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Basics

A short introduction on Homocysteine

Homocysteine (Hcy) is an endogenous sulfure-containing, non protein-forming amino acid which is a product of the one-carbon metabolism. Only trace amount of Hcy circulates in blood as free thiol form; the reminder is present mainly as disulfide complexes in which Hcy binds to (-SH) group supplied by sulfhydryl amino acids of plasma proteins (mainly Albumin). Furthermore, both mixed disulfides (i.e., with cysteine) and symmetric disulfide (homocystine= Hcy-Hcy) complexes have been reported. The concentrations of non-protein bound Hcy are only 1-2% of the total Hcy.

Abnormalities in the homocysteine metabolism with homocystinuria were first described in 1962 by Carson and Neill on two siblings from Northern Ireland, both with mental retardation. Nearly simultaneously, Gerritson et al. (1962) discovered an infant with congenital anomalies, mental retardation and failure to thrive, and provided definitive chemical proof of homocysteine excretion in the urine. Two years later, Mudd and Finkelstein (1964) reported that the cystathionine-ß-synthase was lacking in a liver biopsy specimen from another patient with homocystinuria. Thereafter, the relationship between folate and homocysteine was described by Carey et al. (1966) and low circulating folate levels were found in patients with homocystinuria and mental retardation (Carey et al. 1968). They also demonstrated a decrease in urinary homocystine excretion by high-dose folate supplementation. Later, McCully (1969) suggested the association between homocysteine and the characteristic, premature atherosclerotic vascular disease in these patients. In 1976, Wilcken and Wilcken applied all these principles to the coronary artery disease population. Nowadays, the homocysteine literature is rapidly growing. Besides the role of hyperhomocysteinemia as an important risk factor for atherosclerotic vascular disease, elevated homocysteine levels have been recognized as a risk factor for venous thrombosis. Furthermore, hyperhomocysteinemia is thought to play an important role in the development of neural tube defects, pregnancy complications, cognitive impairments in the elderly and several neuropsychiatric disorders.

Homocysteine-Metabolism

Homocysteine (Hcy) is an endogenous sulfure-containing, non protein-forming amino acid. The physiologic significance of Hcy arises mainly from its central location between three branched metabolic pathways (remethylation, transmethylation and transsulfuration). Methionine is the only known precursor of Hcy in human diet. Methionine is activated in presence of ATP into S-adenosylmethionine (SAM), the novel methyl donor in many biological reactions. SAM donates its methylgroup and is converted into S-adenosylhomocysteine (SAH), which can be hydrolysed into Hcy. The transmethylation pathway is the sole metabolic pathway that is known to produce Hcy in the body. Hcy is catabolized either into cystathionine or into methionine. Vitamin B12 is a cofactor for methionine synthase that converts Hcy into methionine. Vitamin B6 is a cofactor for cystathionase and cystathionine-beta-synthase that catabolise Hcy into cysteine.