Structure and function study of angiotensin converting enzyme 2 (ACE2) activating peptides from food proteins

我的项目将发现研究与高素质人员的培训相结合，以实现了解食品蛋白衍生生物活性多肽的构效关系的目标。生物活性多肽是一种蛋白质的小片段，在改善人类健康和预防慢性病方面具有巨大的潜力。这些多肽在蛋白质中是不活跃的，但可以在食品加工和/或消化过程中释放。我之前通过Discovery Grants的研究进展研究了生物活性多肽的结构和活性与血管紧张素转换酶(ACE)抑制、抗氧化和抗炎特性的关系。血管紧张素转换酶(ACE)负责血管紧张素II(Ang II)的生成，而其同系物ACE2参与树脂血管紧张素系统将Ang II降解为Ang(1-7)。Ang II水平升高导致氧化应激、炎症和血管收缩，导致高血压；因此，ACE2被认为在抵消Ang II的有害影响方面发挥重要作用。抑制ACE是一种成熟的血压控制方法；许多食物蛋白衍生的降压肽的特征是基于ACE抑制。血管紧张素转换酶抑制肽IRW最近被鉴定为ACE2激活肽，而另两个肽IQW和LKP没有激活ACE2的活性。这促使我们进一步研究具有ACE抑制活性的ACE2激活肽的结构特征。由于ACE抑制不是ACE2激活肽的本质属性，因此有必要从不同的蛋白质来源中鉴定ACE2激活肽。通过定量构效关系建模和对接研究，研究ACE2激活肽的结构特征。鉴于ACE2对血管紧张素转换酶II的平衡作用，具有代表性的ACE2激活肽将在小肌肉细胞和动物身上测试其抗氧化和抗炎活性。本研究计划将在ACE2激活肽的结构和功能特性方面取得根本性发现，这将进一步促进我们对食物蛋白质作为生物活性多肽来源的潜力的理解。许多慢性病是与饮食和生活方式有关的疾病。了解它们的作用机制将有助于将生物活性多肽作为有益于心血管疾病的功能食品或营养食品开发的研究成果。心血管疾病是加拿大和全世界发病率和死亡率的主要原因。因此，探索以改善血管内皮细胞功能为目标的新型抗氧化肽，将有助于提高加拿大人的健康水平。

My program integrates discovery research, with training of highly qualified personnel, to achieve the goal of understanding the structure-activity relationships of food protein-derived bioactive peptides. ******Bioactive peptides are small fragments of proteins that may have vast potential for improving human health and preventing chronic diseases. These peptides are inactive within the proteins but can be released during food processing and/or digestion. My previous research progresses through Discovery Grants have studied the structure and activity relationships of bioactive peptides with angiotensin converting enzyme (ACE) inhibitory, anti-oxidative, and anti-inflammatory properties. ACE is responsible for angiotensin II (Ang II) generation, while its homologue, ACE2, is involved in degradation of Ang II into Ang (1-7) in the resin angiotensin system. Elevated Ang II level causes oxidative stress, inflammation, and vasoconstriction, leading to high blood pressure; thus ACE2 is thought to play an important role in counterbalancing the harmful effects of Ang II. Inhibition of ACE is a well-established approach for blood pressure control; many food protein derived antihypertensive peptides are characterized based on ACE inhibition. ACE inhibitory peptide IRW was recently identified as an ACE2 activating peptide, however, other two peptides, IQW and LKP, did not show ACE2 activating activity. This prompted us further research question on the structural features of ACE2 activating peptides with concomitant ACE inhibitory activity. Since ACE inhibition is not an essential property of ACE2 activating peptides, there is a need to identify ACE2 activating peptides from various protein sources. Structural features of ACE2 activating peptides will be studied using quantitative structure and activity relationship modeling and docking study. Representative ACE2 activating peptides will be tested for their antioxidant and anti-inflammatory activities in small muscle cells and in animals, given the counterbalancing effect of ACE2 on Ang II. ******This research program will make fundamental discoveries on the structure and function properties of ACE2 activating peptides, which will further advance our understanding the potential of food proteins as sources of bioactive peptides. Many chronic diseases are diet and life-style related diseases. Understanding their mechanisms of action will facilitate the translation of research towards the development of bioactive peptides as functional foods or nutraceuticals with benefits for cardiovascular diseases. Cardiovascular disease is the leading cause of morbidity and mortality in Canada and worldwide. Therefore, exploration of novel antioxidant peptides targeting at improving endothelial function will help to improve the health and wellness of Canadian.