Methylation demand: a key determinant of homocysteine metabolism.
Languages of publication
Elevated plasma homocysteine is a risk factor for cardiovascular disease and Alzheimer's disease. To understand the factors that determine the plasma homocysteine level it is necessary to appreciate the processes that produce homocysteine and those that remove it. Homocysteine is produced as a result of methylation reactions. Of the many methyltransferases, two are, normally, of the greatest quantitative importance. These are guanidinoacetate methyltransferase (that produces creatine) and phosphatidylethanolamine N-methyltransferase (that produces phosphatidylcholine). In addition, methylation of DOPA in patients with Parkinson's disease leads to increased homocysteine production. Homocysteine is removed either by its irreversible conversion to cysteine (transsulfuration) or by remethylation to methionine. There are two separate remethylation reactions, catalyzed by betaine:homocysteine methyltransferase and methionine synthase, respectively. The reactions that remove homocysteine are very sensitive to B vitamin status as both the transsulfuration enzymes contain pyridoxal phosphate, while methionine synthase contains cobalamin and receives its methyl group from the folic acid one-carbon pool. There are also important genetic influences on homocysteine metabolism.
- Allain P, LeBouil A, Cordillet E, LeQuay L, Bagheri H, Montastrue JL. (1995) Sulfate and cysteine levels in the plasma of patients with Parkinson's disease. Neurotoxicology.; 16: 527-9.
- Bostom AG, Shemin D, Lapane KL, Miller JW, Sutherland P, Nadeau M, Seyoum E, Hartman W, Prior R, Wilson PWF, Selhub J. (1995a) Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage renal disease patients on dialysis: a case controlled study. Atherosclerosis.; 114: 93-103.
- Bostom A, Brosnan JT, Hall B, Nadeau MR, Selhub J. (1995b) Net uptake of homocysteine by the rat kidney in vivo. Atherosclerosis.; 116: 59-62.
- Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA.; 274: 1049-57.
- Cheng H, Gomes-Trolin C, Aquilonius SM, Steinberg A, Lofberg C, Ekblom J, Oreland L. (1997) Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson's disease. Exp Neurol.; 145: 580-5.
- Clarke S, Banfield K. (2001) S-adenosylmethionine-dependent methyltransferases. In Homocysteine in health and disease. Carmel R, Jacobsen DW. eds, pp 63-78. Cambridge University Press, Cambridge, New York.
- Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. (1998) Folate, vitamin B12 and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol.; 55: 1449-55.
- Goyette P, Frosst P, Rosenblatt DS, Rozen R. (1995) Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet.; 56: 1052-9.
- Guttormsen AB, Ueland PM, Svarstad E, Refsum H. (1997) Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure. Kidney Int.; 52: 495-502.
- Jacobsen DW. (2001) Practical chemistry of homocysteine and other thiols. In Homocysteine in health and disease. Carmel R, Jacobsen DW. eds, pp 9-20. Cambridge University Press, Cambridge, New York.
- Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R. (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation.; 93: 7-9.
- Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med.; 340: 1449-54.
- Katz JE, Dlakic M, Clarke S. (2003) Automated identification of putative methyltransferases from genomic open reading frames. Mol Cell Proteomics.; 2: 525-40.
- Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. (2002) MTHFR studies collaboration group MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA.; 288: 2023-31.
- Kraus JP. (1998) Biochemistry and molecular genetics of cystathionine β-synthase deficiency. Eur J Pediatr.; 157 Suppl. 2: S50-3.
- McGuire DM, Gross MD, van Pilsum JF, Towle HC. (1984) Repression of rat kidney L-arginine:glycine amidinotransferase synthesis by creatine at a pre-translational level. J Biol Chem.; 259: 12034-8.
- Miller JW, Nadeau MR, Smith D, Selhub J. (1994) Vitamin B6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr.; 59: 1033-9.
- Miller JW, Shukitt-Hale B, Villalobos-Molina R, Nadeau MR, Selhub J, Joseph JA. (1997) Effect of L-DOPA and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats. Clin Neuropharmacol.; 20: 55-66.
- Mudd SH, Poole JR. (1975) Labile methyl balances for normal humans on various dietary regimens. Metabolism.; 24: 721-35.
- Mudd SH, Ebert MH, Scriver CS. (1980) Labile methyl group balances in the human: the role of sarcosine. Metabolism.; 29: 707-20.
- Muller T, Woitalla D, Hauptmann B, Fowler B, Kuhn W. (2001) Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease. Neurosci Lett.; 308: 54-6.
- Noga AA, Stead LM, Zhao Y, Brosnan ME, Brosnan JT, Vance DE. (2003) Plasma homocysteine is regulated by phospholipid methylation. J Biol Chem.; 278: 5952-5.
- Palma PN, Bonifacio MJ, Loureiro AI, Wright LC, Learmonth DA, Soares-da-Silva P. (2003) Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor. Drug Metab Dispos.; 31: 250-8.
- Reo NV, Adinehzadeh M, Foy BD. (2002) Kinetic analyses of liver phosphatidylcholine and phosphatidylethanolamine biosynthesis using 13C-NMR spectroscopy. Biochim Biophys Acta.; 1580: 171-88.
- Selhub J, Jacques PF, Bostom AG, Wilson PW, Rosenberg IH. (2000) Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. Public Health Rev.; 28: 117-45.
- Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med.; 346: 476-83.
- Silberberg J, Crooks R, Fryer J, Wlodarczyk J, Nair B, Guo XW, Xie LJ, Dudman N. (1997) Gender differences and other determinants of the rise in plasma homocysteine after L-methionine loading. Atherosclerosis; 133: 105-10.
- Stead LM, Au KP, Jacobs RL, Brosnan ME, Brosnan JT. (2001) Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab.; 281: E1095-100.
- van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van der Heuvel LP, Mariman EC, den Heyer M, Rozen R, Blom HJ. (1995) Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet.; 346: 1070-1.
- van Guldener C, Donker AJ, Jakobs C, Teerlink T, de Meer K, Stehouwer CD. (1998) No net renal extraction of homocysteine in fasting humans. Kidney Int.; 54: 166-9.
- Yamada K, Chen Z, Rozen R, Matthews RG. (2001) Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci USA.; 98: 14853-8.
Publication order reference