Document Detail


Structural features of 5,10-dideaza-5,6,7,8-tetrahydrofolate that determine inhibition of mammalian glycinamide ribonucleotide formyltransferase.
MedLine Citation:
PMID:  1993209     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have investigated the structural features of 5,10-dideaza-5,6,7,8-tetrahydrofolate (DDATHF) that determine the activity of this compound as an inhibitor of glycinamide ribonucleotide formyltransferase (GARFT) purified from mouse L1210 cells. 5-Deazatetrahydrofolate was as good an inhibitor of GARFT as DDATHF, indicating that isosteric replacement of nitrogen by carbon at the 5-position of tetrahydrofolate is sufficient for inhibition of GARFT. 5,10-Dideazafolic acid, 5,8,10-trideazatetrahydrofolate, and 2-desamino-5,10-dideazatetrahydrofolate were poor inhibitors of GARFT, indicating that a reduced pyridopyrimidine ring, N-8, and the 2-amino group of DDATHF, respectively, play an important role in the binding of tetrahydrofolate analogues to this enzyme. DDATHF analogues in which the phenyl ring was replaced either by a cyclohexyl ring or by methylene groups retained activity as inhibitors. 5,10-Dideazatetrahydrohomofolate was about 6 times more potent as an inhibitor of GARFT than DDATHF, but 5,10-dideazatetrahydronorfolate had about one-fifth of the activity of DDATHF. An analogue of DDATHF in which the glutamic acid side chain was replaced by aspartic acid (which was not a substrate for polyglutamation and was only weakly cytotoxic) was equiactive with DDATHF as an inhibitor of purified GARFT. Surprisingly, 5,10-dideazatetrahydropteroic acid was about as active as DDATHF as an inhibitor of GARFT, an indication that the glutamic acid in the side chain of DDATHF does not play a role in this ligand-enzyme interaction. The polyglutamate derivatives of DDATHF bound up to 100 times tighter to GARFT than DDATHF itself; longer chain polyglutamates conformed to Goldstein's zone B behavior under experimental conditions and were projected to be in zone C, i.e., stoichiometric inhibition, in vivo. We conclude that the presence of carbon at the 5-position of tetrahydrofolate analogues is sufficient for inhibition of GARFT, that N-8 and the 2-amino group are involved in binding of DDATHF to GARFT, probably through hydrogen bonds, and that the structures of the phenyl ring and amino acid side chain of DDATHF analogues are not primary determinants of GARFT inhibition by monoglutamate forms of these compounds. We also conclude that polyglutamation plays a major role in the potent cytotoxicity of DDATHF.
Authors:
S W Baldwin; A Tse; L S Gossett; E C Taylor; A Rosowsky; C Shih; R G Moran
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemistry     Volume:  30     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  1991 Feb 
Date Detail:
Created Date:  1991-03-21     Completed Date:  1991-03-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1997-2006     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033.
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MeSH Terms
Descriptor/Qualifier:
Acyltransferases / antagonists & inhibitors*,  isolation & purification
Animals
Electrophoresis, Polyacrylamide Gel
Folic Acid Antagonists / pharmacology*
Hydroxymethyl and Formyl Transferases*
Kinetics
Leukemia L1210 / enzymology
Mice
Molecular Structure
Molecular Weight
Phosphoribosylglycinamide Formyltransferase
Stereoisomerism
Structure-Activity Relationship
Tetrahydrofolates / pharmacology*
Grant Support
ID/Acronym/Agency:
CA-27605/CA/NCI NIH HHS; CA-42367/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Folic Acid Antagonists; 0/Tetrahydrofolates; 95693-76-8/lometrexol; EC 2.1.2.-/Hydroxymethyl and Formyl Transferases; EC 2.1.2.2/Phosphoribosylglycinamide Formyltransferase; EC 2.3.-/Acyltransferases

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


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