The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine

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ABSTRACT

A unified, biochemical hypothesis is proposed to explain the pathogenesis of homocysteinemia. This hypothesis is based on the existence of coordinate regulation by S-adenosylmethionine (SAM) of the partitioning of homocysteine between de novo methionine synthesis and catabolism through cystathionine synthesis. This coordination, which serves to modulate the cellular concentration of homocysteine based on the requirements for methionine, is impaired in homocysteinemia. This hypothesis is evaluated in the context of the conditions known to be associated with homocysteinemia, including enzymatic defects and vitamin deficiencies. The novelty of the hypothesis is the assertion that impairment of one homocysteine metabolic pathway must lead to the impairment of the other homocysteine metabolic pathway to cause homocysteinemia. This extends the simplistic view that a block of only one of the pathways is sufficient to cause homocysteinemia.

REFERENCE (80)

  • MuddSH et al.

    Deranged B12 metabolism: effects on sulfur amino acid metabolism

    Biochem Med

    (1970)
  • MuddSH et al.

    Deranged B12 metabolism: studies of fibroblasts grown in tissue culture

    Biochem Med

    (1970)
  • DavisRE

    Clinical chemistry of vitamin Bl2

    Adv Clin Chem

    (1985)
  • BrattstromL et al.

    Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine β-synthase deficiency

    Metabolism

    (1988)
  • HollowellJG et al.

    Homocystinuria and organic aciduria in a patient with vitamin B-12 deficiency

    Lancet

    (1969)
  • KangS-S et al.

    Homocysteinemia due to folate deficiency

    Metabolism

    (1987)
  • LinJ-Y et al.

    Homocysteinemia in rats induced by folic acid deficiency

    Life Sei

    (1989)
  • ArakiA et al.

    Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection

    J Chromatogr

    (1987)
  • BrattstromLE et al.

    Folic acid responsive postmenopausal homocysteinemia

    Metabolism

    (1985)
  • WilckenDEL et al.

    Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: possible implications for prevention of vascular disease

    Metabolism

    (1988)
  • BoersGHJ et al.

    Pyridoxine treatment does not prevent homocystinemia after methionine loading in adult homocystinuria patients

    Metabolism

    (1983)
  • ParkYK et al.

    Effect of vitamin B6 depletion in adult man on the excretion of cystathionine and other methionine metabolites

    J Nutr

    (1970)
  • Murphy-ChutorianDR et al.

    Methionine intolerance: a possible risk factor for coronary artery disease

    J Am Coll Cardiol

    (1985)
  • WilckenDEL et al.

    Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria

    Metabolism

    (1983)
  • ShinHK et al.

    Tryptophan and methionine metabolism of adults females as affected by vitamin B-6 deficiency

    J Nutr

    (1974)
  • SmolinLA et al.

    Factors affecting the accumulation of homocyst(e)ine in rats deficient in vitamin B-6

    J Nutr

    (1984)
  • SmolinLA et al.

    Accumulation of homocyst(e)ine in vitamin B-6 deficiency: a model for the study of cystathionine ^-synthase deficiency

    J Nutr

    (1982)
  • JencksDA et al.

    Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine

    J Biol Chem

    (1987)
  • KutzbachC et al.

    Mammalian methylenetetrahydrofolate reductase: partial purification, properties, and inhibition by S-Ade- nosylmethionine

    Biochim Biophys Acta

    (1971)
  • KutzbachC et al.

    Feedback inhibition of methylene-tet-rahydrofolate reductase in rat fiver by S-Adenosylmethionine

    Biochim Biophys Acta

    (1967)
  • FinkelsteinJD et al.

    Activation of cystathionine synthase by adenosylmethionine and adenosylethionine

    Biochem Biophys Res Commun

    (1975)
  • FinkelsteinJD et al.

    Inactivation of betaine-homocysteine methyltransferase by adenosylmethionine and adenosylethionine

    Biochem Biophys Res Commun

    (1984)
  • WilckenDEL et al.

    Homocystinuria due to cystathionine β-synthase deficiency—the effects of betaine treatment in pyridoxine-response patients

    Metabolism

    (1985)
  • SmolinLA et al.

    The use of betaine for the treatment of homocystinuria

    J Pediatr

    (1981)
  • WileyVC et al.

    Free and protein-bound homocysteine and cysteine in cystathionine β-synthase deficiency: interrelations during short- and long-term changes in plasma concentrations

    Metabolism

    (1989)
  • FinkelsteinJD et al.

    Pyridoxine effects on cystathionine synthase in rat liver

    J Nutr

    (1970)
  • SturmanJA et al.

    Effects of deficiency of vitamin B6 on transsulfuration

    Biochem Med

    (1969)
  • UelandPM et al.

    Homocysteine in tissues of the mouse and rat

    J Biol Chem

    (1984)
  • UelandPM et al.

    Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy

    J Lab Clin Med

    (1989)
  • MuddSH et al.

    Disorders of transsulfuration

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