2018年第7章镰刀贫血病精品课程课件-文档资料.ppt
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1、Chapter 6 蛋白质的结构与功能的关系,蛋白质的分子的生物学功能是与其化学组成和极其复杂的结构密切相关的。同时,蛋白质功能总是跟蛋白质与其他分子相互作用相联系。相互作用中蛋白质构象有时发生微小变化,有时发生剧烈变化。因此蛋白质的构象不是刚性的、静止的,而是柔性的、动态的。 本章主要介绍蛋白质的一级结构与功能的关系一个分子病发现的故事。,一、蛋白质的一级结构与功能的关系 遗传病镰刀贫血病的发现 (Genetic disease-Sickle-cell anemia) 事情发生在1904年,美国东部NewYork ,NewYork city, 当时有一位黑人大学生Smark(18岁),找一位
2、医生(Ingram)看病,自觉头昏、发烧、呼吸困难。医生对Smark 进行了检查,发现病人眼睛有黄疸,心跳有杂音,没有发现寄生虫,只发现Red blood cell 350万/mm3,Blood platelet 25万/ mm3, White blood cell5000/ mm3. 根据正常人的数值(RBC500万/ mm3,WBC6000/ mm3, BP15.6万/ mm3)诊断病人为贫血症。,后来Ingram医生又对病人取血,镜检,发现病人的红血球的是半月型的(形状象镰刀)。,以后这位医生对这位黑人大学生进行了精心治疗,也就是加强营养和一般治疗。结果,病人有所好转,但是,医生发现病人
3、的红血球还是镰刀状的。于是医生建议该生休学。 Ingram对这位黑人大学生进行了6年的跟踪观察。当时医生判断,这个病很可能是一个genetic disease。 后来在美国黑人主要集中的New York, Chicago, Los Angeles, Philadelphia, Detroit and Washington发现了很多这样的病例, 发病率占4/1000,都是由于得此病以至30岁以前,就由于此病引起血栓、肾功能减退、心肌梗塞,特别是毛细血管阻塞引起死亡。病人的红血球很容易溶血和破裂,且红血球寿命比正常的要短,结果造成严重贫血和庰发许多种严重疾病。后来诊断此病是先天性的或遗传性的,而且
4、在一定条件下甚至是一种绝症。,久而久之,医生又发现血红蛋白有缺陷,就是去氧血红蛋白溶解度降低,比正常低1/25。由于溶解度的降低,造成了血红蛋白运氧机能大大降低。 后来,对不正常血红蛋白进行了研究。血红蛋白是由4条肽链以亚基连接起来(2条-链,2条 -链),大家知道去氧血红蛋白对于新陈代谢起着重要作用。它既可以载氧,又可以运走CO2。这位医生把病人的血红蛋白提取出来,用正常人的血红蛋白和病人的血红蛋白进行电泳比较。结果发现有病的与正常的斜率曲线是平行的,也就是说,在电泳时镰刀状的比正常的要快。,+,pH,病例,电泳的泳动速度: V= V速度 E电场强度 Z带电颗粒所带电荷 f带电颗粒的大小,E
5、 Z,f,快的原因有几种可能性: 可能是Z, 也可能是f。,后来经过研究推断,泳动速度的加快是由于Z(带电荷)的不同。 HbA HbS 差异 PI O2-Hb 6.87 7.09 0.22 去氧Hb 6.68 6.91 0.23 异常的去氧Hb比正常的Hb的PI高0.23个pH单位。,在上述基础上,进一步的研究表明,病例的多了几个电荷。 采用滴定法,也就是根据耗碱量知道氨基的数目,耗酸量了解羧基的数目的原理(NH3+可看作可滴定酸,COO-看作可滴定碱)。结果,改变一个PH就有13个电荷数目变化。 设异常带电荷为 X 1:13=0.23:X X=130.23=2.99 3 这样就决定了异常的比
6、正常的Hb多了3个电荷。,当时认为电荷的增多可能是血红蛋白中铁卜啉所引起的,把铁卜啉环提取出来,结晶, 用X-射线衍射,结果没有什么差异。,当时认为电荷的增多可能是血红蛋白中铁卜啉所引起的,把铁卜啉环提取出来,结晶, 用X-射线衍射,结果没有什么差异。后来把目标转向了肽链分析。在肽链上有三种可能电荷增多:,正常 异常 中 + - + - 中,当然,要知道那一种可能,就必须进行研究试验。 把血红蛋白的一级结构进行分析。首先用胰蛋白酶水解HB,得到28个肽段,采用纸上层析分离与电泳相结合的方法对这些肽与正常的进行比较。 得到了Finger-prints . 根据该图的比较,27个肽一样,只有一个肽
7、段是不同的。把这个异常的肽段剪下来,进行测序。结果是链上的一个8肽。 Hba: H2N-Val-His-Leu-Thr-Pro-Glu-Glu-Lys-COOH Hbs : H2N-Val-His-Leu-Thr-Pro-Val-Glu-Lys-COOH,在正常血红蛋白分子的链中,从N-端开始的 第6个氨基酸残基是GLU,而镰刀壮贫血患者的血红蛋白分子的链中的第6个氨基酸残基则被VAL 所代替,这样就明了了产生电荷增多的原因,是第三种可能性,就是说,原来一个带负电荷的8肽变成了一个中性的8肽,H3N+,COO-,COO-,H3N+,COO-,由此可见, 由于HB有4条肽链,而这8肽是在-链上,
8、一个-链多了一个正电荷,而两条- 链就多了2个正电荷。 多了2个电荷的血红蛋白发生了结构改变,异常的HBS与HBS聚集起来,有时HBS与HBA凝集,形成所谓平行排列的非球形(线形)结构镰刀状结构。,Mutation and molecular interactions changes,这个有574个氨基酸残基的HB中,只要两条-链中的2个GLU残基被VAL残基所代替就能引起如此严重的病理现象,可见蛋白质的结构与功能有着如此密切的联系。 清楚了病因以后,INGRAM 医生再治疗就不难了,根据HB的聚集,用脲素可以使这种聚集消失,医生给患者吃大量的尿素,结果是有效的。患者感觉好多了,头昏和呼吸困难
9、都有所改善。但是,由于尿素在体内不能保存太久,就被分解了,这位寻求真理,攀登科学高峰的医生,继续进行了研究。根据:,H2N-CO-NH2 NH4+ + (N=C=O)- 37OC,PH7.4时,有5 10-3M的氰酸盐,证明在体内不是脲素起作用,而是脲素平衡后发生的氰酸盐起作用,后来给患者服氰酸盐,比吃脲素好得多。 RNH2 + H-N=C=O R-NH- CO-NH2 O RNH2 + CO2 R-NH-CO- 这样打断了HBS的聚合,矫正了它的构象,使分子重新获得输氧能力。 由于这种疾病是先天性的“分子病”,还不能完全治愈。到目前为止还在研究之中。在人类中已发现300多种不同的异常血红蛋白
10、,其中中国人30种。 这种疾病只有有赖于基因工程的方法才能彻底根治。,一氧化碳: 神秘的杀手,Carbon Monoxide: A Stealthy Killer Lake Powell莱克. 鲍威尔,Arizona亚利桑那州, August 2000. A family was vacationing度假 in a rented租用 houseboat游艇. They turned on the electrical generator发电机 to power an air conditioner and a television. About 15 minutes later, two b
11、rothers, aged 8 and 11, jumped off the swim deck at the stern船尾. Situated immediately below the deck was the exhaust port for the generator. Within two minutes, both boys were overcome征服 by the carbon monoxide in the exhaust 排气口, which had become concentrated in the space under the deck. Both drowne
12、d淹死了. These deaths, along with a series of deaths in the 1990s linked to houseboats of similar design, eventually led to the recall召回 and redesign of the generator exhaust assembly. Carbon monoxide (CO), a colorless, odorless gas, is responsible for more than half of yearly deaths due to poisoning中毒
13、 worldwide. CO has an approximately 250-fold greater affinity for hemoglobin血红蛋白 than does oxygen. Consequently, relatively low levels of CO can have substantial and tragic悲剧 effects. When CO combines with hemoglobin, the complex is referred to as carboxyhemoglobin,or COHb.,Some CO is produced by na
14、tural processes, but locally high levels generally result only from human activities. Engine and furnace炉子 exhausts are important sources, as CO is a byproduct of the incomplete combustion不完全燃烧 of fossil fuels石油. In the United States alone, nearly 4,000 people succumb to CO poisoning each year, both
15、 accidentally意外地 and intentionally故意地. Many of the accidental deaths involve undetected CO buildup积累 in enclosed spaces, such as when a household furnace malfunctions故障 or leaks泄漏, venting排 CO into a home. However, CO poisoning can also occur in open spaces露天场所, as unsuspecting people at work or pla
16、y休闲 inhale吸入 the exhaust from generators, outboard motors舷外马达, tractor拖拉机 engines, recreational vehicles休闲交通工具, or lawn mowers割草机. Carbon monoxide levels in the atmosphere are rarely dangerous, ranging from less than 0.05 parts per million (ppm) in remote偏僻的 and uninhabited无人居住 areas to 3 to 4 ppm i
17、n some cities of the northern hemisphere北半球. In the United States, the government-mandated (Occupational职业 Safety and Health Administration, OSHA) limit for CO at worksites工地 is 50 ppm for people working an eight-hour shift轮班. The tight binding of CO to hemoglobin means that COHb can accumulate over
18、,time as people are exposed to a constant low-level source of CO. In an average, healthy individual, 1% or less of the total hemoglobin is complexed as COHb. Since CO is a product of tobacco smoke, many smokers have COHb levels in the range of 3% to 8% of total hemoglobin, and the levels can rise to
19、 15% for chain-smokers. COHb levels equilibrate at 50% in people who breathe air containing 570 ppm of CO for several hours. Reliable methods have been developed that relate CO content in the atmosphere to COHb levels in the blood (Fig. 1). In tests of houseboats with a generator exhaust like the on
20、e responsible for the Lake Powell deaths, CO levels reached 6,000 to 30,000 ppm under the swim deck, and atmospheric O2 levels under the deck declined下降 from 21% to 12%. Even above the swim deck, CO levels of up to 7,200 ppm were detected, high enough to cause death within a few minutes. How is a hu
21、man affected by COHb? At levels of less than 10% of total hemoglobin, symptoms症状 are rarely observed. At 15%, the individual experiences体验 mild轻微 headaches. At 20% to 30%, the headache is severe剧烈的 and,图1. 血液中COHb与环境中的CO浓度的关系。图中显示:在4种不同的条件下,短时间中毒的影响和休息状态和轻度运动状态下的比较。,is generally accompanied by nause
22、a呕心, dizziness头昏眼花, confusion混乱, disorientation方向知觉的丧失, and some visual disturbances视觉混乱; these symptoms are generally reversed恢复 rapidly if the individual is treated with oxygen. At COHb levels of 30% to 50%, the neurological symptoms神经学上的症状 become more severe严重, and at levels near 50%, the individ
23、ual loses consciousness失去知觉 and can sink into coma昏迷. Respiratory failure 呼吸衰竭may follow. With prolonged exposure, some damage becomes permanent永久的. Death normally occurs when COHb levels rise above 60%. Autopsy尸体解剖 on the boys who died at Lake Powell revealed显示 COHb levels of 59% and 52%. Binding o
24、f CO to hemoglobin is affected by many factors, including exercise (Fig. 1) and changes in air pressure related to altitude海拔. Because of their higher base levels of COHb, smokers exposed to a source of CO often develop symptoms faster than nonsmokers. Individuals with heart and lung conditions or b
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