Two - step Prorenin - Renin Conversion
نویسنده
چکیده
Prorenin is an inactive form of the aspartic protease renin. Like pepsinogen, it is activated at low pH. The kinetics of acid activation of prorenin were studied in human amniotic fluid and plasma and in preparations of purified prorenin isolated from amniotic fluid and plasma. Conversion of prorenin (pR) into active renin (R) appeared to be a two-step process involving the generation of an intermediary form of activated prorenin (pRa). The pR + pRa step is an acid-induced reversible change in the conformation f the molecule, and the pRa * R step is proteolytic. pRa + R conversion occurred in amniotic fluid at low pH by the action of an endogenous aspartic protease. In plasma pRa + R conversion occurs after restoration of pH to neutral and is caused by the serine protease plasma kallikrein. pRa + R conversion did not occur in purified preparations of prorenin. Thus, in contrast to pepsinogen, the acid-induced reversible conformational change is not followed by autocatalysis. pRa of amniotic fluid and plasma could be separated from R by affinity chromatography on Cibacron blue F3GA-agarose, and R but not pRa was detected by an immunoassay using monoclonal antibodies reacting with R and not with pR. The first-order rate constant for pR + pRa conversion depends on the protonation of a polar group (or groups) with pK 3.4, the rate constant being proportional to the fraction of pR molecules that have this group protonated. This is analogous to the reversible acid-induced conformational change of pepsinogen that occurs before its proteolytic conversion into pepsin. k,,,/K, for pRa R conversion by plasmin and plasma kallikrein at pH 7.4 and 37 “C was 7.8 X 10’ and 5.2 X 10’ M-’ min”, respectively, which was about 50-70 times greater than for pR + R conversion. The susceptibility of pRa to proteolytic attack is high enough for the intrinsic factor XII-kallikrein pathway to cause rapid pRa + R conversion at 37 “C even in whole blood with its abundance of serine protease inhibitors. Formation of pRa may occur in vivo in an acidic cellular compartment, such as exoor endocytotic vesicles.
منابع مشابه
Human prorenin.
Human prorenin is the enzymatically inactive biosynthetic precursor of renin. Recent interest has focused on the posttranslational sorting and processing of prorenin to renin since markedly increased levels of circulating prorenin have been associated with both physiological and pathological changes. These observations raise the question of whether prorenin processing may be a regulatory event ...
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