The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide.
We reported recently that angiotensin-converting enzyme (ACE) significantly degraded amyloid beta-peptide (A beta) to inhibit aggregation and cytotoxicity of A beta in PC12h cells in vitro. On the other hand, others reported that ACE had two domains with highly homologous active centres, the N-domain and C-domain, but that they differed in their characteristics such as optimum chloride ion concentration, inhibition kinetics for various ACE inhibitors and rate of hydrolysis for many substrates. The aim of this study was to determine the specific ACE domain primarily responsible for degradation of A beta. For this purpose, a series of ACE recombinant proteins, each containing only one intact domain, was constructed and expressed in COS7. Our results showed that all ACE recombinant proteins obtained were enzymatically active in terms of angiotensin I cleavage. However, inhibition of A beta aggregation and cytotoxicity of the N-domain were higher than those of the C-domain. Reverse-phase high-performance liquid chromatography analyses confirmed that the N domain degraded A beta. Our results indicate that the N domain of ACE is primarily responsible for the degradation of A beta.
Oba
Ryutaro
R
R & D Center, BioMedical Laboratories, 1361-1 Matoba, Kawagoe-shi, Saitama 350-1101, Japan. roba@bml.co.jp
Igarashi
Akira
A
Kamata
Makiko
M
Nagata
Kinya
K
Takano
Syoichi
S
Nakagawa
Hachiro
H
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats
D016229:Amyloid beta-Peptides; D000806:Angiotensin-Converting Enzyme Inhibitors; D010446:Peptide Fragments; D007703:Peptidyl-Dipeptidase A