Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects

Abstract

This overview addresses homocysteine and folate metabolism. Its functions and complexity are described, leading to explanations why disturbed homocysteine and folate metabolism is implicated in many different diseases, including congenital birth defects like congenital heart disease, cleft lip and palate, late pregnancy complications, different kinds of neurodegenerative and psychiatric diseases, osteoporosis and cancer. In addition, the inborn errors leading to hyperhomocysteinemia and homocystinuria are described. These extreme human hyperhomocysteinemia models provide knowledge about which part of the homocysteine and folate pathways are linked to which disease. For example, the very high risk for arterial and venous occlusive disease in patients with severe hyperhomocysteinemia irrespective of the location of the defect in remethylation or transsulphuration indicates that homocysteine itself or one of its "direct" derivatives is considered toxic for the cardiovascular system. Finally, common diseases associated with elevated homocysteine are discussed with the focus on cardiovascular disease and neural tube defects.

Fig. 1

Schematic representation of the folate cycles and homocysteine metabolism. AdoHcy S-adenosylhomocysteine, AdoMet S-adenosylmethionine, AICAR 5-aminoimidazole-4-carboxamide ribonucleotode, SAHH S-adenosylhomocysteine hydrolase, ATP adenosine triphosphate, BHMT betaine-homocysteine methyltransferase, CBS cystathionine β-synthase, CTH cystathionine γ-lyase, DHF dihydrofolate, DHFR dihydrofolate reductase, dUMP deoxyuridine monophosphate, dTMP deoxythymidine monophosphate, FAICAR formyl-AICAR, MAT methionine-adenosyltransferase, MTHFD methylenetetrahydrofolate dehydrogenase / methenyltetrahydrofolate cyclohydrolase / formyltetrahydrofolate synthetase, MTHFR methylenetetrahydrofolate reductase, MTR methionine synthase, MTRR methionine synthase reductase, SHMT serine-hydroxymethyltransferase, THF tetrahydrofolate, TYMS thymidylate synthase

Fig. 2

Schematic overview of folate uptake and transport from the intestine, via the blood, into the cell. THF tetrahydrofolate, FR-α folate receptor alpha, PCFT proton-coupled folate transporter, RFC1 reduced folate carrier, THF tetrahydrofolate, FGCP folylpoly-γ-glutamate carboxypeptidase