A human homolog of angiotensin-converting enzyme - Cloning and functional expression as a captopril-insensitive carboxypeptidase

A novel human zinc metalloprotease that has considerable homology to human angiotensin-converting enzyme (ACE) (40% identity and 61% similarity) has b een identified, This metalloprotease (angiotensin-converting enzyme homolog (ACEH)) contains a single HEXXH zinc-binding domain and conserves other cr itical residues typical of the ACE family. The predicted protein sequence c onsists of 805 amino acids, including a potential 17-amino acid N-terminal signal peptide sequence and a putative C-terminal membrane anchor. Expressi on in Chinese hamster ovary cells of a soluble, truncated form of ACEH, lac king the transmembrane and cytosolic domains, produces a glycoprotein of 12 0 kDa, which is able to cleave angiotensin I and angiotensin II but not bra dykinin or Hip-His-Leu. In the hydrolysis of the angiotensins, ACEH functio ns exclusively as a carboxypeptidase, ACEH activity is inhibited by EDTA bu t not by classical ACE inhibitors such as captopril, lisinopril, or enalapr ilat, Identification of the genomic sequence of ACEH has shown that the ACE H gene contains 18 exons, of which several have considerable size similarit y with the first 17 exons of human ACE. The gene maps to chromosomal locati on Xp22, Northern blotting analysis has shown that the ACEH mRNA transcript is similar to3.4 kilobase pairs and is most highly expressed in testis, ki dney, and heart. This is the first report of a mammalian homolog of ACE and has implications for our understanding of cardiovascular and renal functio n.