Document Detail


Structural mechanism for substrate inhibition of the adenosine 5'-phosphosulfate kinase domain of human 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 and its ramifications for enzyme regulation.
MedLine Citation:
PMID:  17540769     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In mammals, the universal sulfuryl group donor molecule 3'-phosphoadenosine 5'-phosphosulfate (PAPS) is synthesized in two steps by a bifunctional enzyme called PAPS synthetase. The APS kinase domain of PAPS synthetase catalyzes the second step in which APS, the product of the ATP-sulfurylase domain, is phosphorylated on its 3'-hydroxyl group to yield PAPS. The substrate APS acts as a strong uncompetitive inhibitor of the APS kinase reaction. We generated truncated and point mutants of the APS kinase domain that are active but devoid of substrate inhibition. Structural analysis of these mutant enzymes reveals the intrasubunit rearrangements that occur upon substrate binding. We also observe intersubunit rearrangements in this dimeric enzyme that result in asymmetry between the two monomers. Our work elucidates the structural elements required for the ability of the substrate APS to inhibit the reaction at micromolar concentrations. Because the ATP-sulfurylase domain of PAPS synthetase influences these elements in the APS kinase domain, we propose that this could be a communication mechanism between the two domains of the bifunctional enzyme.
Authors:
Nikolina Sekulic; Manfred Konrad; Arnon Lavie
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-05-31
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-23     Completed Date:  2007-09-20     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  22112-21     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL 60607, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/2PEY;  2PEZ
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MeSH Terms
Descriptor/Qualifier:
Cloning, Molecular
Crystallography, X-Ray
Homeostasis
Humans
Kinetics
Models, Molecular
Multienzyme Complexes / antagonists & inhibitors*,  chemistry,  genetics
Mutagenesis
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*,  chemistry
Protein Conformation
Recombinant Proteins / antagonists & inhibitors
Sequence Deletion
Sulfate Adenylyltransferase / antagonists & inhibitors*,  chemistry,  genetics
Grant Support
ID/Acronym/Agency:
AI046943/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Multienzyme Complexes; 0/Recombinant Proteins; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.25/adenylylsulfate kinase; EC 2.7.7.4/PAPS synthetase; EC 2.7.7.4/Sulfate Adenylyltransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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