000820510 001__ 820510
000820510 005__ 20240625095121.0
000820510 0247_ $$2doi$$a10.1021/acs.biochem.5b01263
000820510 0247_ $$2ISSN$$a0006-2960
000820510 0247_ $$2ISSN$$a1520-4995
000820510 0247_ $$2WOS$$aWOS:000376224000010
000820510 0247_ $$2altmetric$$aaltmetric:6943139
000820510 0247_ $$2pmid$$apmid:27105448
000820510 037__ $$aFZJ-2016-05803
000820510 082__ $$a570
000820510 1001_ $$0P:(DE-Juel1)168597$$aPavlin, Matic$$b0
000820510 245__ $$aCarnosine and Homocarnosine Degradation Mechanisms by the Human Carnosinase Enzyme CN1: Insights from Multiscale Simulations
000820510 260__ $$aColumbus, Ohio$$bAmerican Chemical Society$$c2016
000820510 3367_ $$2DRIVER$$aarticle
000820510 3367_ $$2DataCite$$aOutput Types/Journal article
000820510 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1478775007_18731
000820510 3367_ $$2BibTeX$$aARTICLE
000820510 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000820510 3367_ $$00$$2EndNote$$aJournal Article
000820510 520__ $$aThe endogenous dipeptide l-carnosine, and its derivative homocarnosine, prevent and reduce several pathologies like amytrophic lateral sclerosis (ALS), Alzheimer’s disease, and Parkinson’s disease. Their beneficial action is severely hampered because of the hydrolysis by carnosinase enzymes, in particular the human carnosinase, hCN1. This belongs to the metallopeptidase M20 family, where a cocatalytic active site is formed by two Zn2+ ions, bridged by a hydroxide anion. The protein may exist as a monomer and as a dimer in vivo. Here we used hybrid quantum mechanics/molecular mechanics simulations based on the dimeric apoenzyme’s structural information to predict the Michaelis complexes with l-carnosine and its derivative homocarnosine. On the basis of our calculations, we suggest that (i) l-carnosine degradation occurs through a nucleophilic attack of a Zn2+-coordinated bridging moiety for both monomer and dimer. This mechanistic hypothesis for hCN1 catalysis differs from previous proposals, while it is in agreement with available experimental data. (ii) The experimentally measured higher affinity of homocarnosine for the enzyme relative to l-carnosine might be explained, at least in part, by more extensive interactions inside the monomeric and dimeric hCN1’s active site. (iii) Hydrogen bonds at the binding site, present in the dimer but absent in the monomer, might play a role in the experimentally observed higher activity of the dimeric form. Investigations of the enzymatic reaction are required to establish or disprove this hypothesis. Our results may serve as a basis for the design of potent hCN1 inhibitors.
000820510 536__ $$0G:(DE-HGF)POF3-572$$a572 - (Dys-)function and Plasticity (POF3-572)$$cPOF3-572$$fPOF III$$x0
000820510 536__ $$0G:(DE-HGF)POF3-511$$a511 - Computational Science and Mathematical Methods (POF3-511)$$cPOF3-511$$fPOF III$$x1
000820510 588__ $$aDataset connected to CrossRef
000820510 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b1$$eCorresponding author
000820510 7001_ $$0P:(DE-Juel1)167585$$aDe Vivo, Marco$$b2$$ufzj
000820510 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b3$$ufzj
000820510 773__ $$0PERI:(DE-600)1472258-6$$a10.1021/acs.biochem.5b01263$$gVol. 55, no. 19, p. 2772 - 2784$$n19$$p2772 - 2784$$tBiochemistry$$v55$$x1520-4995$$y2016
000820510 8564_ $$uhttps://juser.fz-juelich.de/record/820510/files/acs.biochem.5b01263.pdf$$yRestricted
000820510 8564_ $$uhttps://juser.fz-juelich.de/record/820510/files/acs.biochem.5b01263.gif?subformat=icon$$xicon$$yRestricted
000820510 8564_ $$uhttps://juser.fz-juelich.de/record/820510/files/acs.biochem.5b01263.jpg?subformat=icon-1440$$xicon-1440$$yRestricted
000820510 8564_ $$uhttps://juser.fz-juelich.de/record/820510/files/acs.biochem.5b01263.jpg?subformat=icon-180$$xicon-180$$yRestricted
000820510 8564_ $$uhttps://juser.fz-juelich.de/record/820510/files/acs.biochem.5b01263.jpg?subformat=icon-640$$xicon-640$$yRestricted
000820510 8564_ $$uhttps://juser.fz-juelich.de/record/820510/files/acs.biochem.5b01263.pdf?subformat=pdfa$$xpdfa$$yRestricted
000820510 909CO $$ooai:juser.fz-juelich.de:820510$$pVDB
000820510 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)145921$$aForschungszentrum Jülich$$b1$$kFZJ
000820510 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)167585$$aForschungszentrum Jülich$$b2$$kFZJ
000820510 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)145614$$aForschungszentrum Jülich$$b3$$kFZJ
000820510 9131_ $$0G:(DE-HGF)POF3-572$$1G:(DE-HGF)POF3-570$$2G:(DE-HGF)POF3-500$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bKey Technologies$$lDecoding the Human Brain$$v(Dys-)function and Plasticity$$x0
000820510 9131_ $$0G:(DE-HGF)POF3-511$$1G:(DE-HGF)POF3-510$$2G:(DE-HGF)POF3-500$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bKey Technologies$$lSupercomputing & Big Data$$vComputational Science and Mathematical Methods$$x1
000820510 9141_ $$y2016
000820510 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS
000820510 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences
000820510 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search
000820510 915__ $$0StatID:(DE-HGF)0550$$2StatID$$aNo Authors Fulltext
000820510 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bBIOCHEMISTRY-US : 2015
000820510 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection
000820510 915__ $$0StatID:(DE-HGF)0110$$2StatID$$aWoS$$bScience Citation Index
000820510 915__ $$0StatID:(DE-HGF)0111$$2StatID$$aWoS$$bScience Citation Index Expanded
000820510 915__ $$0StatID:(DE-HGF)9900$$2StatID$$aIF < 5
000820510 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC
000820510 915__ $$0StatID:(DE-HGF)0310$$2StatID$$aDBCoverage$$bNCBI Molecular Biology Database
000820510 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews
000820510 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline
000820510 915__ $$0StatID:(DE-HGF)0420$$2StatID$$aNationallizenz
000820510 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bThomson Reuters Master Journal List
000820510 920__ $$lyes
000820510 9201_ $$0I:(DE-Juel1)IAS-5-20120330$$kIAS-5$$lComputational Biomedicine$$x0
000820510 9201_ $$0I:(DE-Juel1)INM-9-20140121$$kINM-9$$lComputational Biomedicine$$x1
000820510 9201_ $$0I:(DE-Juel1)JSC-20090406$$kJSC$$lJülich Supercomputing Center$$x2
000820510 980__ $$ajournal
000820510 980__ $$aVDB
000820510 980__ $$aI:(DE-Juel1)IAS-5-20120330
000820510 980__ $$aI:(DE-Juel1)INM-9-20140121
000820510 980__ $$aI:(DE-Juel1)JSC-20090406
000820510 980__ $$aUNRESTRICTED
000820510 981__ $$aI:(DE-Juel1)INM-9-20140121
000820510 981__ $$aI:(DE-Juel1)JSC-20090406