THE ANGIOTENSIN-I-CONVERTING ENZYME (KINI NASE-II) - MOLECULAR AND PHYSIOLOGICAL-ASPECTS

The angiotensin I-converting enzyme (kininase II, ECA) is a membrane b ound enzyme anchored to the cell membrane through a single transmembra ne domain located near its carboxyterminal extremity. Secretion of ACE by the cell occurs most likely as a result of a postranslationnal cle avage of the membrane anchor and intracellular region. The ACE molecul e is organized into two large highly homologous domains, each bearing consensus sequences for zinc binding in metallopeptidases. Site direct ed mutagenesis allowed to establish that both domains bear in fact a f unctional active site, able to convert angiotensin I into angiotensin II and to hydrolyze bradykinin or substance P. The two active sites of ACE, however, do not display the same sensitivity to anion activation (the C terminal active site being more chloride activatable) and also differs in kinetic parameters for peptide hydrolysis. The C terminal active site can hydrolyze faster angiotensin I and substance P and the N terminal active site is able to perform a peculiar endoproteolytic cleavage of an in vitro substrate of ACE, the luteinizing hormone rele asing hormone. Both active sites bind with a high affinity, competitiv e inhibitors but the Kd of the reaction can vary up to 10 between the two active sites. All together, these observations suggest that ACE co ntains two active sites, whose structure is not exactly identical. The y may have a different substrate specificity, however this remains spe culative at the present time. Concerning the regulation of ACE gene ex pression in man, population studies indicated that the large interindi vidual variability in plasma ACE levels is genetically determined. An insertion/deletion polymorphism located in an intron of ACE gene is as sociated with differences in the level of ACE in plasma and cells. The physiological and clinical implications of these observations is disc ussed.