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1a4i

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[[Image:1a4i.gif|left|200px]]<br /><applet load="1a4i" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1a4i, resolution 1.5&Aring;" />
 
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'''HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE'''<br />
 
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==Overview==
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==HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE==
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BACKGROUND: The interconversion of two major folate one-carbon donors occurs through the sequential activities of NAD(P)-dependent methylene[H4]folate dehydrogenase (D) and methenyl[H4]folate cyclohydrolase (C). These activities often coexist as part of a multifunctional enzyme and there are several lines of evidence suggesting that their substrates bind at overlapping sites. Little is known, however, about the nature of this site or the identity of the active-site residues for this enzyme family. RESULTS: We have determined, to 1.5 A resolution, the structure of a dimer of the D/C domain of the human trifunctional cytosolic enzyme with bound NADP cofactor, using the MAD technique. The D/C subunit is composed of two alpha/beta domains that assemble to form a wide cleft. The cleft walls are lined with highly conserved residues and NADP is bound along one wall. The NADP-binding domain has a Rossmann fold, characterized by a modified diphosphate-binding loop fingerprint-GXSXXXG. Dimerization occurs by antiparallel interaction of two NADP-binding domains. Superposition of the two subunits indicates domain motion occurs about a well-defined hinge region. CONCLUSIONS: Analysis of the structure suggests strongly that folate-binding sites for both activities are within the cleft, providing direct support for the proposed overlapping site model. The orientation of the nicotinamide ring suggests that in the dehydrogenase-catalyzed reaction hydride transfer occurs to the pro-R side of the ring. The identity of the cyclohydrolase active site is not obvious. We propose that a conserved motif-Tyr52-X-X-X-Lys56- and/or a Ser49-Gln100-Pro102 triplet have a role in this activity.
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<StructureSection load='1a4i' size='340' side='right'caption='[[1a4i]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1a4i]] 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=1A4I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1A4I FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1a4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1a4i OCA], [https://pdbe.org/1a4i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1a4i RCSB], [https://www.ebi.ac.uk/pdbsum/1a4i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1a4i ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/C1TC_HUMAN C1TC_HUMAN] Defects in MTHFD1 may be a cause of susceptibility to folate-sensitive neural tube defects (FS-NTD) [MIM:[https://omim.org/entry/601634 601634]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Genetic defects in MTHFD1 may affect the risk of spina bifida via the maternal rather than the embryonic genotype.<ref>PMID:9611072</ref> <ref>PMID:12384833</ref> <ref>PMID:16552426</ref> Genetic variation in MTHFD1 could be associated with susceptibility to colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].
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== Function ==
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[https://www.uniprot.org/uniprot/C1TC_HUMAN C1TC_HUMAN]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a4/1a4i_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1a4i ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Abruptio placentae, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=172460 172460]], Spina bifida, folate-sensitive, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=172460 172460]]
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*[[Cyclohydrolase 3D structures|Cyclohydrolase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1A4I 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> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A4I OCA].
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__TOC__
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</StructureSection>
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==Reference==
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The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution., Allaire M, Li Y, MacKenzie RE, Cygler M, Structure. 1998 Feb 15;6(2):173-82. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9519408 9519408]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Allaire, M.]]
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[[Category: Allaire M]]
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[[Category: Cygler, M.]]
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[[Category: Cygler M]]
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[[Category: Li, Y.]]
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[[Category: Li Y]]
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[[Category: Mackenzie, R E.]]
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[[Category: Mackenzie RE]]
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[[Category: NDP]]
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[[Category: bifunctional]]
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[[Category: cyclohydrolase]]
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[[Category: dehydrogenase]]
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[[Category: folate]]
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[[Category: oxidoreductase]]
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[[Category: thf]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:40:51 2008''
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Current revision

HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE

PDB ID 1a4i

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