Conformational changes of blood ACE in chronic uremia

PLoS One. 2012;7(11):e49290. doi: 10.1371/journal.pone.0049290. Epub 2012 Nov 16.


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.

Hypothesis: 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.

Methodology/principal findings: 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/significance: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Antibodies, Monoclonal / metabolism*
  • Biomarkers / metabolism
  • Enalaprilat / pharmacology
  • Epitopes / genetics
  • Epitopes / metabolism
  • Humans
  • Immunoprecipitation
  • Kidney Failure, Chronic / complications*
  • Models, Molecular*
  • Peptidyl-Dipeptidase A / chemistry*
  • Peptidyl-Dipeptidase A / metabolism
  • Protein Binding / drug effects
  • Protein Conformation*
  • Teprotide / pharmacology
  • Uremia / enzymology*
  • Uremia / etiology


  • 1G12 monoclonal antibody
  • Angiotensin-Converting Enzyme Inhibitors
  • Antibodies, Monoclonal
  • Biomarkers
  • Epitopes
  • Teprotide
  • Peptidyl-Dipeptidase A
  • Enalaprilat

Grants and funding

This work was partly financially supported by the Russian Fund for Basic Research (grant number 11-04-01923-a). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.