title: Conformational changes of blood ACE in chronic uremia.
abstract: BACKGROUND
  The pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes.
  
  
  OBJECTIVE
  Toxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors.
  
  
  RESULTS
  The recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The "short" ACE inhibitor enalaprilat (tripeptide analog) and "long" inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors.
  
  
  CONCLUSIONS
  The estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy.
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Petrov
authors.forename: Valery Y
authors.initials: VY
authors.lastname: Shilo
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Tarasov
authors.forename: David E
authors.initials: DE
authors.lastname: Schwartz
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Olga A
authors.initials: OA
authors.lastname: Kost
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Danilov
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015773:Enalaprilat / Q000494:pharmacology; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007676:Kidney Failure, Chronic / Q000150:complications*; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D013722:Teprotide / Q000494:pharmacology; D014511:Uremia / Q000201:enzymology* / Q000209:etiology
chemical_list: C521204:1G12 monoclonal antibody; D000806:Angiotensin-Converting Enzyme Inhibitors; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D000939:Epitopes; D013722:Teprotide; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat