Homocysteine Metabolism

Abstract

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.

Effects of heparin on the production of homocysteine-induced extracellular matrix metalloproteinase-2 in cultured rat vascular smooth muscle cells

“…Hcy is a nonprotein-forming, sulphur-containing amino acid that stands at the crossroads of two metabolic pathways (21). Hcy, which is not a dietary constituent, is formed exclusively on demethylation of methionine and is eliminated through one of two vitamin-dependent pathways.…”

Impairments in pyridoxine-dependent sulphur amino acid metabolism are highly sensitive to the degree of vitamin B6 deficiency and repletion in the pig

“…As depicted in Figure 1, the sulphur amino acid homocysteine stands at the intersection between the remethylation and transsulphuration pathways of methionine metabolism (Selhub, 1999). Pyridoxal-5 0 -phosphate (PLP), a major biological form of vitamin B 6 in animal tissues, is a well established co-factor for the three enzymes directly involved in homocysteine disposition: cystathionine-bsynthase (CBS) and cystathionine-g-lyase (CGL) are key PLP-dependent enzymes in the transsulphuration pathway, and serine hydroxymethyltransferase (SHMT) is a PLPdependent enzyme important for the folate cycle and one carbon metabolism (House et al, 1999).…”

Tailoring recombinant protein quality by rational media design

“…This finding is further supported by the fact that process C generated intermediate asparagine levels, as was also the case for lactate. A similar pattern showed homocysteine, a sulfur amino acid intersecting two pathways: remethylation to methionine and transsulfuration to cystathionine 299 . Once more, process A stood out due to low intra-and extracellular levels, while intermediate homocysteine levels were observed in process C ( figure 8.3).…”

“…Processes B and D featured all at once the highest lactate concentration increases and the highest levels of the two amino acids. Homocysteine is either transformed to methionine (Met) by the Met-synthase using 5-methyltetrahydrofolate or to cystathionine by the cystathionine-β-synthase, involving serine 299 . The non-targeted metabolomic analysis detected neither intra-nor extracellular cystathionine.…”