3ue8: Difference between revisions

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== Structural highlights ==

<table><tr><td colspan='2'>[[3ue8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UE8 FirstGlance]. <br>

<table><tr><td colspan='2'>[[3ue8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UE8 FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=09M:(5-HYDROXY-4-{[(1-HYDROXY-2-OXO-1,2-DIHYDROQUINOLIN-3-YL)AMINO]METHYL}-6-METHYLPYRIDIN-3-YL)METHYL+DIHYDROGEN+PHOSPHATE'>09M</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>~~</td></tr>~~

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.22Å</td></tr>

~~<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AADAT, KAT2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=09M:(5-HYDROXY-4-{[(1-HYDROXY-2-OXO-1,2-DIHYDROQUINOLIN-3-YL)AMINO]METHYL}-6-METHYLPYRIDIN-3-YL)METHYL+DIHYDROGEN+PHOSPHATE'>09M</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ue8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ue8 OCA], [https://pdbe.org/3ue8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ue8 RCSB], [https://www.ebi.ac.uk/pdbsum/3ue8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ue8 ProSAT]</span></td></tr>

</table>

== Function ==

[[https://www.uniprot.org/uniprot/AADAT_HUMAN AADAT_HUMAN]] Transaminase with broad substrate specificity. Has transaminase activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also towards tryptophan, aspartate and hydroxykynurenine. Accepts a variety of oxo-acids as amino-group acceptors, with a preference for 2-oxoglutarate, 2-oxocaproic acid, phenylpyruvate and alpha-oxo-gamma-methiol butyric acid. Can also use glyoxylate as amino-group acceptor (in vitro).<ref>PMID:18620547</ref>

[https://www.uniprot.org/uniprot/AADAT_HUMAN AADAT_HUMAN] Transaminase with broad substrate specificity. Has transaminase activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also towards tryptophan, aspartate and hydroxykynurenine. Accepts a variety of oxo-acids as amino-group acceptors, with a preference for 2-oxoglutarate, 2-oxocaproic acid, phenylpyruvate and alpha-oxo-gamma-methiol butyric acid. Can also use glyoxylate as amino-group acceptor (in vitro).<ref>PMID:18620547</ref>

~~<div style="background-color:#fffaf0;">~~

~~== Publication Abstract from PubMed ==~~

Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.,Dounay AB, Anderson M, Bechle BM, Campbell BM, Claffey MM, Evdokimov A, Evrard E, Fonseca KR, Gan X, Ghosh S, Hayward MM, Horner W, Kim JY, McAllister LA, Pandit J, Paradis V, Parikh VD, Reese MR, Rong S, Salafia MA, Schuyten K, Strick CA, Tuttle JB, Valentine J, Wang H, Zawadzke LE, Verhoest PR ACS Med Chem Lett. 2012 Jan 25;3(3):187-92. doi: 10.1021/ml200204m. eCollection, 2012 Mar 8. PMID:24900455<ref>PMID:24900455</ref>

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

~~</div>~~

~~<div class="pdbe-citations 3ue8" style="background-color:#fffaf0;"></div~~>

== References ==

__TOC__

</StructureSection>

[[Category: ~~Human~~]]

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Anderson, M]]

[[Category: Anderson M]]

[[Category: Bechle~~, B M~~]]

[[Category: Bechle BM]]

[[Category: Campbell~~, B M~~]]

[[Category: Campbell BM]]

[[Category: Claffey~~, M M~~]]

[[Category: Claffey MM]]

[[Category: Dounay~~, A B~~]]

[[Category: Dounay AB]]

[[Category: Edelweiss, E]]

[[Category: Edelweiss E]]

[[Category: Evdokimov, A]]

[[Category: Evdokimov A]]

[[Category: Fonseca~~, K R~~]]

[[Category: Fonseca KR]]

[[Category: Gan, X]]

[[Category: Gan X]]

[[Category: Ghosh, S]]

[[Category: Ghosh S]]

[[Category: Hayward~~, M M~~]]

[[Category: Hayward MM]]

[[Category: Horner, W]]

[[Category: Horner W]]

[[Category: Kim~~, J Y~~]]

[[Category: Kim JY]]

[[Category: McAllister~~, L A~~]]

[[Category: McAllister LA]]

[[Category: Pandit, J]]

[[Category: Pandit J]]

[[Category: Paradis, V]]

[[Category: Paradis V]]

[[Category: Parikh~~, V D~~]]

[[Category: Parikh VD]]

[[Category: Reese~~, M R~~]]

[[Category: Reese MR]]

[[Category: Rong~~, S B~~]]

[[Category: Rong SB]]

[[Category: Salafia~~, M A~~]]

[[Category: Salafia MA]]

[[Category: Schuyten, K]]

[[Category: Schuyten K]]

[[Category: Strick~~, C A~~]]

[[Category: Strick CA]]

[[Category: Tuttle~~, J B~~]]

[[Category: Tuttle JB]]

[[Category: Valentine, J]]

[[Category: Valentine J]]

[[Category: Verhoest~~, P R~~]]

[[Category: Verhoest PR]]

[[Category: Wang, H]]

[[Category: Wang H]]

[[Category: Zawadzke~~, L E]]~~

[[Category: Zawadzke LE]]

~~[[Category: Kat ii]]~~

~~[[Category: Kynurenine aminotransferase]]~~

~~[[Category: Transferase-transferase inhibitor complex~~]]

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@@ Line 3: / Line 3: @@
 <StructureSection load='3ue8' size='340' side='right'caption='[[3ue8]], [[Resolution|resolution]] 3.22&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ue8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UE8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ue8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UE8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=09M:(5-HYDROXY-4-{[(1-HYDROXY-2-OXO-1,2-DIHYDROQUINOLIN-3-YL)AMINO]METHYL}-6-METHYLPYRIDIN-3-YL)METHYL+DIHYDROGEN+PHOSPHATE'>09M</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.22&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AADAT, KAT2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=09M:(5-HYDROXY-4-{[(1-HYDROXY-2-OXO-1,2-DIHYDROQUINOLIN-3-YL)AMINO]METHYL}-6-METHYLPYRIDIN-3-YL)METHYL+DIHYDROGEN+PHOSPHATE'>09M</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ue8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ue8 OCA], [https://pdbe.org/3ue8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ue8 RCSB], [https://www.ebi.ac.uk/pdbsum/3ue8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ue8 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/AADAT_HUMAN AADAT_HUMAN]] Transaminase with broad substrate specificity. Has transaminase activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also towards tryptophan, aspartate and hydroxykynurenine. Accepts a variety of oxo-acids as amino-group acceptors, with a preference for 2-oxoglutarate, 2-oxocaproic acid, phenylpyruvate and alpha-oxo-gamma-methiol butyric acid. Can also use glyoxylate as amino-group acceptor (in vitro).<ref>PMID:18620547</ref>
+[https://www.uniprot.org/uniprot/AADAT_HUMAN AADAT_HUMAN] Transaminase with broad substrate specificity. Has transaminase activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also towards tryptophan, aspartate and hydroxykynurenine. Accepts a variety of oxo-acids as amino-group acceptors, with a preference for 2-oxoglutarate, 2-oxocaproic acid, phenylpyruvate and alpha-oxo-gamma-methiol butyric acid. Can also use glyoxylate as amino-group acceptor (in vitro).<ref>PMID:18620547</ref>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.
-Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.,Dounay AB, Anderson M, Bechle BM, Campbell BM, Claffey MM, Evdokimov A, Evrard E, Fonseca KR, Gan X, Ghosh S, Hayward MM, Horner W, Kim JY, McAllister LA, Pandit J, Paradis V, Parikh VD, Reese MR, Rong S, Salafia MA, Schuyten K, Strick CA, Tuttle JB, Valentine J, Wang H, Zawadzke LE, Verhoest PR ACS Med Chem Lett. 2012 Jan 25;3(3):187-92. doi: 10.1021/ml200204m. eCollection, 2012 Mar 8. PMID:24900455<ref>PMID:24900455</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 3ue8" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Anderson, M]]
+[[Category: Anderson M]]
-[[Category: Bechle, B M]]
+[[Category: Bechle BM]]
-[[Category: Campbell, B M]]
+[[Category: Campbell BM]]
-[[Category: Claffey, M M]]
+[[Category: Claffey MM]]
-[[Category: Dounay, A B]]
+[[Category: Dounay AB]]
-[[Category: Edelweiss, E]]
+[[Category: Edelweiss E]]
-[[Category: Evdokimov, A]]
+[[Category: Evdokimov A]]
-[[Category: Fonseca, K R]]
+[[Category: Fonseca KR]]
-[[Category: Gan, X]]
+[[Category: Gan X]]
-[[Category: Ghosh, S]]
+[[Category: Ghosh S]]
-[[Category: Hayward, M M]]
+[[Category: Hayward MM]]
-[[Category: Horner, W]]
+[[Category: Horner W]]
-[[Category: Kim, J Y]]
+[[Category: Kim JY]]
-[[Category: McAllister, L A]]
+[[Category: McAllister LA]]
-[[Category: Pandit, J]]
+[[Category: Pandit J]]
-[[Category: Paradis, V]]
+[[Category: Paradis V]]
-[[Category: Parikh, V D]]
+[[Category: Parikh VD]]
-[[Category: Reese, M R]]
+[[Category: Reese MR]]
-[[Category: Rong, S B]]
+[[Category: Rong SB]]
-[[Category: Salafia, M A]]
+[[Category: Salafia MA]]
-[[Category: Schuyten, K]]
+[[Category: Schuyten K]]
-[[Category: Strick, C A]]
+[[Category: Strick CA]]
-[[Category: Tuttle, J B]]
+[[Category: Tuttle JB]]
-[[Category: Valentine, J]]
+[[Category: Valentine J]]
-[[Category: Verhoest, P R]]
+[[Category: Verhoest PR]]
-[[Category: Wang, H]]
+[[Category: Wang H]]
-[[Category: Zawadzke, L E]]
+[[Category: Zawadzke LE]]
-[[Category: Kat ii]]
-[[Category: Kynurenine aminotransferase]]
-[[Category: Transferase-transferase inhibitor complex]]