Nutritional regulation of sulphur amino acid metabolism

含硫氨基酸(SAA)的同型半胱氨酸(HCY)位于蛋氨酸(MET)代谢的再甲基化和跨硫途径的交叉点。吡哆醛5‘-磷酸(PLP)是动物组织中维生素B6的主要生物形式，是直接参与HCY代谢的酶的辅因子，包括胱硫醚β合成酶(CBS)和胱硫醚伽马裂解酶(CGL)，这两种依赖于PLP的酶在跨硫途径中作用于产生半胱氨酸(CyS)。半胱氨酸的从头合成是MET碳骨架氧化的主要途径，因此是控制血浆和组织MET水平的重要组成部分。此外，半胱氨酸的合成，除了为蛋白质合成提供底物外，对于调节生物抗氧化剂谷胱甘肽的可用性也是至关重要的。此外，CBS和CGL都参与了硫化氢的内源合成，硫化氢是一种对血管系统具有生理调节作用的气体递质(类似于一氧化氮)。因此，维生素B6的状态是调节动物体内SAA代谢和最佳生理功能(包括肾脏功能)的关键因素。明显或严重的维生素B6缺乏是罕见的；中度缺乏更为普遍，并可由饮食因素加剧，包括大量营养素组成和抗营养因素。膳食蛋白质，更具体地说，膳食的氨基酸含量和组成与维生素B6的需求有关，随着蛋白质/氨基酸摄入量的增加，对B6的需求也随之增加。后一个事实反映了PLP作为参与转氨酶反应的酶中的辅因子的核心重要性。尽管这是众所周知的现象，但膳食蛋白质数量和质量在调节维生素B6需求方面的定量重要性还没有得到很好的表征。除了大量营养素的供应，其他饮食因素也会影响维生素B6的状况。亚麻籽中含有吡哆醇拮抗剂1-氨基-D-丙氨酸的前体--γ-谷氨基-1-氨基-D-丙氨酸(Linatine)。鉴于最近亚麻籽在牲畜和人类饲料中的利用率增加，作为omega-3脂肪酸的来源，有必要评估亚麻籽在体内的口服抗吡哆醇活性，以及维生素B6摄入量和膳食中大量营养素分布的影响。到目前为止，边缘B6状态(在没有明显缺乏症状或体征的情况下，通过B6的血清生物标记物的变化来鉴定)、蛋白质数量/质量的变化和/或饮食中存在的抗吡哆醇因素的综合影响尚未得到评估。然而，健康的动物和人类都会经历后一种情况。**目前的建议旨在研究同时存在的营养挑战对依赖B6的SAA代谢指标(氨基酸动力学、生物标记物、硫化氢)和肾功能的影响。拟议的研究计划将导致获得与SAA代谢的营养调节有关的新知识，强调考虑饮食成分对调节过程的相加影响的重要性，从而反映包括人类在内的动物在习惯性条件下更有可能经历的情况。该计划将继续为HQP提供培训机会，为他们提供未来雇主所需的研究、技术和专业技能。该计划的影响将通过提供HQP以及获取和应用新的营养知识来感受到，以支持最佳的动物和人类健康和性能。

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.