Proteolytic and Non-Proteolytic Activation of Prorenin

Largely because of its importance in the pathophysiology of cardiovascular diseases, renin has been intensely studied as a target for drug inhibition. Like most other aspartyl proteases, mammalian renins are synthesized in vivo as inactive precursors called prorenins. Although the crystal structure of prorenin has not yet been reported, it seems likely by analogy with the known structure of the closely related porcine pepsinogen (1) that the amino terminal prosegment of prorenin blocks access to the substrate-binding cleft of the enzyme. In vivo, activation of prorenin is associated with the proteolytic cleavage of the prosegment. Unlike many other aspartyl proteases, however, prorenin does not undergo an autocatalytic processing, but rather requires the action of one or more distinct proteases to remove its prosegment.