肌肽的抗羰基应激作用：肌肽与丙二醛的反应机理研究
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摘要
长久以来,人类对健康长寿和衰老的探索都是生命科学和医学领域中的重要内容。几百年来无数的科学家们做了大量的研究,但由于衰老的进程非常复杂,影响衰老的因素也极其繁多,其具体的机制并不清楚。到现在为止,有关衰老的理论有几百种,从研究方向上可分为两大类：一类是遗传控制(先天因素)衰老学说,另一类是环境伤害(后天因素)衰老学说。这两大研究领域从不同侧面揭示了衰老的起因,提供了机体衰老的重要信息,但也都存在各自的局限。总而言之,衰老是遗传因素和环境因素共同作用的结果已逐渐成为衰老研究领域公认的科学事实。
脂质过氧化与非酶糖基化反应中生成的具有反应活性的共同中间产物——活性羰基类物质能与生物体内的生物大分子发生反应(羰-氨交联反应),并进一步重排,形成难以降解和溶解的老年色素类的荧光物质。羰基应激衰老学说认为羰-氨交联反应所导致的生物大分子交联过程是积累性衰老损变的核心过程,可能是衰老的本质。
肌肽(Carnosine)是一种天然的、具有高效生物活性的二肽,广泛地存在于哺乳动物的骨骼肌和大脑等组织中,在人的骨骼肌中浓度高达20 mM。肌肽的氨基能与活性羰基类物质发生反应,从而抑制毒性羰基类物质造成的蛋白交联反应,对生物体延缓衰老具有重要作用。
本论文讨论了目前的一些最重要的衰老理论学说,例如自由基衰老学说、非酶糖基化衰老学说以及导师印大中教授在这二者基础上基于老年色素形成的生化机制而提出的羰基应激衰老学说。在本论文中我们探讨了肌肽的抗羰基应激作用,并研究了肌肽与脂质过氧化的典型中间产物——丙二醛(MDA)的反应机理。
本学位论文主要研究工作总结如下：
本论文主要研究肌肽与丙二醛的反应机理以探讨肌肽潜在的抗羰基应激的作用。肌肽与丙二醛温浴在37℃、pH7.4的0.2M磷酸缓冲液中,一段时间后反应液进行荧光分光光度计检测、紫外分光光度计检测、高效液相色谱分离等分析,生成的产物用液相色谱／质谱(LC/MS)鉴定。实验结果表明：肌肽能在生理条件下直接与丙二醛反应,生成两种不同的产物,产物1是无荧光特性的,最大吸收波长为280nm的烯胺衍生物；产物2是类似于脂褐素样的老年色素1、4-二氢吡啶荧光产物(激发波长为392nm,发射波长为452nm)。反应产生的荧光强度与丙二醛的浓度成正比。肌肽也能够极大地抑制丙二醛与小牛血清白蛋白反应体系中脂褐素样荧光类物质的生成。实验结果表明肌肽具有去羰基应激的功能,同时也阐述了肌肽去羰基应激保护蛋白质方面的分子机制。
Exploring healthy longevity and aging of human is playing a crucial role in the area of life sciences and medicine at all times. Because the aging processes is very complex and involves various factors, despite considerable researches over centuries, the exact mechanism underlying aging still remains to be elucidate. Until now, there are hundreds of theories of aging. Those theories from different research points can be summed up to two types:genetic factors and environmental damages on aging. Both of them provide important information of aging from different perspectives, but they have limits to explain the aging. In a word, senescence is a collective consequence of both heredity and environment.
Reactive carbonyl species produced in lipid peroxidation and glycation can inevitably result in carbonyl-amino reaction with biomacromolecules in body, and then the products re-arrange. This process leads to the formation of the age pigment-like fluorescent substance which is difficult to be dissolved or degraded. According to the carbonyl stress theory of aging, the crosslink of biomacromolecule induced by carbonyl-amino reaction is the essential course of aging.
Carnosine is a natural dipeptide that of highly efficient biological activity. It commonly presents, sometimes at a relatively high concentration (up to 20 mM in human muscle), in mammalian tissues, especially in muscle and brain. The amino group of carnosine can react with reactive carbonyl species thereby inhibiting crosslink of protein caused by toxic carbonyl species. Carnosine play important role in anti-aging of the organism.
In this paper we discussed the free radical theory of aging, the glycation theory of aging and carbonyl stress theory of aging that proposed by my tutor professor Yin, based on the biochemical mechanisms of aging pigment formation. We investigated the anti-aging effects of carnosine and studied the reaction mechanisms of carnosine with malondialdehyde (MDA), the typical secondary products in lipid peroxidation.
The studies included in the thesis are summarized as follows:
In this thesis we study the reaction mechanisms between carnosine and MDA to explore the potential de-carbonylation function of carnosine. The carnosine was incubated with MDA in 0.2M phosphate buffer solution at pH7.4,37℃. The mixture of MDA and carnosine was assayed by high performance liquid chromatography (HPLC), spectrophotometry and spectrofluorometry. The reaction products were assayed by LC/MS. The results indicated that carnosine reacted readily with MDA at supra-physiological condition to form different products, such as a non-fluorescent enamine with an absorption peak at 280 nm (productl) and a lipofuscin-like fluorescent (Excite.392nm/Emission.452nm) 1,4-dihydropyridine(product2). The fluorescence intensity of reaction mixture was in direct proportion to the MDA concentration. Carnosine also greatly inhibited the formation of lipofuscin-like fluorescence induced by MDA reacted with bovine serum albumin (BSA). This study suggested that the reaction of carnosine with MDA may reveal toxic effect of unsaturated carbonyls and provided insight into the reaction mechanism of carnosine in protecting proteins against carbonyl stress.
脂质过氧化与非酶糖基化反应中生成的具有反应活性的共同中间产物——活性羰基类物质能与生物体内的生物大分子发生反应(羰-氨交联反应),并进一步重排,形成难以降解和溶解的老年色素类的荧光物质。羰基应激衰老学说认为羰-氨交联反应所导致的生物大分子交联过程是积累性衰老损变的核心过程,可能是衰老的本质。
肌肽(Carnosine)是一种天然的、具有高效生物活性的二肽,广泛地存在于哺乳动物的骨骼肌和大脑等组织中,在人的骨骼肌中浓度高达20 mM。肌肽的氨基能与活性羰基类物质发生反应,从而抑制毒性羰基类物质造成的蛋白交联反应,对生物体延缓衰老具有重要作用。
本论文讨论了目前的一些最重要的衰老理论学说,例如自由基衰老学说、非酶糖基化衰老学说以及导师印大中教授在这二者基础上基于老年色素形成的生化机制而提出的羰基应激衰老学说。在本论文中我们探讨了肌肽的抗羰基应激作用,并研究了肌肽与脂质过氧化的典型中间产物——丙二醛(MDA)的反应机理。
本学位论文主要研究工作总结如下：
本论文主要研究肌肽与丙二醛的反应机理以探讨肌肽潜在的抗羰基应激的作用。肌肽与丙二醛温浴在37℃、pH7.4的0.2M磷酸缓冲液中,一段时间后反应液进行荧光分光光度计检测、紫外分光光度计检测、高效液相色谱分离等分析,生成的产物用液相色谱／质谱(LC/MS)鉴定。实验结果表明：肌肽能在生理条件下直接与丙二醛反应,生成两种不同的产物,产物1是无荧光特性的,最大吸收波长为280nm的烯胺衍生物；产物2是类似于脂褐素样的老年色素1、4-二氢吡啶荧光产物(激发波长为392nm,发射波长为452nm)。反应产生的荧光强度与丙二醛的浓度成正比。肌肽也能够极大地抑制丙二醛与小牛血清白蛋白反应体系中脂褐素样荧光类物质的生成。实验结果表明肌肽具有去羰基应激的功能,同时也阐述了肌肽去羰基应激保护蛋白质方面的分子机制。
Exploring healthy longevity and aging of human is playing a crucial role in the area of life sciences and medicine at all times. Because the aging processes is very complex and involves various factors, despite considerable researches over centuries, the exact mechanism underlying aging still remains to be elucidate. Until now, there are hundreds of theories of aging. Those theories from different research points can be summed up to two types:genetic factors and environmental damages on aging. Both of them provide important information of aging from different perspectives, but they have limits to explain the aging. In a word, senescence is a collective consequence of both heredity and environment.
Reactive carbonyl species produced in lipid peroxidation and glycation can inevitably result in carbonyl-amino reaction with biomacromolecules in body, and then the products re-arrange. This process leads to the formation of the age pigment-like fluorescent substance which is difficult to be dissolved or degraded. According to the carbonyl stress theory of aging, the crosslink of biomacromolecule induced by carbonyl-amino reaction is the essential course of aging.
Carnosine is a natural dipeptide that of highly efficient biological activity. It commonly presents, sometimes at a relatively high concentration (up to 20 mM in human muscle), in mammalian tissues, especially in muscle and brain. The amino group of carnosine can react with reactive carbonyl species thereby inhibiting crosslink of protein caused by toxic carbonyl species. Carnosine play important role in anti-aging of the organism.
In this paper we discussed the free radical theory of aging, the glycation theory of aging and carbonyl stress theory of aging that proposed by my tutor professor Yin, based on the biochemical mechanisms of aging pigment formation. We investigated the anti-aging effects of carnosine and studied the reaction mechanisms of carnosine with malondialdehyde (MDA), the typical secondary products in lipid peroxidation.
The studies included in the thesis are summarized as follows:
In this thesis we study the reaction mechanisms between carnosine and MDA to explore the potential de-carbonylation function of carnosine. The carnosine was incubated with MDA in 0.2M phosphate buffer solution at pH7.4,37℃. The mixture of MDA and carnosine was assayed by high performance liquid chromatography (HPLC), spectrophotometry and spectrofluorometry. The reaction products were assayed by LC/MS. The results indicated that carnosine reacted readily with MDA at supra-physiological condition to form different products, such as a non-fluorescent enamine with an absorption peak at 280 nm (productl) and a lipofuscin-like fluorescent (Excite.392nm/Emission.452nm) 1,4-dihydropyridine(product2). The fluorescence intensity of reaction mixture was in direct proportion to the MDA concentration. Carnosine also greatly inhibited the formation of lipofuscin-like fluorescence induced by MDA reacted with bovine serum albumin (BSA). This study suggested that the reaction of carnosine with MDA may reveal toxic effect of unsaturated carbonyls and provided insight into the reaction mechanism of carnosine in protecting proteins against carbonyl stress.
引文
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