View source for 6de4


==Homo sapiens dihydrofolate reductase complexed with beta-NADPH and 3'-[(2R)-4-(2,4-diamino-6-ethylphenyl)but-3-yn-2-yl]-5'-methoxy-[1,1'-biphenyl]-4-carboxylic acid==
<StructureSection load='6de4' size='340' side='right'caption='[[6de4]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6de4]] 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=6DE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DE4 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]] 2.411&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=G6Y:3-[(2R)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-5-methoxy[1,1-biphenyl]-4-carboxylic+acid'>G6Y</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6de4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6de4 OCA], [https://pdbe.org/6de4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6de4 RCSB], [https://www.ebi.ac.uk/pdbsum/6de4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6de4 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.

Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.,Hajian B, Scocchera E, Shoen C, Krucinska J, Viswanathan K, G-Dayanandan N, Erlandsen H, Estrada A, Mikusova K, Kordulakova J, Cynamon M, Wright D Cell Chem Biol. 2019 Jun 20;26(6):781-791.e6. doi:, 10.1016/j.chembiol.2019.02.013. Epub 2019 Mar 28. PMID:30930162<ref>PMID:30930162</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6de4" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hajian B]]
[[Category: Wright D]]