Fitting homocysteine to disease models, as well as adjusting the models to the disease.

Abstract

Homocysteine is a nonprotein α-amino acid and differs from cysteine by having an additional methylene bridge. Homocysteine is not present in the diet, and all homocysteine in the body is biosynthesized from the essential amino acid methionine. Homocysteine is a product of methionine demethylation and is recycled into methionine or alternatively converted into cysteine with the assistance of B vitamins. Homocysteine is metabolized through two pathways, namely remethylation and transsulfuration. Much information has been generated from mouse models. A summary of this model information, as presented by Dayal and Lentz [1], is shown (Fig. 1). The remethylation pathway requires vitamin B12, folate, and the enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR). In the kidney and liver, homocysteine is also remethylated by the enzyme betaine homocysteine methyltransferase (BHMT), which transfers a methyl group to homocysteine via the demethylation of betaine to dimethylglycine (DMG). The transsulfuration pathway requires the enzyme cystathionine beta-synthase (CBS) and vitamin B6 (pyridoxal-5′-phosphate). Once formed from cystathionine, cysteine can be utilized in protein synthesis and glutathione (GSH) production. Genetics has contributed greatly to our understanding of homocysteine, its metabolism, and cardiovascular risk. Classical homocystinuria, an autosomal-recessive disease, is caused by CBS deficiency. The defect leads to a multisystem disorder involving connective tissue, muscle, the central nervous system, and the cardiovascular system [2]. Genetic variation in the MTHFR gene influences the susceptibility to occlusive vascular disease, neural tube defects, Alzheimer’s disease and other dementias, colon cancer, and acute leukemia [2]. Thus, homocysteine, its metabolism, and the enzymes involved are of great interest in biomedical research. Homocysteine contributes to endothelial injury and subsequent atherosclerosis and is a specific risk factor for cardiovascular disease. As a result, much effort has been expended in clinical trials for various vascular diseases in the hopes that by reducing homocysteine levels, cardiovascular endpoints could be ameliorated. For instance, an updated Cochrane review found no evidence to suggest that homocysteinelowering interventions in the form of supplements of vitamins B6, B9, or B12 given alone or in combination should be used for preventing cardiovascular events [3, 4]. Neither has the supplementation of dietary folic acid to lower homocysteine levels led to more favorable outcomes [5, 6]. Nevertheless, folic acid supplementation has a major impact on reducing neural tube defects [7]. J Mol Med this month features a homocysteine-based hypothesis in a complicated animal model. Muthuramu et al. point out that a Bcausal role of homocysteine in myocardial biology and function cannot be proven since residual confounding in multivariable models may occur^ [8]. How very true! They studied Cbs heterozygous gene-deleted (Cbs +/−) mice. These mice were crossed with low-density lipoprotein receptor (Ldlr −/−) gene-deleted mice to generate Cbs +/−/ Ldlr −/− mice. The mice were divided into three groups and fed regular chow, folic acid-depleted chow, or methionineenriched chow. Three weeks after diet initiation, the mice were intravenously injected with a hepatocyte-specific adenoviral vector expressing Cbs (AdCBS), with the same dose of control vector, or with saline buffer. Two weeks after that, the mice were subjected to thoracic aortic constriction (TAC), an experimental aortic coarctation, or sham operation to induce * Friedrich C. Luft luft@charite.de