Nutritional regulation of sulphur amino acid metabolism

硫氨基酸代谢的营养调节

• 批准号: RGPIN-2014-05376
• 负责人: House, James
• 金额: $ 3.57万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611602
• 关键词: Nutritional; regulation; sulphur; amino; acid

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.

含硫氨基酸（SAA）同型半胱氨酸（HCY）位于蛋氨酸（MET）代谢的再甲基化和转硫途径之间。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处置的酶的公认辅因子，所述酶包括胱硫醚β合酶（CBS）和胱硫醚γ裂解酶（CGL），这两种PLP依赖性的转硫途径的酶起产生半胱氨酸（CYS）的作用。CYS的从头合成代表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。同样，CYS合成，除了为蛋白质合成提供重要的底物外，对于调节生物抗氧化剂谷胱甘肽的可用性至关重要。此外，CBS和CGL都参与硫化氢的内源性合成，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状态是调节动物SAA代谢和最佳生理（包括肾）功能的关键因素。明显或严重的维生素B6缺乏症是罕见的;中度缺乏症更为普遍，并可因饮食因素而加剧，包括常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的需求也会增加。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。尽管这是一个众所周知的现象，但在调节维生素B6需求方面，膳食蛋白质的数量和质量的重要性还没有得到很好的表征。除了常量供应，其他饮食因素也会影响维生素B6的状态。亚麻籽含有二肽γ-谷氨酰-1-氨基-D-脯氨酸（linatine），吡哆醇拮抗剂1-氨基-D-脯氨酸的前体。鉴于最近在牲畜和人类饮食中亚麻籽的使用增加，作为ω-3脂肪酸的来源，有必要评估亚麻籽的体内口服抗吡哆醇活性，受维生素B6摄入量和膳食常量营养素分布的影响。迄今为止，尚未评估边际B6状态（通过在没有明显缺乏症状或体征的情况下B6血清生物标志物的变化确定）、蛋白质数量/质量变化和/或饮食抗吡哆醇因子存在的综合效应。然而，后一种情况是由健康的动物和人类经历的。 目前的提案旨在研究同时营养挑战对B6依赖性SAA代谢（氨基酸动力学、生物标志物、硫化氢）和肾功能指标的影响。拟议的研究计划将导致获得有关SAA代谢的营养调节的新知识，强调考虑饮食成分对调节过程的添加剂效应的重要性，从而反映动物（包括人类）在习惯条件下更可能经历的条件。该计划将继续为HQP提供培训机会，使他们具备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，以及获得和应用新的营养知识来支持最佳的动物和人类健康和性能。