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A mutation of angiotensinogen in a patent with preeclampsia leads to alteredkinetics of the renin-angiotensin system

Item Type:Article
Title:A mutation of angiotensinogen in a patent with preeclampsia leads to alteredkinetics of the renin-angiotensin system
Creators Name:Inoue, I. and Rohrwasser, A. and Helin, C. and Jeunemaitre, X. and Crain, P. and Bohlender, J. and Lifton, R.P. and Corvol, P. and Ward, K. and Lalouel, J.M.
Abstract:Angiotensinogen exhibits genetic linkage to and association with essential hypertension and preeclampsia, a common hypertensive disorder of pregnancy; however, the polymorphisms detected thus far provide no functional clues. In a preeclamptic patient, we have identified a mutation leading to the replacement of leucine by phenylalanine at position 10 of mature angiotensinogen (L10F), the site of renin cleavage. Kinetic analyses of the enzymes of the renin-angiotensin system, using either model peptides or full-length substrates, show that this mutation significantly alters the reactions with both renin and angiotensin-converting enzyme. For the renin reaction on a full-length substrate, this substitution leads to a 10-fold decrease in Km (from 1.1 to 0.09 microM) and a 5-fold decrease in kcat (from 1.0 to 0.22 s-1); as a result, catalytic efficiency (kcat/Km) is increased by a factor of 2 (1.1 versus 2.4 microM-1 s-1). In the reaction of angiotensin-converting enzyme on angiotensin decapeptides, the substitution has no effect on Km (38.0 versus 30.0 microM), but increases kcat and catalytic efficiency > 2-fold (kcat = 15.0 versus 37.0 s-1; kcat/Km = 0.41 versus 1.23). The renin-angiotensin system, challenged by the profound physiological adaptations of pregnancy, is perturbed in preeclampsia; consequently, the L10F mutation may promote this condition in carrier subjects.
Keywords:Angiotensinogen, Base Sequence, Kinetics, Leucine, Molecular Sequence Data, Oligodeoxyribonucleotides, Peptides, Phenylalanine, Point Mutation, Pre-Eclampsia, Pregnancy, Renin-Angiotensin System, Substrate Specificity
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:270
Number:19
Page Range:11430-11436
Date:12 May 1995
Official Publication:http://www.jbc.org/content/270/19/11430.abstract
PubMed:View item in PubMed

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