FIX(29-461) variant is not activated (factor XIa catalyst)

Stable Identifier
Reaction [transition]
Homo sapiens
failed activation of factor IX variant (factor XIa catalyst)
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In healthy individuals, conversion of factor IX (FIX) to the activated FIX is a calcium-dependent process catalyzed by factor VIIa (FVIIa) in the presence of tissue factor and phosphatidyl serine-rich phospholipid (Vadivel K & Bajaj SP 2012) or by factor XIa (FXIa) in a phospholipid-independent reaction (Wolberg AS et al. 1997; Smith SB et al. 2008; Geng Y et al. 2012). Regardless of the activating protease, FIX is cleaved first after Arg191 (R191-A192, the α-cleavage) forming the intermediate FIX product, then after the residue 226 (R226-V227, the β-cleavage) to form the activated FIXa (FIXaβ) (Smith SB et al. 2008; Geng Y et al. 2012; Mohammed BM et al. 2018). Deficiency or dysfunction of FIX leads to hemophilia B (HB), an X-linked, recessive, bleeding disorder. On a molecular level, HB is due to a heterogeneous spectrum of mutations spread throughout the F9 gene (Rallapalli PM et al. 2013).

The Reactome event describes the defective proteolytic activation of FIX by factor XIa due to the presence of HB-associated point mutations R191C, R191H, R226Q and R226W in the cleavage sites of FIX (Liddell MB et al. 1989; Monroe DM et al. 1989; Suehiro K et al. 1989; Diuguid DL et al. 1989; Bertina RM et al.1990). In addition, naturally occurring point mutations in the FIX propeptide sequence such as R43Q, R43L or R46S are also annotated here. These FIX variants are secreted into the circulation with a mutant 18-amino acid propeptide still attached (Bentley AK et al. 1986; Galeffi P & Brownlee GG 1987). The unprocessed FIX variants were found to affect the function of the protein by destabilizing the calcium-induced conformation of FIX (Wojcik EG et al. 1997) and showed delayed activation by FXIa (Liddell MB et al. 1989; Ware J et al. 1989; de la Salle C et al. 1993; Wojcik EG et al. 1997; Bristol JA et al. 1993).

Literature References
PubMed ID Title Journal Year
8463288 Propeptide processing during factor IX biosynthesis. Effect of point mutations adjacent to the propeptide cleavage site.

Furie, B, Bristol, JA, Furie, BC

J Biol Chem 1993
2738071 Factor IX San Dimas. Substitution of glutamine for Arg-4 in the propeptide leads to incomplete gamma-carboxylation and altered phospholipid binding properties.

Furie, B, Stafford, DW, Diuguid, DL, Liebman, HA, Rabiet, MJ, Ware, J, Kasper, CK, Furie, BC

J Biol Chem 1989
2775660 Factor IX Cardiff: a variant factor IX protein that shows abnormal activation is caused by an arginine to cysteine substitution at position 145

Giddings, JC, Bloom, AL, Peake, IR, Lillicrap, DP, Taylor, SA, Liddell, MB

Br. J. Haematol. 1989
2752109 Molecular defects of factor IX Chicago-2 (Arg 145----His) and prothrombin Madrid (Arg 271----cys): arginine mutations that preclude zymogen activation

Diuguid, DL, Furie, BC, Rabiet, MJ, Furie, B

Blood 1989
2162822 Mutations in hemophilia Bm occur at the Arg180-Val activation site or in the catalytic domain of factor IX

Reitsma, PH, Poort, SR, Mannucci, PM, van der Linden, IK, Bertina, RM, Reinalda-Poot, HH, Cupers, R

J. Biol. Chem. 1990
2592373 Blood clotting factor IX BM Nagoya. Substitution of arginine 180 by tryptophan and its activation by alpha-chymotrypsin and rat mast cell chymase

Niho, Y, Suehiro, K, Saito, H, Ogata, K, Takeya, H, Kawabata, S, Kamiya, T, Miyata, T, Iwanaga, S, Takamatsu, J

J. Biol. Chem. 1989
2713493 Functional consequences of an arginine180 to glutamine mutation in factor IX Hilo

Lundblad, RL, Roberts, HR, McCord, DM, High, KA, Huang, MN, Kasper, CK, Monroe, DM

Blood 1989
9169594 Modification of the N-terminus of human factor IX by defective propeptide cleavage or acetylation results in a destabilized calcium-induced conformation: effects on phospholipid binding and activation by factor XIa

Van Den Berg, M, Wojcik, EG, Poort, SR, Bertina, RM

Biochem. J. 1997
3009023 Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position -4

Bentley, AK, Brownlee, GG, Rizza, C, Rees, DJ

Cell 1986
2788012 Defective propeptide processing and abnormal activation underlie the molecular pathology of factor IX Troed-y-Rhiw

Bloom, AL, Peake, IR, Lillicrap, DP, Liddell, MB

Br. J. Haematol. 1989
Catalyst Activity

serine-type endopeptidase activity of factor XIa:GPIb:GPIX:GPV complex [plasma membrane]

This event is regulated
Positively by