PDF herunterladen
Semin Vasc Med 2005; 5(2): 77-86
DOI: 10.1055/s-2005-872394
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA.

Homocysteine: Overview of Biochemistry, Molecular Biology, and Role in Disease Processes

Brian Fowler1
  • 1Metabolic Unit, University Children's Hospital Basel (UKBB), Basel, Switzerland
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
27. Juli 2005 (online)

    Lizenzen und Reprints

ABSTRACT

Homocysteine is derived from the essential amino acid methionine and plays a vital role in cellular homeostasis in man. Homocysteine levels depend on its synthesis, involving methionine adenosyltransferase, S-adenosylmethionine-dependent methyltransferases such as glycine N-methyltransferase, and S-adenosylhomocysteine hydrolase; its remethylation to methionine by methionine synthase, which requires methionine synthase reductase, vitamin B12, and 5-methyltetrahydrofolate produced by methylenetetrahydrofolate reductase or betaine methyltransferase; and its degradation by transsulfuration involving cystathionine β-synthase. The control of homocysteine metabolism involves changes of tissue content or inherent kinetic properties of the enzymes. In particular, S-adenosylmethionine acts as a switch between remethylation and transsulfuration through its allosteric inhibition of methylenetetrahydrofolate reductase and activation of cystathionine β-synthase. Mutant alleles of genes for these enzymes can lead to severe loss of function and varying severity of disease. Several defects lead to severe hyperhomocysteinemia, the most common form being cystathionine β-synthase deficiency, with more than a hundred reported mutations. Less severe elevations of plasma homocysteine are caused by folate and vitamin B12 deficiency, and renal disease and moderate hyperhomocysteinemia are associated with several common disease states such as cardiovascular disease. Homocysteine toxicity is likely direct or caused by disturbed levels of associated metabolites; for example, methylation reactions through elevated S-adenosylhomocysteine.

KEYWORDS

Homocysteine - enzymes - genes - inherited metabolic disorder - S-adenosylmethionine

REFERENCES

  • 1 Finkelstein J D. Methionine metabolism in mammals.  J Nutr Biochem. 1990;  1 228-237
    PubMedGoogle Scholar
  • 2 Finkelstein J D. Pathways and regulation of homocysteine metabolism in mammals.  Semin Thromb Hemost. 2000;  26(3) 219-225 , Review
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 3 Mudd S H, Levy H L, Kraus J P. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York; McGraw-Hill 2001: 2007-2056
    Google Scholar
  • 4 Finkelstein J D. The metabolism of homocysteine: pathways and regulation.  Eur J Pediatr. 1998;  157(Suppl 2) S40-S44
    PubMedGoogle Scholar
  • 5 Clarke S, Banfield K. S-adenosylmethionine-dependent methyltransferases. In: Carmel R, Jacobsen D Homocysteine in Health and Disease Cambridge; Cambridge University Press 2001: 63-78
    Google Scholar
  • 6 Johnson J L, Duran M. Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease, 8th ed New York; McGraw-Hill 2001: 3163-3177
    Google Scholar
  • 7 Okada G, Teraoka H, Tsukada K. Multiple species of mammalian S-adenosylmethionine synthetase. Partial purification isolation and characterisation.  Biochemistry. 1981;  20 934-940
    CrossrefPubMedGoogle Scholar
  • 8 Kutzbach C, Stokstad E L. Mammalian methylenetetrahydrofolate reductase. Partial purification and inhibition by S-adenosylmethionine.  Biochim Biophys Acta. 1971;  250 459-477
    PubMedGoogle Scholar
  • 9 Konishi K, Fujioka M. Rat liver glycine methyltransferase. Cooperative binding of S-adenosylmethionine and loss of cooperativity by removal of a short NH2-terminal segment.  J Biol Chem. 1988;  263 13381-13385
    PubMedGoogle Scholar
  • 10 Rosenblatt D S, Erbe R W. Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease, 8th ed New York; McGraw-Hill 2001 2007-2056 3897-3933
    Google Scholar
  • 11 Fenton W A, Gravel R A, Rosenblatt D S. Disorders of propionate and methylmalonate metabolism. In: Scriver C, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease 8th ed. New York; McGraw-Hill 2001: 2165-2193
    Google Scholar
  • 12 Alvarez L, Corrales F, Martin-Duce A, Mato J M. Characterization of a full-length cDNA encoding human liver S-adenosylmethionine synthetase-tissue-specific gene expression and messenger RNA levels in hepatopathies.  Biochem J.. 1993;  293 481-486
    PubMedGoogle Scholar
  • 13 Kotb M. Kredich NM: Regulation of human lymphocyte S-adenosylmethionine synthetase by product inhibition.  Biochim Biophys Acta. 1990;  1039 253-260
    PubMedGoogle Scholar
  • 14 Ubagai T, Lei K J, Huang S, Mudd S H, Levy H L, Chou J Y. Molecular mechanisms of an inborn error of methionine pathway. Methionine adenosyltransferase deficiency.  J Clin Invest. 1995;  96 1943-1947
    PubMedGoogle Scholar
  • 15 Chamberlin M E, Ubagai T, Mudd S H, Wilson W G, Leonard J V, Chou J Y. Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency.  J Clin Invest. 1996;  98 1021-1027
    PubMedGoogle Scholar
  • 16 De La Rosa J, Ostrowski J, Hryniewicz M M et al.. Chromosomal localization and catalytic properties of the recombinant alpha subunit of human lymphocyte methionine adenosyltransferase.  J Biol Chem. 1995;  270 21860-21868
    CrossrefPubMedGoogle Scholar
  • 17 Horikawa S, Tsukada K. Molecular cloning and developmental expression of a human kidney S-adenosylmethionine synthetase.  FEBS Lett. 1992;  312 37-41
    CrossrefPubMedGoogle Scholar
  • 18 Kim S Z, Santamaria E, Jeong T E et al.. Methionine adenosyltransferase I/III deficiency: two Korean compound heterozygous siblings with a novel mutation.  J Inherit Metab Dis. 2002;  25 661-671
    PubMedGoogle Scholar
  • 19 Mathews C K, van Holde K E. Biochemistry Redwood City, CA; Benjamin/Cummins 1990: 713
  • 20 Yeo E, Wagner C. Tissue binding of glycine N-methyltransferase a major folate-binding protein of liver.  Proc Natl Acad Sci USA. 1994;  91 210-214
    PubMedGoogle Scholar
  • 21 Cantoni G L, Richards H H, Chiang P K. Inhibitors of S-adenosylhomocysteine hydrolase and their role in the regulation of biological methylation. In: Usdin E, Borchardt RT, Creveling CR Transmethylation New York; Elsevier/North-Holland 1979: 155-164
    Google Scholar
  • 22 Chen Y M, Chen L Y, Wong F H, Lee C M, Chang T J, Yang-Feng T L. Genomic structure, expression, and chromosomal localization of the human glycine N-methyltransferase gene.  Genomics. 2000;  66 43-47
    CrossrefPubMedGoogle Scholar
  • 23 Luka Z, Cerone R, Phillips III J A, Mudd H S, Wagner C. Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism.  Hum Genet. 2002;  110 68-74
    PubMedGoogle Scholar
  • 24 Hershfield M S, Aiyar V N, Premakumar R, Small W C. S-adenosylhomocysteine hydrolase from human placenta. Affinity purification and characterisation.  Biochem J. 1985;  230 43-52
    PubMedGoogle Scholar
  • 25 Coulter-Karis D E, Hershfield M S. Sequence of full length cDNA for human S-adenosylhomocysteine hydrolase.  Ann Hum Genet. 1989;  53 169-175
    PubMedGoogle Scholar
  • 26 Ault-Riche D B, Yuan C S, Borchardt R T. A single mutation at lysine 426 of human placental S-adenosylhomocysteine hydrolase inactivates the enzyme.  J Biol Chem. 1994;  269 31472-31478
    PubMedGoogle Scholar
  • 27 Baric I, Fumic K, Glenn B et al.. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism.  Proc Natl Acad Sci USA. 2004;  101 4234-4239
    CrossrefPubMedGoogle Scholar
  • 28 Matthews R G, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology.  Eur J Pediatr. 1998;  157(Suppl 2) S54-S59
    PubMedGoogle Scholar
  • 29 Utley C S, Marcell P D, Allen R H, Antony A C, Kolhouse J F. Isolation and characterization of methionine synthetase from human placenta.  J Biol Chem. 1985;  260 13656-13665
    PubMedGoogle Scholar
  • 30 Chen Z, Crippen K, Gulati S, Banerjee R. Purification and kinetic mechanism of mammalian methionine synthase from pig liver.  J Biol Chem. 1994;  269 27193-27197
    PubMedGoogle Scholar
  • 31 Hall D A, Jordan-Starck T C, Loo R O, Ludwig M L, Matthews R G. Interaction of flavodoxin with cobalamin-dependent methionine synthase.  Biochemistry. 2000;  39 10711-10719
    CrossrefPubMedGoogle Scholar
  • 32 Leclerc D, Campeau E, Goyette P et al.. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders.  Hum Mol Genet. 1996;  5 1867-1874
    CrossrefPubMedGoogle Scholar
  • 33 Li Y N, Gulati S, Baker P J, Brody L C, Banerjee R, Kruger W D. Cloning, mapping and RNA analysis of the human methionine synthase gene.  Hum Mol Genet. 1996;  5 1851-1858
    CrossrefPubMedGoogle Scholar
  • 34 Chen L H, Liu M L, Hwang H Y, Chen L S, Korenberg J, Shane B. Human methionine synthase. cDNA cloning, gene localization, and expression.  J Biol Chem. 1997;  272 3628-3634
    CrossrefPubMedGoogle Scholar
  • 35 Watkins D, Ru M, Hwang H Y et al.. Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene genotype diversity, and recognition of a common mutation, P1173L.  Am J Hum Genet. 2002;  71 143-153
    CrossrefPubMedGoogle Scholar
  • 36 Leclerc D, Wilson A, Dumas R et al.. Cloning, and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.  Proc Natl Acad Sci USA. 1998;  95 3059-3064
    CrossrefPubMedGoogle Scholar
  • 37 Leclerc D, Odievre M, Wu Q et al.. Molecular cloning, expression and physical mapping of the human methionine synthase reductase gene.  Gene. 1999;  240 75-88
    CrossrefPubMedGoogle Scholar
  • 38 Olteanu H, Banerjee R. Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation.  J Biol Chem. 2001;  276 35558-35563
    CrossrefPubMedGoogle Scholar
  • 39 Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilova K, Kozich V. CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families.  J Inherit Metab Dis. 2002;  25 461-476
    CrossrefPubMedGoogle Scholar
  • 40 Zavadakova P, Fowler B, Suormala T et al.. CblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.  Hum Mutat. 2005;  25 239-247
    CrossrefPubMedGoogle Scholar
  • 41 Park E I, Garrow T A. Interaction between dietary methionine and methyl donor intake on rat liver betaine-homocysteine methyltransferase gene expression and organization of the human gene.  J Biol Chem. 1999;  274 7816-7824
    CrossrefPubMedGoogle Scholar
  • 42 Garrow T A. Purification, kinetic properties, and cDNA cloning of mammalian betaine-homocysteine methyltransferase.  J Biol Chem. 1996;  271 22831-22838
    PubMedGoogle Scholar
  • 43 Weisberg I S, Park E, Ballman K V et al.. Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease.  Atherosclerosis. 2003;  167 205-214
    CrossrefPubMedGoogle Scholar
  • 44 Daubner S C, Matthews R G. Purification and properties of methylenetetrahydrofolate reductase from pig liver.  J Biol Chem. 1982;  257 140-145
    PubMedGoogle Scholar
  • 45 Zhou J, Kang S, Wong P WK, Fournier B, Rozen R. Purification and characterisation of methylenetetrahydrofolate reductase from human cadaver liver.  Biochem Med Metab Biol. 1990;  43 234-242
    CrossrefPubMedGoogle Scholar
  • 46 Jencks D A, Matthews R G. Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine.  J Biol Chem. 1987;  262 2485-2493
    PubMedGoogle Scholar
  • 47 Goyette P, Sumner J S, Milos R et al.. Human methylenetetrahydrofolate reductase: Isolation of cDNA, mapping and mutation identification.  Nat Genet. 1994;  7 195-200
    CrossrefPubMedGoogle Scholar
  • 48 Goyette P, Pai A, Milos R et al.. Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR).  Mamm Genome. 1998;  9 652-656
    CrossrefPubMedGoogle Scholar
  • 49 Tran P, Leclerc D, Chan M et al.. Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms.  Mamm Genome. 2002;  13 483-492
    CrossrefPubMedGoogle Scholar
  • 50 Sibani S, Leclerc D, Weisberg I S et al.. Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation.  Hum Mutat. 2003;  21 509-520
    CrossrefPubMedGoogle Scholar
  • 51 Tonetti C, Saudubray J M, Echenne B, Landrieu P, Giraudier S, Zittoun J. Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency.  Eur J Pediatr. 2003;  162 466-475
    CrossrefPubMedGoogle Scholar
  • 52 Yano H, Nakaso K, Yasui K et al.. Mutations of the MTHFR gene (428C > T and [458G > T + 459C > T]) markedly decrease MTHFR enzyme activity.  Neurogenetics. 2004;  5 135-140
    CrossrefPubMedGoogle Scholar
  • 53 Suormala T, Koch H G, Rummel T, Häberle J, Fowler B. Methyltetrahyrofolate reductase (MTHFR) deficiency: mutations and functional abnormalities.  J Inherit Metab Dis. 2004;  27-231
    PubMedGoogle Scholar
  • 54 Suormala T, Gamse G, Fowler B. 5,10-Methylenetetrahydrofolate reductase (MTHFR) assay in the forward direction: residual activity in MTHFR deficiency.  Clin Chem. 2002;  48 835-843
    PubMedGoogle Scholar
  • 55 Weisberg I S, Jacques P F, Selhub J et al.. The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. R.  Atherosclerosis. 2001;  156 409-415
    CrossrefPubMedGoogle Scholar
  • 56 Kraus J, Packman S, Fowler B, Rosenberg L E. Purification and properties of cystathionine β-synthase from human liver. Evidence for identical subunits.  J Biol Chem. 1978;  253 6523-6528
    PubMedGoogle Scholar
  • 57 Skovby F, Kraus J P, Rosenberg L E. Biosynthesis and proteolytic activation of cystathionine β-synthase in rat liver.  J Biol Chem. 1984;  259 588-593
    PubMedGoogle Scholar
  • 58 Kery V, Bukovska G, Kraus J P. Transsulfuration depends on heme in addition to pyridoxal 5′-phosphate-cystathionine beta-synthase is a heme protein.  J Biol Chem. 1994;  269 25283-25288
    PubMedGoogle Scholar
  • 59 Kraus J P, Le K, Swaroop M et al.. Human cystathionine beta-synthase cDNA-sequence, alternative splicing and expression in cultured cells.  Hum Mol Genet. 1993;  2 1633-1638
    PubMedGoogle Scholar
  • 60 Kraus J P. Molecular basis of phenotype expression in homocystinuria.  J Inherit Metab Dis. 1994;  17 383-390
    CrossrefPubMedGoogle Scholar
  • 61 Kraus J P, Oliveriusova J, Sokolova J et al.. The human cystathionine beta-synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms.  Genomics. 1998;  52 312-324
    CrossrefPubMedGoogle Scholar
  • 62 Bao L, Vlcek C, Paces V, Kraus J P. Identification and tissue distribution of human cystathionine beta-synthase mRNA isoforms.  Arch Biochem Biophys. 1998;  350 95-103
    CrossrefPubMedGoogle Scholar
  • 63 Maclean K N, Janosik M, Kraus E et al.. Cystathionine beta-synthase is coordinately regulated with proliferation through a redox-sensitive mechanism in cultured human cells and Saccharomyces cerevisiae .  J Cell Physiol. 2002;  192 81-92
    CrossrefPubMedGoogle Scholar
  • 64 Miles E W, Kraus J P. Cystathionine beta-synthase: structure function regulation and location of homocystinuria-causing mutations.  J Biol Chem. 2004;  279 29871-29874
    CrossrefPubMedGoogle Scholar
  • 65 Heydrick S J, Weiss N, Thomas S R et al.. L-Homocysteine and L-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells.  Free Radic Biol Med. 2004;  36 632-640
    CrossrefPubMedGoogle Scholar
  • 66 Jakubowski H. Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease.  J Biol Chem. 2002;  277 30425-30428
    CrossrefPubMedGoogle Scholar
  • 67 Stabler S P, Marcell P D, Podell E R, Allen R H, Savage D G, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry.  J Clin Invest. 1988;  81 466-474
    CrossrefPubMedGoogle Scholar
  • 68 Ubbink J B. The role of vitamins in the pathogenesis and treatment of hyperhomocyst(e)inaemia.  J Inherit Metab Dis. 1997;  20 316-325
    CrossrefPubMedGoogle Scholar
  • 69 Selhub J, Jacques P F, Wilson P W, Rush D, Rosenberg I H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population.  JAMA. 1993;  270 2693-2698
    CrossrefPubMedGoogle Scholar
  • 70 van Ede A E, Laan R F, Blom H J et al.. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis.  Rheumatology (Oxford). 2002;  41 658-665
    CrossrefPubMedGoogle Scholar
  • 71 Badner N H, Beattie W S, Freeman D, Spence J D. Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy.  Anesth Analg. 2000;  91 1073-1079
    PubMedGoogle Scholar
  • 72 Homocysteine Studies Collaboration . Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA. 2002;  288 2015-2022
    CrossrefPubMedGoogle Scholar
  • 73 Jacobsen D W. Cellular mechanisms of homocysteine pathogenesis in atherosclerosis. In: Carmel R, Jacobsen D Homocysteine in Health and Disease Cambridge; Cambridge University Press 2001: 425-440
    Google Scholar
  • 74 Brattstrom L, Wilcken D E. Homocysteine and cardiovascular disease: cause or effect?.  Am J Clin Nutr. 2000;  72 315-323
    PubMedGoogle Scholar

Brian FowlerPh.D. 

Head of Labs/Metabolic Unit, University Children's Hospital Basel (UKBB)

Postfach CH-4005, Basel, Switzerland