Angiotensin-converting enzyme (ACE) N-domain (ACE N-domain)

The N-domain of somatic Angiotensin-converting enzyme (ACE) is one of two homologous catalytic sites within the enzyme, the other being the C-domain. While both domains can convert Angiotensin I to the vasoconstrictor Angiotensin II, the N-domain exhibits a unique substrate preference for the tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), which acts as an anti-fibrotic agent and an inhibitor of hematopoietic stem cell proliferation (UniProt P12821). Because the N-domain is the primary site for Ac-SDKP degradation, selective inhibition of this domain is a therapeutic area of interest for treating organ fibrosis and preventing chemotherapy-induced bone marrow suppression (PubMed: 11566458). Most clinically available ACE inhibitors, such as Lisinopril and Captopril, are non-selective and target both domains, leading to blood pressure reduction and potential side effects like angioedema due to bradykinin accumulation (PubMed: 12663522). Research into N-domain selective inhibitors, such as the experimental compound RXP407, aims to decouple the anti-fibrotic benefits from the potent hemodynamic effects primarily driven by the C-domain (PubMed: 15153604).

Other names

N-ACEN-terminal domain of somatic ACEPeptidyl-dipeptidase A N-domainACE1 N-domain

Competitive inhibition of the N-terminal catalytic domain of somatic angiotensin-converting enzyme, which selectively increases levels of the anti-fibrotic peptide Ac-SDKP while having a lesser effect on systemic blood pressure compared to C-domain inhibition.