Related papers: molecules in focus
Homocysteine

https://doi.org/10.1016/S1357-2725(99)00138-7Get rights and content

Abstract

Homocysteine does not occur in the diet but it is an essential intermediate in normal mammalian metabolism of methionine. Each compound, methionine or homocysteine, is the precursor of the other. Similarly, the synthesis of one is the mechanism for the detoxification of the other. The ubiquitous methionine cycle is the metabolic basis for this relationship. In some tissues the transsulfuration pathway diverts homocysteine from the cycle and provides a means for the synthesis of cysteine and its derivatives. Methionine, (or homocysteine) metabolism is regulated by the disposition of homocysteine between these competing sequences. Both pathways require vitamin-derived cofactors, pyridoxine for transsulfuration and both folate and cobalamin in the methionine cycle. The clinical consequences of disruption of these pathways was apparent first in rare inborn errors of metabolism that cause homocystinuria, but recent studies focus on “hyperhomocysteinemia” — a lesser metabolic impairment that may result from genetic variations, acquired pathology, toxicity and nutritional inadequacy. Hyperhomocysteinemia is an independent risk factor for thrombovascular diseases however it is not clear whether the minimally increased concentration of the amino acid is the causative agent or merely a marker for the pathology. Until we resolve that question we cannot predict the potential efficacy of therapies based on folate administration with or without additional cobalamin and pyridoxine.

Introduction

Homocysteine (2-amino-4-mercaptobutyric acid) was synthesized in 1932 by duVigneaud who was studying the sulfur of insulin. In his biography he states, “…the entire homocystine work leading to the studies of transulfuration (sic) and transmethylation would not have taken place if we had been able to account for the sulfur of insulin at the beginning and if the absence of methionine in insulin had been known at that time. The paths which research may take are indeed curious.” [1].

Section snippets

Structure

Fig. 1 illustrates the structure of homocysteine, a thiol formed by the demethylation of methionine. Animal tissues contain some free thiol but most of the compound occurs as homocystine, the disulfide of homocysteine; homocysteine–cysteine mixed disulfide, and homocysteine bound to protein by disulfide bonds.

The pathways

Homocysteine represents a point of intersection of two pathways — the methionine cycle and the transsulfuration sequence (Fig. 2) [2]. The methionine cycle is formed by the synthesis of S-adenosylmethionine (AdoMet); the numerous specific transmethylation reactions that yield S-adenosylhomocysteine (AdoHcy) as a product; the reversible adenosylhomocysteinase reaction that favors synthesis of AdoHcy unless the products — adenosine and homocysteine — are removed; and the remethylation of

Biological functions

The four biological functions of homocysteine, implicit in Fig. 2, are (1) as a precursor for cystathionine, cysteine and further metabolites; (2) as a means for methionine conservation; (3) as a methyl receptor in the betaine–homocysteine methyltransferase reaction, an obligatory step in choline catabolism; and (4) as a substrate that is essential for the recycling of tissue folates. Since methionine synthase is the only reaction that utilizes methyltetrahydrofolate, folates will be “trapped”

Medical applications

The clinical relevance of homocyst(e)ine became apparent in 1962 with the first descriptions of patients with “Homocystinuria” due to a homozygous defect in cystathionine synthase [8]. Thrombovascular events dominated the clinical picture. When these also occurred in patients with homocystinuria due to failure of remethylation (defects in cobalamin metabolism or methylenetetrahydrofolate reductase deficiency), the link between homocysteine and vascular disorders was established. Patients with

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    Homocysteine is a non-proteinogenic amino acid, which is not a constituent of our diet, but part of the methionine cycle (Moretti and Caruso, 2019). The metabolism of homocysteine forms the interface between two different pathways, one leading back to methionine and the other to cystathionine (Finkelstein and Martin, 2000; Selhub, 1999). Apart from its important metabolic role, increased homocysteine can also be harmful.

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