Nutritional regulation of sulphur amino acid metabolism

长期目的：了解动物硫氨基酸（SAA）代谢的营养因子，考虑到这些氨基酸在中间代谢和最佳生理功能中发挥的核心作用。为了这项NSERC发现基金，我的小组将调查当维生素B6低于要求时，饮食蛋白质含量和质量（氨基酸组成）以及饮食来源的抗营养因子如何影响SAA代谢。背景：维生素B6 （pyridoxal 5'-phosphate； PLP）是参与脂肪、碳水化合物和蛋白质代谢的100多种酶的重要辅助因子，包括参与SAA代谢的酶。日粮中提供的SAA蛋氨酸通过两种b6依赖性酶——半胱硫氨酸-合成酶（CBS）和半胱硫氨酸-裂解酶（CGL）的作用转化为半胱氨酸。因此，缺乏B6会损害半胱氨酸的合成，影响蛋白质合成、谷胱甘肽（氧化状态调节剂）的产生和硫化氢的产生。后者被认为是一种气体生物调节剂（气体递质），在维持血管张力方面起着重要作用，类似于一氧化氮。明显或严重的维生素B6缺乏症很少见，但中度缺乏症更为普遍（占加拿大人口的25-30%），并可能因饮食因素而加剧，包括宏量营养素组成和抗营养因素（营养共同损害）。因此，了解影响B6状态和SAA代谢的因素将提高我们为包括人类在内的所有动物量身定制营养供应的能力。具体目标：使用我们实验室建立的边缘性维生素B6缺乏症模型，将解决以下具体研究问题：1)当SAA以蛋氨酸形式供应与蛋氨酸+半胱氨酸平衡供应时，半胱氨酸的可用性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，食用亚麻籽会影响维生素B6状态和SAA代谢吗？3)受损的SAA和B6状态将如何影响动物对特定炎症挑战的反应能力？研究计划的影响：研究计划的影响将通过以下方式得到认可：1)获得与调节关键营养素（SAA和B6）需求的因素有关的新知识；2)加强对增加接触亚麻籽的影响的理解；3) HQP培训。这个设计的研究项目将继续培训HQP（18名直接资助，为期5年）的技术技能（高级营养分析、生物测定、饮食配方、实验设计和统计分析）和专业技能（沟通、与利益相关者的互动），这些技能是学术界、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。

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).