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Molecular pathlogy of Hemoglobin M

血红蛋白 M 的分子病理学

基本信息

批准号：
62480132
负责人：
TOMODA Akio
金额：
$ 3.26万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1987
资助国家：
日本
起止时间：
1987 至 1988
项目状态：
已结题

项目摘要

In the hemoglobin (Hb) molecule, the proximal and distal histidines are the most important for preventing the ferrous heme from oxidation and for the cooperative ligand binding. Hbs M are mutant hemoglobins, one of these histidines of which is replaced with tyrosine, and their hemes are stabilized usually in ferric state. Although patients of Hbs M show obvious cyanosis, only individuals with Hb M Saskatoon (beta E7 His-Tyr) have less cyanosis than those of the other Hbs M (Hb M Iwate, alpha F8 His-Tyr; Hb M Boston, alpha E7 His-Tyr; Hb M Hyde Park, beta F8 His-Tyr). In order to know why such symptoms for indivisuals with Hb M differ from each other, we have investigated the reducibility of abnormal chains of Hbs M by erythrocyte methemoglobin reductases and the structure of abnormal chains by using resonance Raman (RR), and electron spin resonance (ESR) spectrometry.Under anaerobic conditions, abnormal chains of Hb M Saskatoon was reduced by methemoglobin reductases purified from huma … More n erythrocytes at almost the same rate as was metHb A. However, abnormal chains of the other Hbs M were scarcely reduced by these enzymes. In fact, we have found recently that more than half of the abnormal chains remained in ferrous state in the fresh bloods of individuals with Hb M Sastakoon.In the RR spectra, all of four Hbs M exhibited the fingerprint bands for the Fe-tyrosinate proteins (1600, 1500 and 1270 cm^<-1>) and Fe-tyrosinate proteins (1600, 1500 and 1270 cm^<-1>) and Fe-tyrosinate stretching frequency in abnormal chain of Hb M Saskatoon was the lowest among them. However, only Hb M Saskatoon displayed the Raman spectral pattern of a six-coordinate heme for the abnormal subunit while others displayed that of a five-cooordinate heme. From these observations, it is concluded that the heme in abnormal chains of Hb M Iwate, Hb M Boston and Hb M Hyde Park, bind only with the substituted tyrosine, whereas that of Hb M Saskatoon binds weakly both the proximal histidine and the substituted tyrosine.As abnormal chains of Hbs M can bind with carbonmonooxide (CO) after reduction by dithionite, we examined their unusual lignad binding properties by RR, infrared, and ^<13>C-NMR spectroscopy and discussed the role of the proximal and distal His on ligand binding properties in normal hemoglobin. Less

在血红蛋白（Hb）分子中，近端组氨酸和远端组氨酸对防止亚铁血红素氧化和配合配体结合最为重要。Hbs M是突变型血红蛋白，其中一个组氨酸被酪氨酸取代，其血红素通常稳定在铁态。虽然Hbs M患者表现出明显的发绀，但只有Saskatoon Hb M （β E7 His-Tyr）个体的发绀程度低于其他Hbs M （Hb M Iwate, α F8 His-Tyr; Hb M Boston, α E7 His-Tyr; Hb M Hyde Park, β F8 His-Tyr）。为了了解Hb M个体症状不同的原因，我们利用红细胞高铁血红蛋白还原酶研究了Hb M异常链的可还原性，并利用共振拉曼（RR）和电子自旋共振（ESR）光谱法研究了异常链的结构。在厌氧条件下，从人体内纯化的高铁血红蛋白还原酶能使Saskatoon Hb M的异常链还原，其还原速率与metha几乎相同。然而，其他Hbs M的异常链几乎不能被这些酶还原。事实上，我们最近发现，在患有Hb M Sastakoon的人的新鲜血液中，超过一半的异常链仍处于铁态。在RR光谱中，4种Hb M均出现铁-酪氨酸蛋白（1600、1500和1270 cm^<-1>）和铁-酪氨酸蛋白（1600、1500和1270 cm^<-1>）的指纹带，其中Saskatoon Hb M异常链中铁-酪氨酸拉伸频率最低。然而，只有Hb M sas卡通显示了异常亚基的六坐标血红素的拉曼光谱模式，而其他人显示了五坐标血红素的拉曼光谱模式。从这些观察可以得出结论，Hb M Iwate， Hb M Boston和Hb M Hyde Park异常链中的血红素仅与取代的酪氨酸结合，而Hb M Saskatoon的血红素与近端组氨酸和取代的酪氨酸结合较弱。由于Hbs - M的异常链在被二亚硝酸盐还原后可以与一氧化碳结合，我们通过RR、红外和^<13>C-NMR谱分析了它们不同寻常的木质素结合特性，并讨论了近端和远端His对正常血红蛋白配体结合特性的作用。少