Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding

• Published in: Scientific reports Vol. 6; no. 1; p. 34913
• Main Authors: Danilov, Sergei M, Lünsdorf, Heinrich, Akinbi, Henry T, Nesterovitch, Andrew B, Epshtein, Yuliya, Letsiou, Eleftheria, Kryukova, Olga V, Piegeler, Tobias, Golukhova, Elena Z, Schwartz, David E, Dull, Randal O, Minshall, Richard D, Kost, Olga A, Garcia, Joe G N
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.10.2016
• Subjects: ACE protein; Angiotensin; Angiotensin I; Animals; Antibodies, Monoclonal - chemistry; Bilirubin; Bilirubin - chemistry; Binding sites; Blood pressure; Cardiovascular diseases; Case-Control Studies; Cell Membrane - metabolism; Cell surface; CHO Cells; Cricetinae; Cricetulus; Flow Cytometry; Humans; Intercellular Signaling Peptides and Proteins; Lysozyme; Mice; Molecular weight; Muramidase - chemistry; Mutation; Peptides - chemistry; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - chemistry; Phenotype; Point mutation; Protein Binding; Protein Domains; Proteolysis; Pulmonary Surfactant-Associated Protein C; Sarcoidosis; Sarcoidosis - blood; Surface Plasmon Resonance
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep34913

Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients.