Nutritional regulation of sulphur amino acid metabolism

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The sulphur amino acid (SAA) homocysteine (HCY) stands at the intersection between the remethylation and transsulphuration pathways of methionine (MET) metabolism. Pyridoxal 5’-phosphate (PLP), a major biological form of vitamin B6 in animal tissues, is a well-established co-factor for enzymes directly involved in HCY disposition, including cystathionine beta synthase (CBS) and cystathionine gamma lyase (CGL), two PLP-dependent enzymes of the transsulphuration pathway that function to yield cysteine (CYS). De novo synthesis of CYS represents the primary route for the oxidation of the carbon skeleton of MET, and is therefore an important component in the control of plasma and tissue MET levels. As well, CYS synthesis, besides being important for providing a substrate for protein synthesis, is crucial for the regulation of the availability of the biological antioxidant glutathione. Furthermore, both CBS and CGL are involved in the endogenous synthesis of hydrogen sulphide, a gasotransmitter with physiological regulatory effects on the vasculature (akin to nitric oxide). Vitamin B6 status is thus a critical factor regulating SAA metabolism and optimal physiological, including renal, function in animals. Overt or severe vitamin B6 deficiency is rare; moderate deficiency is more prevalent, and can be exacerbated by dietary factors, including macronutrient composition and anti-nutritive factors. Dietary protein and, more specifically, the amino acid content and composition of the diet is linked to vitamin B6 requirements, with the need for B6 increasing as protein/amino acid intake increases. This latter fact reflects the central importance of PLP as a cofactor in enzymes involved in aminotransferase reactions. Despite this well-known phenomenon, the quantitative importance of dietary protein quantity and quality in modulating vitamin B6 requirements is poorly characterized. Beyond macronutient supply, other dietary factors can influence vitamin B6 status. Flaxseed contains the dipeptide gamma-glutamyl-1-amino-D-proline (linatine), the precursor to the pyridoxine antagonist 1-amino-D-proline. Given the recent increase in the utilization of flaxseed in both livestock and human diets, as a source of omega-3 fatty acids, there is a need to assess the in vivo, oral anti-pyridoxine activity of flaxseed, as influenced by vitamin B6 intake and dietary macronutrient distribution. To date, the combined effects of marginal B6 status (identified by changes in serum biomarkers of B6 in the absence of overt deficiency symptoms or signs), alterations in protein quantity/quailty, and/or the presence of dietary anti-pyridoxine factors have not been assessed. However, the latter scenario is experienced by healthy animals and humans. The current proposal seeks to study the impact of concurrent nutritional challenges on indices of B6-dependent SAA metabolism (amino acid kinetics, biomarkers, hydrogen sulphide) and renal function. The proposed research program will lead to the acquisition of new knowledge in relation to the nutritional regulation of SAA metabolism, highlighting the importance of considering the additive effects of dietary components on the regulatory processes, thus reflecting conditions more likely to experienced by animals, including humans, under habitual conditions. This program will continue to provide training opportunities for HQP, equipping them with research, technical and professional skills in demand by future employers. The impact of the program will be felt through the provision of HQP, and the acquisition and application of new nutritional knowledge in support of optimal animal and human health and performance.