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Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
Since l-MET is an essential amino acid, the l-MET deprivation could be harmful for the human body, but it was proved that long-term nutritional deprivation of l-MET does not compromise the human life because cells have several pathways to ensure the l-MET recycle. l-MET can be recovered through the re-methylation of homocysteine by the l-methionine synthase (MS) or, in the liver, by the betaine-homocysteine methyltransferase (BHMT) (Cellarier et al. 2003; Hoffman, 1984; Guo et al., 1993). Additionally, methylthioadenosine phosphorylase (MTAP) is also able to catalyse the production of l-MET from 5’-methylthioadenosine.
Recent Studies on the Neoplasia and Abnormal Cellular Differentiation in Methyl Insufficiency
Published in Maryce M. Jacobs, Vitamins and Minerals in the Prevention and Treatment of Cancer, 2018
Of critical importance to this area of research is the extent to which physiological methyl insufficiency contributes to the carcinogenic process. As is shown in Figure 1, there are two major sources of methyl groups in vivo: the preformed and the de novo. The preformed sources consist of dietary methionine and choline; the de novo consists of methionine which is synthesized from 1-carbon fragments in the folate pool transferred to homocysteine via the cobalamin-dependent enzyme methionine synthase. A second pathway of methionine biosynthesis is mediated by the enzyme, betaine homocysteine methyltransferase, but this pathway mainly conserves pre-existing methyl groups derived from choline. It is worth noting that this enzyme is active principally in the liver and that human liver contains less than does rodent liver.11,12
Emerging ergogenic aids for strength/power development
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
Betaine (i.e., N,N,N-trimethylglycine) is a methyl derivative of glycine. It is a zwitterion with a positively charged trimethylammonium group and a negatively charged carboxyl group (Figure 14.1). It is a naturally occurring by-product of sugar beet (Beta vulgaris) refinement. In humans, approximately 20–70 μmol/L of betaine is found in the blood (16). Plasma values in women tend to be lower than men possibly due to faster rates of methylation metabolism via oestrogen-related increased enzymatic activity of betaine-homocysteine methyltransferase (BHMT) in women (12). Betaine is found in most tissues, but highest concentrations are seen in the liver, kidneys and testes. Once betaine is ingested, it is filtered in the kidneys, reabsorbed into circulation and either catabolizes or is taken up and stored at the tissue level. Virtually all tissues can absorb and store betaine at concentrations higher than those found in the blood. Other major sources of betaine in the human diet (per 100 g of food) include wheat bread (201 mg), white bread (93 mg), spinach (645 mg), wheat bran (1339 mg), wheat germ (1241 mg), shrimp (218 mg), hard plain salted pretzels (236 mg), raw beets (114 mg) and canned beets (297 mg) (64). Betaine may also be synthesized endogenously in the liver and kidneys from choline. Average daily intake of betaine ranges from 100 to 500 mg, with several studies reporting in the 100–200 mg range (23). Absolute betaine dietary consumption may be similar between men and women; however, relative intake (to body mass) appears higher in women (23). Oral ingestion of betaine increases blood concentrations in a dose-dependent manner, with an absorption half-life of ~17 min and peak concentrations seen within 40–60 min of ingestion (32). Betaine supplementation of 2.5–6.0 g/day has been shown to increase plasma betaine concentrations significantly (3, 10, 11, 40, 51). In fact, supplementation with 6 g/day of betaine was shown to increase serum betaine concentrations ten-fold (51). Dietary intakes as high as 9–12 g/day have been shown to be safe (10) as studies report no changes in blood pressure, blood glucose, triglycerides, liver enzymes or adverse side effects during supplementation (3, 40, 51). Minimal betaine is excreted in urine, but a substantial amount may be lost in sweat (11).
Plasma choline, homocysteine and vitamin status in healthy adults supplemented with krill oil: a pilot study
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2018
Bodil Bjørndal, Inge Bruheim, Vegard Lysne, Marie S. Ramsvik, Per M. Ueland, Jan E. Nordrehaug, Ottar K. Nygård, Rolf K. Berge
Elevated plasma total homocysteine (tHcy) is related to increased risk of atherosclerosis and cardiovascular disase (CVD) [1], but lowering of tHcy with B-vitamins has not improved prognosis among CVD patients [2]. Hcy may be remethylated back to methionine (Met) through the B12-dependent methionine synthase, using 5′-methyltetrahydrofolate (mTHF) as the methyl donor. In the liver and kidney, Hcy may also be remethylated by betaine-homocysteine methyltransferase (BHMT), using betaine as the methyl donor. This couples the Hcy metabolism to the choline oxidation pathway, and the reaction yields dimethylglycine (DMG). Recently, it has been found that higher plasma concentration of DMG is associated with increased CVD risk [3,4]. Irreversible catabolism of Hcy takes place through the B6-dependent transsulfuration pathway (Figure 1).
Investigation of the Gastroprotective Effect of Betaine-Homocysteine Homeostasis on Oxidative Stress, Inflammation and Apoptosis in Ethanol-Induced Ulcer Model
Published in Journal of Investigative Surgery, 2022
Ayşe Çakır Gündoğdu, Fatih Kar, Cansu Özbayer
Betaine (trimethylglycine) is a glycine derivative that has three extra methyl groups. This stable and nontoxic natural compound is exogenously obtained through the dietary intake of certain food sources including shellfish, wheat, spinach, grain, and beet [6]. Notwithstanding that most of the betaine content in the body is obtained through alimentation, betaine can be endogenously synthesized from choline in the body [7]. Betaine is a crucial molecule in the methionine-homocysteine cycle and an essential methyl donor in the transmethylation reaction. In this reaction, a methyl group is transferred from betaine to homocysteine by way of betaine-homocysteine methyltransferase (BHMT) and, ultimately, dimethylcysteine and methionine are produced [8]. Methionine serves as the initiating amino acid in protein synthesis while choline is important for the maintenance of the phospholipids of cell membranes and also contributes to neurotransmitter acetylcholine production [9]. Both methionine and choline are necessary for β-oxidation in the liver and the synthesis of very low-density lipoprotein (VLDL). In addition, deficiency of these nutrients is associated with lipid accumulation, inflammation, oxidative stress, and hepatic toxicity [10]. Nuclear magnetic resonance (NMR) spectroscopy analyses have shown that betaine levels are downregulated in both the biopsy [11] and serum and plasma specimens [12] of ulcerative colitis patients. Similarly, it has been shown that the betaine, choline, and methionine levels are substantially reduced in the indomethacin-induced gastric ulcer and, therefore, betaine and methionine metabolism are among the most important pathways involved in the pathogenesis of gastric ulcer [13].
Metabolomic evaluation of Euphorbia pekinensis induced nephrotoxicity in rats
Published in Pharmaceutical Biology, 2018
Zhenzhen Liu, Yan Zeng, Pengyi Hou
Amino acids play important roles in our daily life. Phenylalanine and DMG are two essential amino acids in human body. Phenylalanine is mainly hydroxylated by phenylalanine hydroxylase to tyrosine. In our study, phenylalanine was markedly increased in the PE-treated group compared with the HCG group, indicating renal damage induced by PE section. DMG is a metabolite of homocysteine. Some studies have shown plasma DMG might accumulate in chronic renal failure and contribute to hyperhomocysteinaemia by inhibiting betaine homocysteine methyltransferase activity (McGregor et al. 2001). The disturbance of amino acids metabolism might be one of the nephrotoxicity mechanisms of EPR.