Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding
AuthorDanilov, Sergei M.
Akinbi, Henry T.
Nesterovitch, Andrew B.
Kryukova, Olga V.
Golukhova, Elena Z.
Schwartz, David E.
Dull, Randal O.
Minshall, Richard D.
Kost, Olga A.
Garcia, Joe G. N.
AffiliationUniv Arizona Hlth Sci
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationLysozyme and bilirubin bind to ACE and regulate its conformation and shedding 2016, 6:34913 Scientific Reports
Rights© The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractAngiotensin 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.
VersionFinal published version
SponsorsMinistry of Science and Education of Russian Federation [14.Z50.31.0026]
- An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding.
- Authors: Danilov SM, Gordon K, Nesterovitch AB, Lünsdorf H, Chen Z, Castellon M, Popova IA, Kalinin S, Mendonca E, Petukhov PA, Schwartz DE, Minshall RD, Sturrock ED
- Issue date: 2011
- Angiotensin I-converting enzyme mutation (Trp1197Stop) causes a dramatic increase in blood ACE.
- Authors: Nesterovitch AB, Hogarth KD, Adarichev VA, Vinokour EI, Schwartz DE, Solway J, Danilov SM
- Issue date: 2009 Dec 14
- The effect of structural motifs on the ectodomain shedding of human angiotensin-converting enzyme.
- Authors: Conrad N, Schwager SL, Carmona AK, Sturrock ED
- Issue date: 2016 Dec 2
- Inhibitory antibodies to human angiotensin-converting enzyme: fine epitope mapping and mechanism of action.
- Authors: Skirgello OE, Balyasnikova IV, Binevski PV, Sun ZL, Baskin II, Palyulin VA, Nesterovitch AB, Albrecht RF 2nd, Kost OA, Danilov SM
- Issue date: 2006 Apr 18
- The influence of angiotensin converting enzyme mutations on the kinetics and dynamics of N-domain selective inhibition.
- Authors: Lubbe L, Sewell BT, Sturrock ED
- Issue date: 2016 Nov