Abstract
Somatic angiotensin-converting enzyme (ACE) - well known for its role in cardiovascular pathophysiology - has an unusual, two-domain, double active-site structure. The two domains (designated N and C) are 55% identical and each contains a similar active site with overlapping but distinct substrate preferences. While both convert angiotensin I to angiotensin II in vitro, current evidence suggests the C domain site predominates in this role in vivo. The N domain site inactivates a hemoregulatory and antifibrotic peptide, AcSDKP, in vivo, although the significance of this remains unclear. However, differences in the characteristics of the two domains may result in different context-dependent activities, as is the case with other enzymes containing tandem repeats. The N domain may also have a role in modulating C domain activity, through a combination of inter-domain cooperativity and structural stabilization. Comparison of ACE with its structural homologues reveals conservation of peptidase activity and a tendency to hinge about the active-site cleft. Recent work on ACE active-site mutants containing one or more key residues replaced by their cognate residues from the other domain, synthesis of domain-selective inhibitors, and co-crystal structures of each domain with such inhibitors, has led to a better resolution of the basis for domain selectivity and should enable the design of next-generation, domain-selective inhibitors with distinct pharmacological profiles.
Keywords: Angiotensin-converting enzyme (ACE), domain-selective inhibitors, AcSDKP, crystal, structure, metallopeptidase
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