Nutritional regulation of homocysteine metabolism

含硫氨基酸蛋氨酸在动物细胞中作为蛋白质合成(结构、酶、激素)的底物、甲基供体(神经递质合成、DNA稳定性)和半胱氨酸的合成起着至关重要的作用。后者通过一种称为跨硫代谢的途径发生，同型半胱氨酸在该途径中起到中介作用。同型半胱氨酸代谢为半胱氨酸需要关键营养物质作为酶的辅助因子，包括几种水溶性维生素。当辅因子的供应不平衡时，同型半胱氨酸的代谢就会受到干扰。我们对同型半胱氨酸代谢的大部分知识来自于研究血液或组织浓度的变化与营养供应的关系。虽然很重要，但它们并没有提供半胱氨酸的合成在多大程度上受到阻碍的定量数据。这具有重要的后果，因为供应含硫氨基酸的目标是以满足全身需求的比率提供这些氨基酸。目前的建议试图通过使用全身模型来测量半胱氨酸的跨硫合成途径来解决这一问题，并阐明不同的营养供应对半胱氨酸合成的具体影响。在授予周期中，建议的研究计划将导致开发一个有效的模型来评估同型半胱氨酸代谢的定量部分。该计划的创新之处在于整合了全身和组织/细胞的特定信息，这将导致对调节硫磺氨基酸代谢的关键因素的整体图景的发展。

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.