LR16是一种对血红蛋白的氧亲和力、血液胆固醇和低密度脂蛋白有显著作用的化合物。
LR16, a compound with potent effects on the oxygen affinity of hemoglobin, on blood cholesterol, and on low density lipoprotein.
作者信息
Lalezari I, Rahbar S, Lalezari P, Fermi G, Perutz M F
机构信息
Department of Anesthesiology, Montefiore Medical Center, Bronx, NY.
出版信息
Proc Natl Acad Sci U S A. 1988 Aug;85(16):6117-21. doi: 10.1073/pnas.85.16.6117.
Abstract
2-[4-(3,4-Dichlorophenylureido)phenoxy]-2-methylpropionic acid, LR16, combines with two symmetrically related sites in the central cavity of deoxyhemoglobin, 20 A away from the binding site of 2,3-bisphosphoglycerate, and acts as an allosteric effector synergistic with 2,3-bisphosphoglycerate. LR16 (1 mM) raises P50, the partial pressure of oxygen needed to achieve half-saturation with oxygen of a hemolysate of human hemoglobin, about 50 times more strongly than 1 mM 2,3-bisphosphoglycerate. Oral administration of LR16 (at small doses that produced no ill effects) to rats that were fed a diet rich in cholesterol caused substantial reductions of total serum cholesterol and low density lipoprotein-cholesterol, while high density lipoprotein-cholesterol remained unchanged.
摘要
2-[4-(3,4-二氯苯脲基)苯氧基]-2-甲基丙酸，LR16，与脱氧血红蛋白中央腔中的两个对称相关位点结合，该位点距2,3-二磷酸甘油酸的结合位点20埃，并作为与2,3-二磷酸甘油酸协同的变构效应剂。LR16（1 mM）提高P50，即人血红蛋白溶血产物与氧气达到半饱和所需的氧气分压，其作用强度比1 mM 2,3-二磷酸甘油酸强约50倍。给喂食富含胆固醇饮食的大鼠口服LR16（小剂量且无不良影响）可使总血清胆固醇和低密度脂蛋白胆固醇大幅降低，而高密度脂蛋白胆固醇保持不变。
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LR16, a compound with potent effects on the oxygen affinity of hemoglobin, on blood cholesterol, and on low density lipoprotein.LR16是一种对血红蛋白的氧亲和力、血液胆固醇和低密度脂蛋白有显著作用的化合物。
Proc Natl Acad Sci U S A. 1988 Aug;85(16):6117-21. doi: 10.1073/pnas.85.16.6117.
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本文引用的文献
1
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Lancet. 1983 Oct 15;2(8355):881-2. doi: 10.1016/s0140-6736(83)90870-x.
2
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Biochim Biophys Acta. 1970 Feb 17;200(2):189-96. doi: 10.1016/0005-2795(70)90163-7.
3
The removal of organic phosphates from hemoglobin.从血红蛋白中去除有机磷酸盐。
Arch Biochem Biophys. 1971 Jul;145(1):236-9. doi: 10.1016/0003-9861(71)90031-2.
4
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J Med Chem. 1972 Apr;15(4):436-7. doi: 10.1021/jm00274a036.
5
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Radiat Res. 1987 Oct;112(1):164-72.
6
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8
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