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(Circulation Research. 2003;93:91.)
© 2003 American Heart Association, Inc.

Editorials

Do Studies With ACE N- and C-Domain–Selective Inhibitors Provide Evidence for a Non-ACE, Non-Chymase Angiotensin II–Forming Pathway?

Ahsan Husain, Ming Li, Robert M. Graham

From the Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.

Correspondence to Ahsan Husain, PhD, Victor Chang Cardiac Research Institute, 384 Victoria St, Sydney, NSW 2010, Australia. E-mail a.husain@victorchang.unsw.edu.au

Key Words: angiotensin-converting enzyme • angiotensin-converting enzyme inhibitors • angiotensin II • bradykinin • AcSDKP

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Angiotensin I–converting enzyme (ACE, EC 3.4.15.1) is a zinc metalloprotease of the gluzincin family.¹ Gluzincins characterized to date include thermolysin-like enzymes in Gram-positive and -negative bacteria (M4 family), mycolysin from Streptomyces (M5), botulinum neurotoxin (M27), a family of aminopeptidases (M1), neprilysin-like enzymes (M13), and ACE (M2). Of these, some of the neprilysin-like enzymes, eg, neutral endopeptidase (NEP or neprilysin) and ACE possess peptidyl-dipeptidase character. Furthermore, sequence similarity between neprilysin-like enzymes and ACE suggests that the M13 family is the closest gluzincin relatives of ACE and that these enzymes are the more recently evolved of the gluzincin group.² The Caenorhabditis elegans genome contains an ACE-like and several neprilysin-like sequences, but similar sequences have not been detected in unicellular eukaryotes, suggesting that an ACE/neprilysin ancestor arose during the Cambrian radiation about 530 million years ago. After divergence from neprilysin, ACE acquired a unique chloride activation mechanism that has been identified in invertebrates through to mammals.³ Some time before the divergence of bird and mammalian ancestors 310 million years ago, an internal duplication produced the vertebrate gene with two catalytic domains, N and C.⁴ Dual- and single-module ACEs acquired a C-terminal membrane anchor as retained in the ACE-like enzyme ACEH,⁵ although the acquisition dates are uncertain. Tick and mammalian sequences have hydrophobic—potentially membrane spanning—sequences, but C elegans and dipterans sequences do not.

Most mammalian tissues contain ACE with two catalytic domains¹; however, the use of an internal promoter has additionally led to the expression of an ACE with a single catalytic domain . . . [Full Text of this Article]