Document Detail


Kinetics of human peptidylarginine deiminase 2 (hPAD2)--reduction of Ca2+ dependence by phospholipids and assessment of proposed inhibition by paclitaxel side chains.
MedLine Citation:
PMID:  18923545     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multiple sclerosis is a complex human neurodegenerative disease, characterized by the active destruction of the insulating myelin sheath around the axons in the central nervous system. The physical deterioration of myelin is mediated by hyperdeimination of myelin basic and other proteins, catalysed by the Ca2+ -dependent enzyme peptidylarginine deiminase 2 (PAD2). Thus, inhibition of PAD2 may be of value in treatment of this disease. Here, we have first characterized the in vitro kinetic properties of the human peptidylarginine deiminase isoform 2 (hPAD2). Phosphatidylserine and phosphatidylcholine reduced its Ca2+ dependence by almost twofold. Second, we have explored the putative inhibitory action of the methyl ester side chain of paclitaxel (TSME), which shares structural features with a synthetic PAD substrate, viz., the benzoyl-L-arginine ethyl ester (BAEE). Using the known crystallographic structure of the homologous enzyme hPAD4 and in silico molecular docking, we have shown that TSME interacted strongly with the catalytic site, albeit with a 100-fold lower affinity than BAEE. Despite paclitaxel having previously been shown to inhibit hPAD2 in vitro, the side chain of paclitaxel alone did not inhibit this enzyme's activity.
Authors:
Abdiwahab A Musse; Eugenia Polverini; Reinout Raijmakers; George Harauz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry and cell biology = Biochimie et biologie cellulaire     Volume:  86     ISSN:  0829-8211     ISO Abbreviation:  Biochem. Cell Biol.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-16     Completed Date:  2008-12-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8606068     Medline TA:  Biochem Cell Biol     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  437-47     Citation Subset:  IM    
Affiliation:
Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Antineoplastic Agents, Phytogenic* / chemistry,  metabolism
Calcium / metabolism*
Catalytic Domain
Humans
Hydrolases / chemistry,  genetics,  metabolism*
Isoenzymes / chemistry,  genetics,  metabolism*
Kinetics
Models, Molecular
Molecular Sequence Data
Molecular Structure
Multiple Sclerosis / enzymology
Paclitaxel* / chemistry,  metabolism
Phospholipids / metabolism*
Protein Conformation
Sequence Alignment
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Isoenzymes; 0/Phospholipids; 33069-62-4/Paclitaxel; 7440-70-2/Calcium; EC 3.-/Hydrolases; EC 3.5.3.15/peptidylarginine deiminase type IV; EC 3.5.3.15/protein-arginine deiminase

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


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