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Abstract

Human Factor IX (Christmas factor) is a single-chain plasma glycoprotein (mol wt 57,000) that participates in the middle phase of the intrinsic pathway of blood coagulation. It is present in plasma as a zymogen and is converted to a serine protease, Factor IXabeta, by Factor XIa (activated plasma thromboplastin antecedent) in the presence of calcium ions. In the activation reaction, two internal peptide bonds are hydrolyzed in Factor IX. These cleavages occur at a specific arginyl-alanine peptide bond and a specific arginyl-valine peptide bond. This results in the release of an activation peptide (mol wt approximately equal to 11,000) from the internal region of the precursor molecule and the generation of Factor IXabeta (mol wt approximately equal to 46,000). Factor IXabeta is composed of a light chain (mol wt approximately equal to 18,000) and a heavy chain (mol wt approximately equal to 28,000), and these chains are held together by a disulfide bond(s). The light chain originates from the amino terminal portion of the precursor molecule and has an amino terminal sequence of Tyr-Asn-Ser-Gly-Lys. The heavy chain originates from the carboxyl terminal region of the precursor molecule and contains an amino terminal sequence of Val-Val-Gly-Gly-Glu. The heavy chain of Factor IXabeta also contains the active site sequence of Phe-Cys-Ala-Gly-Phe-His-Glu-Gly-Arg-Asp-Ser-Cys-Gln-Gly-Asp-SER-Gly-Gly-Pro. The active site serine residue is shown in capital letters. Factor IX is also converted to Factor IXaalpha by a protease from Russell's viper venom. This activation reaction, however, occurs in a single step and involves only the cleavage of the internal arginyl-valine peptide bond. Human Factor IXabeta was inhibited by human antithrombin III by the formation of a one-to-one complex of enzyme and inhibitor. In this reaction, the inhibitor was tightly bound to the heavy chain of the enzyme. These data indicate that the mechanism of activation of human Factor IX and its inhibition by antithrombin III is essentially identical to that previously shown for bovine Factor IX.

Authors

R G Di Scipio, K Kurachi, E W Davie

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Citations to this article in year 2008 (5)

Title and authors Publication Year
Identification of mutations in theF9gene including exon deletion by multiplex ligation-dependent probe amplification in 33 unrelated Korean patients with haemophilia B
MJ Kwon, KY Yoo, HJ Kim, SH Kim
Haemophilia 2008
Expression of functional recombinant human factor IX in milk of mice
SF Lisauskas, NB Cunha, GR Vianna, ÉA Mendes, GL Ramos, AQ Maranhão, MM Brígido, JO Almeida, HA Baptista, FL Motta, JB Pesquero, FJ Aragão, EL Rech
Biotechnology Letters 2008
Characterization of Novel Forms of Coagulation Factor XIa: independence of factor XIa subunits in factor IX activation
SB Smith, IM Verhamme, M Sun, PE Bock, D Gailani
The Journal of biological chemistry 2008
Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa
W Wu, D Sinha, S Shikov, CK Yip, T Walz, PC Billings, JD Lear, PN Walsh
The Journal of biological chemistry 2008
Functional role of residue 193 (chymotrypsin numbering) in serine proteases: influence of side chain length and beta-branching on the catalytic activity of blood coagulation factor XIa
AE Schmidt, M Sun, T Ogawa, SP Bajaj, D Gailani
Biochemistry 2008

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