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A Mutation of Angiotensinogen in a Patient with Preeclampsia Leads to Altered Kinetics of the Renin-Angiotensin System *

Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 270, Issue: 19, Page: 11430-11436
1995
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Article Description

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 µ m ) and a 5-fold decrease in k cat (from 1.0 to 0.22 s –1 ); as a result, catalytic efficiency ( k cat / Km ) is increased by a factor of 2 (1.1 versus 2.4 µ m –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 µ m ), but increases k cat and catalytic efficiency >2-fold ( k cat = 15.0 versus 37.0 s –1 ; k cat /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.

Bibliographic Details

Ituro Inoue; Andreas Rohrwasser; Catherine Helin; Xavier Jeunemaitre; Pam Crain; Jurgen Bohlender; Richard P. Lifton; Pierre Corvol; Kenneth Ward; Jean-Marc Lalouel

Elsevier BV

Biochemistry, Genetics and Molecular Biology

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