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

TitleLysozyme and bilirubin bind to ACE and regulate its conformation and shedding.
Publication TypeJournal Article
Year of Publication2016
AuthorsDanilov SM, Lünsdorf H, Akinbi HT, Nesterovitch AB, Epshtein Y, Letsiou E, Kryukova OV, Piegeler T, Golukhova EZ, Schwartz DE, Dull RO, Minshall RD, Kost OA, Garcia JGN
JournalSci Rep
Volume6
Pagination34913
Date Published2016 Oct 13
ISSN Number2045-2322
Abstract

<p>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.</p>

DOI10.1038/srep34913
Alternate JournalSci Rep
PubMed ID27734897
PubMed Central IDPMC5062130
Grant ListR01 HL125356 / HL / NHLBI NIH HHS / United States