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| | ==2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as Novel PKM2 Activators== | | ==2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as Novel PKM2 Activators== |
| - | <StructureSection load='4jpg' size='340' side='right' caption='[[4jpg]], [[Resolution|resolution]] 2.33Å' scene=''> | + | <StructureSection load='4jpg' size='340' side='right'caption='[[4jpg]], [[Resolution|resolution]] 2.33Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4jpg]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JPG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JPG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4jpg]] is a 4 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=4JPG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JPG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1OX:2-(1H-BENZIMIDAZOL-1-YLMETHYL)-4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE'>1OX</scene>, <scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1OX:2-(1H-BENZIMIDAZOL-1-YLMETHYL)-4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE'>1OX</scene>, <scene name='pdbligand=FBP:BETA-FRUCTOSE-1,6-DIPHOSPHATE'>FBP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PKM, OIP3, PK2, PK3, PKM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4jpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jpg OCA], [https://pdbe.org/4jpg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jpg RCSB], [https://www.ebi.ac.uk/pdbsum/4jpg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jpg ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.40 2.7.1.40] </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=4jpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jpg OCA], [http://pdbe.org/4jpg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jpg RCSB], [http://www.ebi.ac.uk/pdbsum/4jpg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jpg ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KPYM_HUMAN KPYM_HUMAN]] Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.<ref>PMID:17308100</ref> <ref>PMID:18191611</ref> <ref>PMID:21620138</ref> | + | [https://www.uniprot.org/uniprot/KPYM_HUMAN KPYM_HUMAN] Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.<ref>PMID:17308100</ref> <ref>PMID:18191611</ref> <ref>PMID:21620138</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Pyruvate Kinase|Pyruvate Kinase]] | + | *[[Pyruvate kinase 3D structures|Pyruvate kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Pyruvate kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Cronin, C]] | + | [[Category: Cronin C]] |
| - | [[Category: Greasley, S E]] | + | [[Category: Greasley SE]] |
| - | [[Category: Hickey, M]] | + | [[Category: Hickey M]] |
| - | [[Category: Phonephaly, H]] | + | [[Category: Phonephaly H]] |
| - | [[Category: Transferase-transferase activator complex]]
| + | |
| Structural highlights
Function
KPYM_HUMAN Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.[1] [2] [3]
Publication Abstract from PubMed
The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.
Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators.,Guo C, Linton A, Jalaie M, Kephart S, Ornelas M, Pairish M, Greasley S, Richardson P, Maegley K, Hickey M, Li J, Wu X, Ji X, Xie Z Bioorg Med Chem Lett. 2013 Jun 1;23(11):3358-63. doi: 10.1016/j.bmcl.2013.03.090., Epub 2013 Apr 1. PMID:23622982[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Stetak A, Veress R, Ovadi J, Csermely P, Keri G, Ullrich A. Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death. Cancer Res. 2007 Feb 15;67(4):1602-8. PMID:17308100 doi:10.1158/0008-5472.CAN-06-2870
- ↑ Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol. 2008;40(5):1043-54. doi: 10.1016/j.biocel.2007.11.009., Epub 2007 Nov 29. PMID:18191611 doi:10.1016/j.biocel.2007.11.009
- ↑ Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. PMID:21620138 doi:10.1016/j.cell.2011.03.054
- ↑ Guo C, Linton A, Jalaie M, Kephart S, Ornelas M, Pairish M, Greasley S, Richardson P, Maegley K, Hickey M, Li J, Wu X, Ji X, Xie Z. Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3358-63. doi: 10.1016/j.bmcl.2013.03.090., Epub 2013 Apr 1. PMID:23622982 doi:10.1016/j.bmcl.2013.03.090
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