Angiotensin converting enzyme (ACE) is a key enzyme of the renin-angiotensin and kallikrein-kinin systems responsible for the regulation of blood pressure. Recently the new physiological function of ACE has been revealed: the enzyme hydrolyses in vivo the natural peptide (N-AcSer-Asp-Lys-Pro), a negative regulator of hematopoietic stem cell proliferation. Somatic ACE is a single-chain glycoprotein, which contains two highly homologous domains (N- and C-domains, respectively), possessing a zinc-dependent active site. The domains differ in the rate of substrate hydrolysis, interaction with ACE inhibitors and chloride activation profiles. Specific ACE inhibitors used for treatment of hypertension, inhibit both domains, but their dissociation rates of enzyme-inhibitor complex are different. Selective binding of ACE inhibitors to either N- or C-domain may influence their biological effect during treatment. Different functional significance of these domains may be due to some differences in their three-dimentional structures. X-ray structure of testicular ACE was recently solved and three-dimentional structure of N-domain was modeled. The structural features of domain active sites may be useful for construction of new selective inhibitors.
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