lens dislocation. Perturbation in these pathways can lead to elevated plasma Hcy levels. The remethylation pathway requires folate and cobalamin (vitamin B 12) as cofactors. When the diet is deficient in methionine, Hcy is remethylated back to methionine via the remethylation pathway involving the enzymes methylene tetrahydrofolate reductase (MTHFR) and methionine synthase. Cysteine is used in synthesis of downstream products such as glutathione (GSH), taurine, and hydrogen sulfide (H 2S). Cystathionine is converted to cysteine via cystathionase (CTH), also known as cystathionine γ-lyase (CSE). When the diet is replete with methionine, Hcy is catabolized to cystathionine by cystathionine-β-synthase (CBS) via the transsulfuration pathway. Homocysteine (Hcy) is a sulfur-containing nonproteinogenic amino acid, which sits at the intersection of the remethylation and transsulfuration metabolic pathways important for synthesis of methionine ( Fig. Elevation of H 2S is particularly intriguing owing to neuroprotective properties reported for this gasotransmitter. Ganglion cell loss and vasculopathy observed in Mthfr +/− and Cbs +/− mouse retinas may be milder than expected, not because of compensatory increases of enzymes in remethylation/transsulfuration pathways, but because downstream transsulfuration pathway products GSH, taurine, and H 2S are maintained at robust levels. Interestingly, levels of H 2S were markedly increased in retinas of Mthfr +/− and Cbs +/− mice compared with WT. Glutathione and taurine levels in Mthfr +/− and Cbs +/− retinas were similar to WT, which may be due to robust levels of xCT and TAUT in mutant retinas. Retinas were evaluated for levels of reduced:oxidized GSH (GSH:GSSG), Slc7a11 (xCT), taurine, taurine transporter (TAUT), and H 2S.Īside from decreased CBS RNA/protein levels in Cbs +/− retinas, there were minimal alterations in remethylation/transsulfuration pathways in the two mutant mice strains. ![]() Retinas isolated from wild-type (WT), Mthfr +/−, and Cbs +/− mice (12 and 22 weeks) were analyzed for methylene tetrahydrofolate reductase (MTHFR), cystathionine-β-synthase (CBS), and cystathionase (CTH) RNA/protein levels. ![]() The current work investigated compensation in vivo of one pathway for the other, and, because the transsulfuration pathway yields cysteine necessary for formation of glutathione (GSH), taurine, and hydrogen sulfide (H 2S), they were analyzed also. In isolated ganglion cells (GCs), mild Hhcy induces profound death, whereas retinal phenotypes in Hhcy mice caused by mutations in remethylation (methylene tetrahydrofolatereductase ) or transsulfuration pathways (cystathionine β-synthase ) demonstrate mild GC loss and mild vasculopathy. Hyperhomocysteinemia (Hhcy) is implicated in certain retinal neurovascular diseases, although whether it is causative remains uncertain. ![]()
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