A Human Homolog of Angiotensin-converting Enzyme

TLDR

A human zinc metalloprotease homolog of ACE, containing a conserved HEXXH zinc‑binding domain and other ACE family residues, is encoded on chromosome Xp22. The study identified a 805‑amino‑acid ACE homolog (ACEH) that, when expressed as a soluble 120‑kDa glycoprotein in CHO cells, cleaves angiotensin I and II as a carboxypeptidase, is inhibited by EDTA but not by standard ACE inhibitors, and is encoded by an 18‑exon gene highly expressed in testis, kidney, and heart, marking the first mammalian ACE homolog and suggesting new roles in cardiovascular and renal physiology.

Abstract

A novel human zinc metalloprotease that has considerable homology to human angiotensin-converting enzyme (ACE) (40% identity and 61% similarity) has been identified. This metalloprotease (angiotensin-converting enzyme homolog (ACEH)) contains a single HE<i>XX</i>H zinc-binding domain and conserves other critical residues typical of the ACE family. The predicted protein sequence consists of 805 amino acids, including a potential 17-amino acid N-terminal signal peptide sequence and a putative C-terminal membrane anchor. Expression in Chinese hamster ovary cells of a soluble, truncated form of ACEH, lacking the transmembrane and cytosolic domains, produces a glycoprotein of 120 kDa, which is able to cleave angiotensin I and angiotensin II but not bradykinin or Hip-His-Leu. In the hydrolysis of the angiotensins, ACEH functions exclusively as a carboxypeptidase. ACEH activity is inhibited by EDTA but not by classical ACE inhibitors such as captopril, lisinopril, or enalaprilat. Identification of the genomic sequence of ACEH has shown that the ACEH gene contains 18 exons, of which several have considerable size similarity with the first 17 exons of human ACE. The gene maps to chromosomal location Xp22. Northern blotting analysis has shown that the ACEH mRNA transcript is ∼3.4 kilobase pairs and is most highly expressed in testis, kidney, and heart. This is the first report of a mammalian homolog of ACE and has implications for our understanding of cardiovascular and renal function.