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Nutritional Deficiencies
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Deepa Bhupali, Fernando D. Testai
Dietary methionine is metabolized to S-adenosylmethionine, which is necessary for the methylation of myelin sheath products. Downstream, S-adenosylmethionine is converted to homocysteine, and this may enter the remethylation or the transsulfuration pathway. In the remethylation pathway, the methionine synthase, which requires methylcobalamin as a cofactor, catalyzes the reaction of homocysteine and methyltetrahydrofolate to produce methionine and tetrahydrofolate. Tetrahydrofolate is the precursor required for purine and pyrimidine synthesis (Figure 10.9). Adenosylcobalamin is necessary for the conversion of l-methylmalonyl-CoA to succinyl-CoA in the mitochondria (Figure 17.1).
Epigenetics, Nutrition, and Infant Health
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Philip T. James, Matt J. Silver, Andrew M. Prentice
S-adenosyl methionine (SAM) methylates a wide variety of acceptors in reactions catalyzed by methyl transferases. Over 200 methylation reactions are required for transcription, translation, protein localization, and signaling purposes [45], but it is the methylation of cytosine bases and amino acids on histone tails that play a role in epigenetics. The donation of SAM’s methyl group forms S-adenosyl homocysteine (SAH), which is further hydrolyzed to homocysteine (Hcy), where it is maintained in an equilibrium state that thermodynamically favors SAH over Hcy [46]. A buildup of Hcy results in an increase in SAH, which in turn impedes methylation reactions since SAH competes with SAM for the active site on methyl transferase enzymes [47]. The SAM:SAH ratio is therefore often used as a proxy indicator of methylation potential [48]. In order to maintain favorable methylation conditions, Hcy has to be removed from the system. One way in which this can happen is by accepting a methyl group to form methionine, which can then in turn be condensed with ATP to form SAM and continue the cycle. Hcy can also be removed through its irreversible degradation to cystathionine and cysteine in the transsulfuration pathway requiring vitamin B6.
Homocysteine: A Risk Factor for Atherothrombotic Cardiovascular Disease
Published in P. K. Shah, Risk Factors in Coronary Artery Disease, 2006
Mathew J Price, Andrew A Zadeh, Sanjay Kaul
As noted previously, homocysteine concentration is inversely related to the levels of vitamin B12, folate, and to a lesser extent, vitamin B6 (24). The elevated homocysteine in patients with thermolabile MTHFR is manifested predominantly in those with low serum folate (20). One meta-analysis of vitamin supplementation in patients with mild to moderate hyperhomocysteinemia reports that folate supplementation in doses of 0.5 to 5 mg/day significantly reduces total homocysteine concentration (74). A greater degree of reduction is observed in those with higher pretreatment homocysteine concentration (top quintile, approximately 40% proportional reduction) and in those with lower pretreatment folate concentration. After standardization to the approximate average concentrations for Western populations, treatment with folate lowers homo-cysteine concentrations by 25% (CI 23% to 28%). Supplementation with vitamin B-12 (dosage 0.02–1 mg/day, mean 0.5 mg) produces a small additional effect of about 7% (93). Vitamin B6 treatment alone does not lower fasting total homocysteine concentrations but does reduce post-methionine load concentrations, although not as much as in combination with folate (94). This finding is consistent with the role of vitamin B6 as a co-factor in the transsulfuration pathway of homocysteine to cysteine. Betaine-dependent remethylation of homocysteine to methionine occurs in the liver. Betaine supplementation in patients with homocystinuria significantly decreases total homocysteine concentration (95). In healthy patients, betaine supplementation significantly reduces fasting homocysteine, but to a far lesser degree than folate (96). Choline, a precursor to Betaine, can serve as a dietary supplement in phosphatidylcholine. This may act as another mechanism to decrease fasting and post-methionine load homocysteine concentrations in serum (97).
Effects of homocysteine and memantine on oxidative stress related TRP cation channels in in-vitro model of Alzheimer’s disease
Published in Journal of Receptors and Signal Transduction, 2021
İshak Suat Övey, Mustafa Nazıroğlu
Homocysteine (Hcy) is a non-protein, sulfur-bearing amino acid that is converted to essential amino acid methionine in the remethylation pathway [16]. Cystathionine β synthase enzyme (CβS) catalyzes Hcy to cysteine in the transsulfuration pathway. As source of these two important amino acids, however accumulation of Hcy caused by deficiency of CβS is led to homocysteinemia that has significant effects in the etiology of neurological diseases, including AD [17–19]. Involvement of cysteine residues in the N domain of TRPA1 were indicated by a mass spectrometry study [20]. In addition to TRPA1, oxidative alterations of multiple Cys residues in different cells are involved in this mode of TRPV1 activation [21]. Recent studies have observed perturbations of Ca2+ homeostasis through TRPA1, TRPM2 and TRPV1 activations caused by excessive levels of oxidative stress in cells from experimental animals and patients with AD [10,11]. Increased Hcy concentration elevates oxidative stress levels in neurons [18,22], and as a consequence of excessive Ca2+ influx, apoptosis takes place upon cation channels’ activation [22,23]. We have recently observed that Hcy induced oxidative stress is able to increase [Ca2+]i and apoptosis levels via activation of TRPM2 and TRPV1 channels in hippocampal (HPC) neurons [24]. Moreover, Hcy may cause oxidative stress dependent-activation of TRP superfamily members such as TRPA1, TRPM2 and TRPV1 in the HPC neurons.
Cystathionine β-synthase Deficiency Impairs Vision in the Fruit Fly, Drosophila melanogaster
Published in Current Eye Research, 2021
Marycruz Flores-Flores, Leonardo Moreno-García, Felipe Castro-Martínez, Marcos Nahmad
Classic homocystinuria is a metabolic disease mainly caused by inherited deficiency of Cystathionine-β-synthase (CBS), a vitamin B6-dependent enzyme that catalyzes the flux of sulfur from methionine to cysteine in the transsulfuration pathway.1 In humans, genetic variants causing low CBS expression lead to the accumulation of toxic levels of homocysteine and methionine in urine and plasma, affecting skeletal, visual, the central nervous system,2,3 and also poses an independent risk factor for thrombosis and vascular disease.4,5 One of the most common clinical manifestations of homocystinuria is severe myopia followed by ectopia lentis that affects about 90% of patients with a CBS deficiency.6,7 Despite the high prevalence of eye-related abnormalities caused by this disease, the molecular mechanisms that relate CBS deficiency to vision problems are poorly understood. Murine models of genetic deficiency of cbs have been used as a model of homocystinuria,8,9 including visual manifestations. For instance, studies using cbs-mutant mice have reported alterations of retinal vasculature,10 retinal ganglion cell death,11,12 and visual function.13 However, the widespread use of this experimental model is challenging due to a large degree of neonatal lethality.9
Proteomic exploration of cystathionine β-synthase deficiency: implications for the clinic
Published in Expert Review of Proteomics, 2020
Metabolic turnover of Hcy occurs via three pathways: (i) remethylation to Met, (ii) transsulfuration to Cys, and (iii) the Hcy-thiolactone pathway (Figure 1). The remethylation pathway (i) is catalyzed by Met synthase (MS), which requires vitamin B12 and methyltetrahydrofolate [21], and by betaine:Hcy methyltransferase (BHMT) [22]. The transsulfuration pathway (ii) is catalyzed by two enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL), both of which require vitamin B6. (iii) The Hcy-thiolactone pathway is catalyzed by methionyl-tRNA synthetase (MetRS), which requires ATP. The flow through the Hcy-thiolactone pathway is relatively small but greatly increases when the transsulfuration or remethylation pathway is impaired due to genetic or nutritional deficiencies, which causes accumulation of Hcy-thiolactone and its downstream metabolites, such as N-Hcy-protein and N-Hcy-Lys (Table 1).