Miyata T, Morita T, Inomoto T, Kawauchi S, Shirakami A, Iwanaga S
Biochemistry. 1987 Feb 24;26(4):1117-22. doi: 10.1021/bi00378a020.
Structural studies on a hereditarily abnormal prothrombin, prothrombin Tokushima, have been performed to identify the difference responsible for its reduced fibrinogen clotting activity upon conversion to thrombin. The prothrombin sample used was from a heterozygote but contained exclusively a defective prothrombin molecule, since the patient was heterozygous for both dysprothrombinemia and hypoprothrombinemia. Amino acid sequence analysis of a peptide isolated from a lysyl endopeptidase digest of the abnormal thrombin indicated that Arg-418 (equivalent to Asn-101 in the chymotrypsin numbering system) had been replaced by Trp. This amino acid substitution can result from a single nucleotide change in the codon for Arg-418 (CGG----TGG). The Arg----Trp replacement found in the thrombin portion of prothrombin Tokushima appears to reduce its interaction with various substrates including fibrinogen and platelet receptors and accounts for the recurrent bleeding episode observed in the propositus.
针对一种遗传性异常凝血酶原——德岛凝血酶原，开展了结构研究，以确定其转化为凝血酶后纤维蛋白原凝血活性降低的原因。所用的凝血酶原样本来自一名杂合子，但仅包含有缺陷的凝血酶原分子，因为该患者同时为异常凝血酶血症和低凝血酶原血症的杂合子。对从异常凝血酶的赖氨酰内肽酶消化产物中分离出的一种肽进行氨基酸序列分析表明，精氨酸 -418（在胰凝乳蛋白酶编号系统中相当于天冬酰胺 -101）已被色氨酸取代。这种氨基酸替换可能源于精氨酸 -418密码子（CGG----TGG）的单个核苷酸变化。在德岛凝血酶原的凝血酶部分发现的精氨酸到色氨酸的替换，似乎降低了它与包括纤维蛋白原和血小板受体在内的各种底物的相互作用，并解释了先证者中观察到的反复出血事件。
