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[[Image:1dib.gif|left|200px]]<br /><applet load="1dib" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1dib, resolution 2.7&Aring;" />
'''HUMAN METHYLENETETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE COMPLEXED WITH NADP AND INHIBITOR LY345899'''<br />


==Overview==
==HUMAN METHYLENETETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE COMPLEXED WITH NADP AND INHIBITOR LY345899==
Enzymes involved in tetrahydrofolate metabolism are of particular pharmaceutical interest, as their function is crucial for amino acid and DNA biosynthesis. The crystal structure of the human cytosolic methylenetetrahydrofolate dehydrogenase/cyclohydrolase (DC301) domain of a trifunctional enzyme has been determined previously with a bound NADP cofactor. While the substrate binding site was identified to be localized in a deep and rather hydrophobic cleft at the interface between two protein domains, the unambiguous assignment of catalytic residues was not possible. We succeeded in determining the crystal structures of three ternary DC301/NADP/inhibitor complexes. Investigation of these structures followed by site-directed mutagenesis studies allowed identification of the amino acids involved in catalysis by both enzyme activities. The inhibitors bind close to Lys56 and Tyr52, residues of a strictly conserved motif for active sites in dehydrogenases. While Lys56 is in a good position for chemical interaction with the substrate analogue, Tyr52 was found stacking against the inhibitors' aromatic rings and hence seems to be more important for proper positioning of the ligand than for catalysis. Also, Ser49 and/or Cys147 were found to possibly act as an activator for water in the cyclohydrolase step. These and the other residues (Gln100 and Asp125), with which contacts are made, are strictly conserved in THF dehydrogenases. On the basis of structural and mutagenesis data, we propose a reaction mechanism for both activities, the dehydrogenase and the cyclohydrolase.
<StructureSection load='1dib' size='340' side='right'caption='[[1dib]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1dib]] 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=1DIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DIB 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]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L34:4-(7-AMINO-9-HYDROXY-1-OXO-3,3A,4,5-TETRAHYDRO-2,5,6,8,9B-PENTAAZA-CYCLOPENTA[A]NAPHTHALEN-2-YL)-PHENYLCARBONYL-GLUTAMIC+ACID'>L34</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=1dib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dib OCA], [https://pdbe.org/1dib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dib RCSB], [https://www.ebi.ac.uk/pdbsum/1dib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dib ProSAT]</span></td></tr>
</table>
== Disease ==
[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].
== Function ==
[https://www.uniprot.org/uniprot/C1TC_HUMAN C1TC_HUMAN]
== 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/di/1dib_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=1dib ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
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]]
*[[Cyclohydrolase 3D structures|Cyclohydrolase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1DIB 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=NAP:'>NAP</scene> and <scene name='pdbligand=L34:'>L34</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DIB OCA].
__TOC__
 
</StructureSection>
==Reference==
Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase., Schmidt A, Wu H, MacKenzie RE, Chen VJ, Bewly JR, Ray JE, Toth JE, Cygler M, Biochemistry. 2000 May 30;39(21):6325-35. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10828945 10828945]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Bewly, J R.]]
[[Category: Bewly JR]]
[[Category: Chen, V J.]]
[[Category: Chen VJ]]
[[Category: Cygler, M.]]
[[Category: Cygler M]]
[[Category: MacKenzie, R E.]]
[[Category: MacKenzie RE]]
[[Category: Ray, J E.]]
[[Category: Ray JE]]
[[Category: Schmidt, A.]]
[[Category: Schmidt A]]
[[Category: Toth, J E.]]
[[Category: Toth JE]]
[[Category: Wu, H.]]
[[Category: Wu H]]
[[Category: L34]]
[[Category: NAP]]
[[Category: cyclohydrolase]]
[[Category: dehydrogenase]]
[[Category: inhibitor]]
[[Category: nadp]]
[[Category: rossmann fold]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:16:49 2008''

Latest revision as of 09:54, 7 February 2024

HUMAN METHYLENETETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE COMPLEXED WITH NADP AND INHIBITOR LY345899HUMAN METHYLENETETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE COMPLEXED WITH NADP AND INHIBITOR LY345899

Structural highlights

1dib is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

C1TC_HUMAN Defects in MTHFD1 may be a cause of susceptibility to folate-sensitive neural tube defects (FS-NTD) [MIM: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.[1] [2] [3] Genetic variation in MTHFD1 could be associated with susceptibility to colorectal cancer (CRC) [MIM:114500.

Function

C1TC_HUMAN

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

  1. ↑ Hol FA, van der Put NM, Geurds MP, Heil SG, Trijbels FJ, Hamel BC, Mariman EC, Blom HJ. Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin Genet. 1998 Feb;53(2):119-25. PMID:9611072
  2. ↑ Brody LC, Conley M, Cox C, Kirke PN, McKeever MP, Mills JL, Molloy AM, O'Leary VB, Parle-McDermott A, Scott JM, Swanson DA. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet. 2002 Nov;71(5):1207-15. Epub 2002 Oct 16. PMID:12384833 doi:S0002-9297(07)60415-7
  3. ↑ Parle-McDermott A, Kirke PN, Mills JL, Molloy AM, Cox C, O'Leary VB, Pangilinan F, Conley M, Cleary L, Brody LC, Scott JM. Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet. 2006 Jun;14(6):768-72. PMID:16552426 doi:5201603

1dib, resolution 2.70Å

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