title: [Angiotensin converting enzyme: the antigenic properties of the domain, role in Alzheimer's disease and tumor progression].
abstract: Angiotensin converting enzyme (ACE, EC 3.4.15.1) was discovered and characterized in the Laboratory of biochemistry and chemical pathology of proteins under the direction of academician V.N. Orekhovich, where its physiological function, associated with a key role in the regulation of the renin-angiotensin (RAS) and the kallikrein-kinin systems that control blood flow in the body and homeostasis was first deciphered. We carried out a search for structural differences between the two highly homologous domains (N- and C-domains) of somatic ACE (sACE); it was based on a comparative analysis of antigenic determinants (or B-epitopes) of both domains. The revealed epitopes were classified with variable and conserved regions and functionally important sites of the molecule ACE. Essential difference was demonstrated between locations of the epitopes in the N- and C-domains. These data indicate the existence of structural differences between the domains of sACE. We studied the role of the domains of ACE in the metabolism of human amyloid beta peptide (Ab) - the main component of senile plaques, found in the brains of patients with Alzheimer's disease (AD). Our results demonstrated that only N-domain ACE cleaved the Ab between residues R5-H6, while, the C-domain of ACE failed to hydrolyze this region. In addition, the effect of post-translational modifications of Ab on its hydrolysis by the ACE was investigated. We show that isomerization of residue D7, a common non-enzymatic age-related modification found in AD-associated species, does not reduce the affinity of the peptide to the N-domain of ACE, and conversely, it increases. According to our data, the role of ACE in the metabolism of Ab becomes more significant in the development of AD. RAS is involved in malignant transformation and tumor progression. RAS components, including ACE and angiotensin II receptors type 1 (AT1R) are expressed in various human tumors. We found a significant increase in the level of ACE activity in the tumor tissue of squamous cell carcinoma of the cervix. In our viewpoint, the increase in ACE activity may be a marker of poor clinical prognosis.
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: E V
authors.initials: EV
authors.lastname: Kugaevskaya
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: O S
authors.initials: OS
authors.lastname: Timoshenko
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: N I
authors.initials: NI
authors.lastname: Solovyeva
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000502:physiology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D000939:Epitopes; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A
keywords: Alzheimer's disease; amyloid beta peptide; angiotensin converting enzyme; antigenic determinants; squamous cervical carcinoma; tumor progression