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| {{STRUCTURE_1njd| PDB=1njd | SCENE= }} | | {{STRUCTURE_1njd| PDB=1njd | SCENE= }} |
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| '''THYMIDYLATE SYNTHASE, MUTATION, N229D WITH 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (DUMP)'''
| | ===THYMIDYLATE SYNTHASE, MUTATION, N229D WITH 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (DUMP)=== |
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| ==Overview==
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| Thymidylate synthase (TS) methylates only dUMP, not dCMP. The crystal structure of TS.dCMP shows sCMP 4-NH2 excluded from the space between Asn-229 and His-199 by the hydrogen bonding and steric properties and Asn-229. Consequently, 6-C of dCMP is over 4 A from the active site sulfhydryl. The Asn-229 side chain is prevented from flipping 180 degrees to and orientation the could hydrogen bond to dCMP by a hydrogen bond network between conserved residues. Thus, the specific binding of dUMP by TS results from occlusion of competing substrates by steric and electronic effects of residues in the active site cavity. When Asn-229 is replaced by a cysteine, the Cys-229 S gamma rotates out of the active site, and the mutant enzyme binds both dCMP and dUMP tightly but does not methylate dCMP. Thus simply admitting dCMP into the dUMP binding site of TS is not sufficient for methylation of dCMP. Structures of nucleotide complexes of TS N229D provide a reasonable explanation for the preferential methylation of dCMP instead of dUMP by this mutant. In TS N229D.dCMP, Asp-229 forms hydrogen bonds to 3-N and 40NH2 of dCMP. Neither the Asp-229 carboxyl moiety nor ordered water appears to hydrogen bond to 4-O of dUMP. Hydrogen bonds to 4-O (or 4-NH2) have been proposed to stabilize reaction intermediates. If their absence in TS N229D.dUMP persists in the ternary complex, it could explain the 10(4)-fold decrease in kcat/Km for dUMP.
| | The line below this paragraph, {{ABSTRACT_PUBMED_8611496}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 8611496 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_8611496}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Nucleotide biosynthesis]] | | [[Category: Nucleotide biosynthesis]] |
| [[Category: Transferase]] | | [[Category: Transferase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:36:09 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 11:49:23 2008'' |