Document Detail

Crystal structure-based selective targeting of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II for cognitive enhancement.
MedLine Citation:
PMID:  20684605     Owner:  NLM     Status:  MEDLINE    
Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(-)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs. From a medicinal chemistry perspective our results demonstrate that the issue of inhibitor specificity for highly conserved PLP-dependent enzymes could be successfully addressed.
Franca Rossi; Casazza Valentina; Silvia Garavaglia; Korrapati V Sathyasaikumar; Robert Schwarcz; Shin-Ichi Kojima; Keisuke Okuwaki; Shin-Ichiro Ono; Yasushi Kajii; Menico Rizzi
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-05     Completed Date:  2010-09-08     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5684-9     Citation Subset:  IM    
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MeSH Terms
Brain / drug effects,  enzymology
Crystallography, X-Ray
Fluoroquinolones / chemistry*,  pharmacology
Models, Molecular
Nootropic Agents / chemistry*,  pharmacology
Piperazines / chemistry*,  pharmacology
Protein Conformation
Pyridoxal Phosphate / physiology*
Transaminases / antagonists & inhibitors,  chemistry*
Grant Support
Reg. No./Substance:
0/9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid; 0/Fluoroquinolones; 0/Nootropic Agents; 0/Piperazines; 5V5IOJ8338/Pyridoxal Phosphate; EC 2.6.1.-/Transaminases; EC transaminase

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