Structural Studies on Functional Abnormality of Fibrinogen and Factor IX
| Project/Area Number |
01571236
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
医学一般
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| Research Institution | Kyushu University |
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Principal Investigator |
MIYATA Toshiyuki Fac. of Sci., kyushu Univ., Research associate, 理学部, 助手 (90183970)
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| Co-Investigator(Kenkyū-buntansha) |
NIHO Yoshiyuki Fac. of Med., Kyushu Univ., Professor, 医学部, 教授 (60091287)
SAITO Hidehiko Fac. of Med., Nagoya Univ., Professor, 医学部, 教授 (20153819)
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| Project Period (FY) |
1989 – 1990
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| Project Status |
Completed (Fiscal Year 1990)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1990: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1989: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | Hemophilia B / Coagulation factor IX / Molecular defect / Peptide map / Serine protease / Coagulation factor XII / 先天性異常症 / 血友病 / 第IX因子 / フィブリノ-ゲン / 血液凝固異常症 |
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| Research Abstract |
1. Blood Clotting Factor IX Kashihara : Hemophilia B Kashihara is a severe hemorrhagic disorder in which the factor IX antigen is present in normal amounts but factor IX biological activity is markedly reduced. Amino acid sequence analysis of one of the tryptic peptides isolated from factor IX Kashihara indicated that Val-182 had been replaced by phe. The val-to-phe replacement appears to sterically hinder the cleavage of Arg 180-Val 181 by factor XIa required for the activation of this zymogen.
2. Factor IX Kawachinagano : Factor IX Kawachinagano (KWC) is a mutant factor IX protein initially recognized in a patient with severe hemophilia B, who had 46% of normal factor IX antigen and no detectable clotting activity. Amino acid sequence analysis demonstrated that the mutant retained the propeptide region of 18 amino acid due to a substitution of arginine- (-4) by glutamine. We assumed that this propeptide directly interferes with the adjacent NH_2- terminus and prevents the metal-induce
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d conformational changes which are essential for biological activity of normal factor IX.
3. Coagulation factor XII (Hageman factor ) Washington D. C. : Structural studies on a congenital abnormal coagulation factor XII (Hageman factor), factor XII Washington D. C., have been performed to identify the defect responsible for its lack of procoagulant activity. Amino acid sequence analysis of a tryptic peptide indicated that Cys-571 had been replaced by serine. We propose that the Cysー571->Ser replacement destroys the formation of the disulfide linkage between Cys-540 and Cys-571, giving rise to an altered conformation of the active-site serine residue or the secondary substrate-binding site and, thus, leads to the loss of enzyme activity.
4. Blood clotting Factor IX B_M Nagoya : A patient with this mutant is characterized by a markedly prolonged ox brained prothrombin time. Primary structure analysis of one of the AspーN peptides revealed that Arg180 is replaced by Trp. We also found that IX Nagoya is activated by alpha- chymotrypsin or rat mast cell chymase. These results indicate that the substitution of Arg180 by Trp impairs the cleavage by factor XIa required for activation of this zymogen and that the substitution causes hemophilia B_M. Less
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Report
(3 results)
Research Products
(22 results)
