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1a4i

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Revision as of 10:32, 22 December 2014

HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE

Structural highlights

1a4i 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.
Ligands:
Resources:	FirstGlance, OCA, RCSB, PDBsum

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

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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:9519408^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ 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
↑ 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
↑ Allaire M, Li Y, MacKenzie RE, Cygler M. The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution. Structure. 1998 Feb 15;6(2):173-82. PMID:9519408

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1a4i"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1a4i]] is a 2 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1A4I FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1a4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1a4i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1a4i RCSB], [http://www.ebi.ac.uk/pdbsum/1a4i PDBsum]</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=1a4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1a4i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1a4i RCSB], [http://www.ebi.ac.uk/pdbsum/1a4i PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://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:[http://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:[http://omim.org/entry/114500 114500]].
@@ Line 33: / Line 33: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Allaire, M.]]
+[[Category: Allaire, M]]
-[[Category: Cygler, M.]]
+[[Category: Cygler, M]]
-[[Category: Li, Y.]]
+[[Category: Li, Y]]
-[[Category: Mackenzie, R E.]]
+[[Category: Mackenzie, R E]]
 [[Category: Bifunctional]]
 [[Category: Cyclohydrolase]]

1a4i

From Proteopedia

Revision as of 10:32, 22 December 2014

HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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