NEW EFFECTORS OF HUMAN HEMOGLOBIN - STRUCTURE AND FUNCTION
NEW EFFECTORS OF HUMAN HEMOGLOBIN - STRUCTURE AND FUNCTION
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DOI：
10.1021/bi00458a024
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发表时间：
1990-02-13
期刊：
影响因子：
2.9
通讯作者：
PERUTZ, MF
中科院分区：
文献类型：
--
作者：
LALEZARI, I;LALEZARI, P;PERUTZ, MF
本文报道了两种新的血红蛋白变构效应物2-[4-（3，5-二氯苯脲基）苯氧基]-2-甲基丙酸（L35）和2-[4-（3，4，5-三氯苯脲基）苯氧基]-2-甲基丙酸（L345）的作用。它们中的每一个都结合到人脱氧血红蛋白中央腔中的两对与免疫相关的位点上。一对位点与苯扎贝特占据的位点重叠[Perutz等人（1986）J. Am. 108，1064-1078]。其他位点是新的，L35占据的对与L345占据的对不同。所有位点均为至少20埃。从有机磷酸盐结合的位置。L345是迄今为止所描述的血红蛋白的最有效的变构效应物。在0.1 mM浓度下，它将红细胞悬浮液的P50提高50%;在0.2 mM浓度下，它将P50提高2.5倍。在酸性pH值下，它将Hill系数降低到接近1，即使在1 atm纯氧下也能防止完全氧饱和。在pH 6的叠氮高铁血红蛋白中，它诱导向更高自旋的转变。这些性质使人想起那些硬骨鱼血红蛋白，表现出根效应。L35和L345以及有机磷酸盐对氧亲和力的影响是加和的，但它们与氯竞争。L35的作用比L345弱，但可通过加入肌醇六磷酸使其诱导与单独的L345相同的效果。这两种化合物都增加了碱性和酸性玻尔效应。他们改变双分子动力学的CO重组闪光后，通过增加血红蛋白在T状态的慢反应分数在R状态的快速反应分数的费用。当[L345] > 1 mM时，由于解离成α，慢级分再次减少。β的二聚体。生理浓度的人或牛血清白蛋白抑制效应器的作用，即使当棕榈酸或三棕榈酸甘油酯作为诱饵。
We describe the actions of two new allosteric effectors of hemoglobin, 2-[4-(3,5-dichlorophenylureido)phenoxy]-2-methylpropionic acid (L35) and 2-[4-(3,4,5-trichlorophenylureido)phenoxy]-2-methylpropionic acid (L345). Each of them binds to two pairs of symmetry-related sites in the central cavity of human deoxyhemoglobin. One pair of sites overlaps with that occupied by bezafibrate [Perutz et al. (1986) J. Am. Chem. Soc. 108, 1064-1078]. The other sites are new, and the pair occupied by L35 is different from that occupied by L345. All the sites are at least 20 .ANG. from the site where organic phosphates are bound. L345 is by far the most potent allosteric effector of hemoglobin ever described. At a concentration of 0.1 mM, it raises the P50 of a suspension of red cells by 50%; at 0.2 mM it raises the P50 2.5-fold. At acid pH, it reduces Hill''s coefficient to near unity and prevents complete oxygen saturation even under 1 atm of pure oxygen. In azidemethemoglobin at pH 6, it induces a transition to higher spin. These properties are reminiscent of those of teleost fish hemoglobins that exhibit a Root effect. The influence of L35 and L345 and that of organic phosphates on the oxygen affinity are additive, but they compete with chloride. L35 acts more weakly than L345, but can be made to induce the same effects as L345 alone by adding inositol hexaphosphate. Both compounds increase the alkaline and acid Bohr effects. They alter the bimolecular kinetics of CO recombination after a flash by increasing the slowly reacting fraction of hemoglobin in the T state at the expense of the fast-reacting fraction in the R state. When [L345] > 1 mM, the slow fraction decreases again due to dissociation into .alpha..beta. dimers. Physiological concentrations of human or bovine serum albumin inhibit the actions of the effectors, even when palmitic acid or tripalmitin is added as decoy.