r-VKORC1 expression in factor IX BHK cells increases the extent of factor IX carboxylation but is limited by saturation of another carboxylation component or by a shift in the rate-limiting step.

Biochemistry
Kevin W HallgrenKathleen L Berkner

Abstract

Carboxylation of vitamin K-dependent (VKD) proteins is required for their activity and depends on reduced vitamin K generated by vitamin K oxidoreductase (VKOR) and a redox protein that regenerates VKOR activity. VKD protein carboxylation is inefficient in mammalian cells, and to understand why carboxylation becomes saturated, we developed an approach that directly measures the extent of intracellular VKD protein carboxylation. Analysis of factor IX (fIX)-expressing BHK cells indicated that slow egress of fIX from the endoplasmic reticulum and preferential secretion of the carboxylated form contribute to secreted fIX being more fully carboxylated. The analysis also revealed the first reported in vivo VKD protein turnover, which was 14-fold faster than that which occurs in vitro, suggesting facilitation of this process in vivo. r-VKORC1 expression increased the rate of fIX carboxylation and the extent of secreted carboxylated fIX approximately 2-fold, which shows that carboxylation is the rate-limiting step in fIX turnover and which was surprising because turnover in vitro is limited by release of carboxylated fIX. Interestingly, the increases were significantly smaller than the amount of VKOR overexpression (15-fold). However, ...Continue Reading

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Citations

Oct 1, 2013·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Daniel A RibeiroLeda R Castilho
Aug 12, 2006·Blood·Nadeem WajihReidar Wallin
Jun 24, 2014·BioMed Research International·Meng-Hwan LeeChon-Ho Yen
Dec 14, 2006·Proceedings of the National Academy of Sciences of the United States of America·Pei-Hsuan ChuD W Stafford
Jul 14, 2010·Translational Research : the Journal of Laboratory and Clinical Medicine·Gerold HolzerChristine Mannhalter
Aug 19, 2007·Biochimica Et Biophysica Acta·Monia MontiFrancesco Bernardi

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