Nutritional regulation of homocysteine metabolism

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The sulphur amino acid methionine plays critical roles in animal cells as a substrate for protein synthesis (structural, enzymes, hormones), as a methyl donor (neurotransmitter synthesis, DNA stability), and for the synthesis of the amino acid cysteine. The latter occurs through a pathway called transsulphuration, for which homocysteine acts as an intermediate. Homocysteine metabolism to cysteine requires the assistance of key nutrients as cofactors for enzymes, including several water soluble vitamins. When the supply of cofactors is imbalanced, homocysteine metabolism is perturbed. Much of our knowledge of homocysteine metabolism comes from research examining changes in blood or tissue concentrations in relation to nutrient supply. While important, they do not provide quantitative data as to how much the synthesis of cysteine is hampered. This has important consequences, as the goal in supplying the sulphur amino acids is their provision at rates to meet whole body demands. The current proposal seeks to address this issue by using a whole body model for the measurement of cysteine synthesis through the transsulphuration pathway and to elucidate the specific impacts of varying nutrient supply on this conversion. Over the course of the granting cycle, the proposed research program will lead to the development of a valid model for the assessment of the quantitative partion of homocysteine metabolism. The novelty of the program lies in the integration of whole body and tissue/cellular specific information, which will lead to the development of a holistic picture of the key factors regulating sulphur amino acid metabolism.