Renin enzymic nature

The natural blood globulin, angiotensinogen, Is converted by the proteolytic kidney enzyme, renin, to the decapeptide angiotensin 1. This substance is not a pressor agent but is cleaved by plasma converting enzyme to the powerful vasoconstrictor angiotensin II, an octapeptide. 

Hypertensin is soluble in alcohol, glacial acetic acid, phenol, and water, and insoluble in ether (61). Because it is inactivated by tyrosinase it probably contains a catechol or phenol group, and by amine oxidase, an amine group on an a-carbon atom (Figure 2). Hypertensin is inactivated by certain phenolic, catecholic, and amine oxidases, by pepsin, trypsin, chymotrypsin, and carboxypeptidase, and by hypertensinase found in plasma. The nature of hypertensinase is unknown, but it is probably not an oxidative enzyme. Because it is heat-labile, hypertensinase can be removed from blood and renin preparations by heating hypertensin itself is heat-stable. Lack of pure preparations of hypertensin has delayed its further chemical identification. 

As had been predicted prior to the determination of the X-ray structure, the proteinase assembles its catalytic machinery using a C2 symmetric homodimer (as opposed to a monomer in renin). The symmetrical nature of the enzyme suggested that C2 symmetric inhibitors might be effective. The X-ray structure also revealed the presence of an ordered water molecule bound to two of the carbonyl groups of the inhibitor. Displacement of such a water molecule with an inhibitor should, theoretically, lead to greatly enhanced activity. This theory was exploited with a class of cyclic inhibitors that mimicked the interactions of the water molecule with functionality within the inhibitor leading to highly potent and compact inhibitors, e.g., XM-323 (see Scheme 9) (15). 

The inactive forms of renin could be precursors of active renin by analogy with many other proteolytic enzymes which are synthesized as high-molecular-weight inactive proenzymes or zymogens and then undergo a limited proteolysis to produce the active enzyme. Some peptide hormones such as insulin (15) also have large inactive precursors. This paper describes the evidence for the presence of inactive renin in humans and rabbits and discusses the nature of the material. 

Many of the early examples of maerocyeles in drug discovery relied on these classical reaction types for the formation of the ring and they remain in regular use. This was due, in part, to the peptidomimetic nature of many of these structures, which often were targeted at protease enzyme inhibition, and thus lent themselves readily to macrolactamization for amide bond formation or macrolactonization for cyclic depsipeptide-like compounds. Representative examples of these two general transformations are shown in Scheme 11.1 (BOP (benzotriazol-l-ylo5ytris(dimethylamino)-phosphonium hexafluorophosphate, Castro s reagent), EDC (l-ethyl-3-(3-dimethylamino-propyl)-carbodiimide), DMAP (4-dimethylamino-pyridine)) for the matrix metalloproteinase (MMP) inhibitor template 2 and the renin inhibitor scaffold 4. °... 

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