A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system.
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.
Inoue
I
I
Howard Hughes Medical Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
Rohrwasser
A
A
Helin
C
C
Jeunemaitre
X
X
Crain
P
P
Bohlender
J
J
Lifton
R P
RP
Corvol
P
P
Ward
K
K
Lalouel
J M
JM
D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D005260:Female; D006801:Humans; D007700:Kinetics; D007930:Leucine; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D010649:Phenylalanine; D017354:Point Mutation; D011225:Pre-Eclampsia / Q000097:blood*; D011247:Pregnancy; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System; D013379:Substrate Specificity
D009838:Oligodeoxyribonucleotides; D010455:Peptides; D000808:Angiotensinogen; D010649:Phenylalanine; D012083:Renin; D007930:Leucine