Nutritional regulation of sulphur amino acid metabolism

长期目标：了解调节动物体内含硫氨基酸(SAA)代谢的营养因素，了解这些氨基酸在中间代谢和最佳生理功能中所起的中心作用。对于这项NSERC发现拨款，我的团队将研究当维生素B6低于要求时，膳食蛋白质含量和质量(氨基酸组成)以及饮食衍生的抗营养因子如何影响SAA新陈代谢。 背景：维生素B6(5‘-磷酸吡哆醛，PLP)是包括SAA代谢在内的100多种参与脂肪、碳水化合物和蛋白质代谢的酶的重要辅因子。SAA蛋氨酸(在饮食中提供)通过两种依赖B6的酶，即胱硫醚β合成酶(CBS)和胱硫氨酸伽马裂解酶(CGL)的作用转化为半胱氨酸。因此，B6缺乏会损害半胱氨酸的合成，影响蛋白质的合成、谷胱甘肽的产生(氧化状态的调节)和硫化氢的产生。后者被认为是一种气体生物调节器(气体递质)，与一氧化氮类似，在维持血管紧张性方面具有重要作用。明显或严重的维生素B6缺乏是罕见的，但中度缺乏更为普遍(占加拿大人口的25%-30%)，并可由饮食因素加剧，包括大量营养素组成和抗营养因素(营养共同侮辱)。因此，了解影响B6状态和SAA代谢的因素将增强我们为包括人类在内的所有动物量身定做营养供应的能力。 具体目标：使用我们实验室建立的边际维生素B6缺乏症模型，将解决以下具体研究问题： 1)当SAA以蛋氨酸和蛋氨酸+半胱氨酸的平衡供应时，半胱氨酸的供应是否会受到限制并影响：a)蛋白质沉积；b)抗氧化状态和免疫功能；c)组织健康和完整性？ 2)由于天然B6抑制剂的存在，亚麻籽的消费是否会影响维生素B6状态和SAA代谢？ 3)SAA和B6状态受损将如何影响动物应对特定炎症挑战的能力？ 研究计划的影响：研究计划的影响将通过：1)获得与调节关键营养素需求的因素(SAA和B6)有关的新知识；2)加强对增加亚麻籽暴露的影响的理解；以及3)HQP培训。这一设计的学习计划将继续培训HQP(18人在5年内直接资助)在学术、牲畜饲养和人类营养职业(营养师、营养政策、食品开发)所需的技术技能(高级营养分析、生物分析、饮食配方、实验设计和统计分析)和专业技能(沟通、与利益相关者互动)方面的培训。

LONG-TERM OBJECTIVE: To understand the nutritional factors regulating sulphur amino acid (SAA) metabolism in animals, given the central role these amino acids play in intermediary metabolism and optimal physiological function. For this NSERC Discovery Grant, my group will be investigating how dietary protein content and quality (amino acid composition), as well as diet-derived anti-nutritive factors, impact SAA metabolism when vitamin B6 is present below requirements. BACKGROUND: Vitamin B6 (pyridoxal 5'-phosphate; PLP) is an important cofactor for over 100 enzymes involved in fat, carbohydrate and protein metabolism, including those involved in SAA metabolism. The SAA methionine (provided in the diet) is converted to cysteine through the action of two B6-dependent enzymes, cystathionine beta synthase (CBS) and cystathionine gamma-lyase (CGL). As such, a B6 deficiency impairs cysteine synthesis, with impacts on protein synthesis, glutathione production (regulator of oxidative status) and the production of hydrogen sulphide. The latter is recognized as a gaseous biological regulator (gasotransmitter) with important roles in maintaining vascular tone, akin to nitric oxide. Overt or severe vitamin B6 deficiency is rare, however moderate deficiency is more prevalent (25-30% of Canadian population), and can be exacerbated by dietary factors, including macronutrient composition and anti-nutritive factors (nutritional co-insults). As such, understanding the factors impacting B6 status and SAA metabolism will enhance our ability to tailor nutrient supply to all animals, including humans. SPECIFIC OBJECTIVES: Using a model of marginal vitamin B6 deficiency established in our lab, the following specific research questions will be addressed: 1) When SAA are supplied as methionine vs. a balanced supply of methionine+cysteine, will cysteine availability be limited and impact: a) protein deposition; b) antioxidant status and immune function; and c) tissue health and integrity? 2) Will flaxseed consumption, due to the presence of a natural B6 inhibitor, impact vitamin B6 status and SAA metabolism? 3) How will compromised SAA and B6 status impact the ability of an animal to respond to specific inflammatory challenges? IMPACT OF THE RESEARCH PROGRAM: The impact of the research program will be recognized through: 1) the acquisition of new knowledge pertaining to factors regulating the requirements for key nutrients (SAA and B6); 2) enhanced understanding of the implications of increasing exposure to flaxseed; and 3) HQP training. This designed program of study will continue to train HQP (18 directly funded over 5 years) in both technical skills (advanced nutrient analyses; bioassays; diet formulation; experimental design and statistical analyses) and professional skills (communication; interaction with stakeholders) needed for careers in academia, livestock feeding, and human nutrition careers (dietitians; nutrition policy; food product development).