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4y0h

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Revision as of 01:48, 10 March 2017

Gamma-aminobutyric acid aminotransferase inactivated by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115)

Structural highlights

4y0h is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4y0d
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GABT_PIG] Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively. Can also convert delta-aminovalerate and beta-alanine.

Publication Abstract from PubMed

gamma-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently, CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5'-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly formed carboxylate produced by hydrolysis of the difluoromethylene group in CPP-115, resulting in a noncovalent, tightly bound complex. This represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general.

Mechanism of Inactivation of gamma-Aminobutyric Acid Aminotransferase by (1S,3S)-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115).,Lee H, Doud EH, Wu R, Sanishvili R, Juncosa JI, Liu D, Kelleher NL, Silverman RB J Am Chem Soc. 2015 Feb 10. PMID:25616005^[1]

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

References

↑ Lee H, Doud EH, Wu R, Sanishvili R, Juncosa JI, Liu D, Kelleher NL, Silverman RB. Mechanism of Inactivation of gamma-Aminobutyric Acid Aminotransferase by (1S,3S)-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115). J Am Chem Soc. 2015 Feb 10. PMID:25616005 doi:http://dx.doi.org/10.1021/ja512299n

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4y0h"

@@ Line 1: / Line 1: @@
 ==Gamma-aminobutyric acid aminotransferase inactivated by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115)==
 <StructureSection load='4y0h' size='340' side='right' caption='[[4y0h]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4y0d|4y0d]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4y0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y0h OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4y0h RCSB], [http://www.ebi.ac.uk/pdbsum/4y0h PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4y0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y0h OCA], [http://pdbe.org/4y0h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y0h RCSB], [http://www.ebi.ac.uk/pdbsum/4y0h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y0h ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4y0h" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Aminotransferase|Aminotransferase]]
 == References ==
 <references/>

4y0h

From Proteopedia

Revision as of 01:48, 10 March 2017

Gamma-aminobutyric acid aminotransferase inactivated by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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