Angiotensin-Converting Enzyme - New Insights into Structure, Biological Significance and Prospects for Domain-Selective Inhibitors

Abstract

Somatic angiotensin-converting enzyme (ACE) -well known for its role in cardiovascular pathophysiologyhas 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.

Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides

“…These findings have given rise to the pursuit of C-domain selective inhibitors which, it is hoped, will provide control of blood pressure, while leaving the N-domain active site to prevent bradykinin accumulation and the associated side effects926.…”

Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration

“…The major form of somatic ACE involves two very similar protein domains (N- and C-domains) [35, 36], with the C-domain of ACE responsible for Ang-II formation [37, 38], the principal final product of the renin-angiotensin system. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates.…”

Structural characterization of angiotensin I‐converting enzyme in complex with a selenium analogue of captopril

“…Human angiotensin I‐converting enzyme (ACE; http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/4/15/1.html) is a zinc metallopeptidase that plays a critical role in blood pressure regulation [1–7] by catalysing the proteolysis of angiotensin I to the vasopressor angiotensin II [8–10]. There are two isoforms of human ACE: in somatic tissues, it exists as a glycoprotein composed of a mature single polypeptide chain of 1277 amino acids with two active centres, one in each of the N‐ and C‐domains [11].…”