|
|
| (20 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | [[Image:2c2s.gif|left|200px]]<br /><applet load="2c2s" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2c2s, resolution 1.40Å" /> | |
| - | '''HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, A NOVEL BORON CONTAINING, NONCLASSICAL ANTIFOLATE'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Human Dihydrofolate Reductase Complexed With NADPH and 2,4-Diamino-5-(1-o-carboranylmethyl)-6-methylpyrimidine, A novel boron containing, nonclassical Antifolate== |
| - | Two boron-containing, ortho-icosahedral carborane lipophilic antifolates, were synthesized, and the crystal structures of their ternary complexes, with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine, dinucleotide phosphate were determined. The compounds were screened for, activity against DHFR from six sources (human, rat liver, Pneumocystis, carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei), and showed good to modest activity against these enzymes. The compounds, were also tested for antibacterial activity against L. casei, M., tuberculosis H37Ra, and three M. avium strains and for cytotoxic activity, against seven different human tumor cell lines. Antibacterial and, cytotoxic activity was modest, with one sample, the closo-carborane 4, showing about 10-fold greater activity. The less toxic nido-carborane 2, was also tested as a candidate for boron neutron capture therapy, but, showed poor tumor retention and low selectivity ratios for boron, distribution in tumor tissue versus normal tissue.
| + | <StructureSection load='2c2s' size='340' side='right'caption='[[2c2s]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2c2s]] 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=2C2S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C2S FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=34B:2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE'>34B</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=2c2s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c2s OCA], [https://pdbe.org/2c2s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c2s RCSB], [https://www.ebi.ac.uk/pdbsum/2c2s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c2s ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c2/2c2s_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2c2s ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | ==About this Structure== | + | ==See Also== |
| - | 2C2S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NDP:'>NDP</scene>, <scene name='pdbligand=34B:'>34B</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Known structural/functional Site: <scene name='pdbsite=AC1:Gol Binding Site For Chain B'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C2S OCA].
| + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] |
| - | | + | == References == |
| - | ==Reference==
| + | <references/> |
| - | Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation., Reynolds RC, Campbell SR, Fairchild RG, Kisliuk RL, Micca PL, Queener SF, Riordan JM, Sedwick WD, Waud WR, Leung AK, Dixon RW, Suling WJ, Borhani DW, J Med Chem. 2007 Jul 12;50(14):3283-9. Epub 2007 Jun 15. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17569517 17569517]
| + | __TOC__ |
| - | [[Category: Dihydrofolate reductase]]
| + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Borhani, D.W.]] | + | [[Category: Borhani DW]] |
| - | [[Category: Leung, A.K.W.]] | + | [[Category: Leung AKW]] |
| - | [[Category: Reynolds, R.C.]] | + | [[Category: Reynolds RC]] |
| - | [[Category: Riordan, J.M.]] | + | [[Category: Riordan JM]] |
| - | [[Category: 34B]]
| + | |
| - | [[Category: GOL]]
| + | |
| - | [[Category: NDP]]
| + | |
| - | [[Category: lipophilic antifolates]]
| + | |
| - | [[Category: nadp]]
| + | |
| - | [[Category: nonclassical antifolates]]
| + | |
| - | [[Category: one-carbon metabolism]]
| + | |
| - | [[Category: oxidoreductase]]
| + | |
| - | [[Category: reductase]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:28:03 2008''
| + | |
| Structural highlights
Disease
DYR_HUMAN Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.[1] [2]
Function
DYR_HUMAN Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.[3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
References
- ↑ Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet. 2011 Feb 11;88(2):216-25. doi: 10.1016/j.ajhg.2011.01.004. PMID:21310276 doi:10.1016/j.ajhg.2011.01.004
- ↑ Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011 Feb 11;88(2):226-31. doi: 10.1016/j.ajhg.2011.01.007. PMID:21310277 doi:10.1016/j.ajhg.2011.01.007
- ↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
- ↑ Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW. Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol. 2002 Jul 12;320(3):677-93. PMID:12096917
|
