Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs

The metabolism of 5,10-dideazatetrahydrofolate (DDATHF [lometrexol]) to polyglutamate derivatives by folylpoly-gamma-glutamate synthetase (FPGS) plays a central role in the activity of this compound as an antineoplastic agent. The availability of a series of DDATHF derivatives differing in structure...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Molecular pharmacology 1995-08, Vol.48 (2), p.326-333
Hauptverfasser: Habeck, L L, Mendelsohn, L G, Shih, C, Taylor, E C, Colman, P D, Gossett, L S, Leitner, T A, Schultz, R M, Andis, S L, Moran, R G
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 333
container_issue 2
container_start_page 326
container_title Molecular pharmacology
container_volume 48
creator Habeck, L L
Mendelsohn, L G
Shih, C
Taylor, E C
Colman, P D
Gossett, L S
Leitner, T A
Schultz, R M
Andis, S L
Moran, R G
description The metabolism of 5,10-dideazatetrahydrofolate (DDATHF [lometrexol]) to polyglutamate derivatives by folylpoly-gamma-glutamate synthetase (FPGS) plays a central role in the activity of this compound as an antineoplastic agent. The availability of a series of DDATHF derivatives differing in structure throughout the molecule has allowed a study of the structural requirements for substrate activity with mouse liver and hog liver FPGS. Kinetics of the polyglutamation reaction in vitro have been related to the potency of these compounds as inhibitors of the growth of human CEM leukemic cells. The structure-activity relationships for enzyme from both sources were nearly identical. FPGS from both species showed a broad acceptance for structural changes in the pyridopyrimidine ring, in the phenyl group, and in the intermediate bridge region, with structural changes in these regions being reflected in changes in Km for FPGS but much more modest alterations in Vmax. The data suggested that the phenyl ring was not contributing to any pi-pi hydrophobic interactions. It appeared to function primarily in maintaining a favorable distance between the pyridopyrimidine ring and the glutamate side chain. The lowest Km values were found for DDATHF analogs in which there were small alterations at the 10 position, e.g., 5-deazatetrahydrofolate, 10-methyl-DDATHF, and 10-formyl-5-deazatetrahydrofolate; the first-order rate constants for these substrates were the highest in this series, an indication of the efficiency of polyglutamation at low substrate concentrations. After correction for the intrinsic inhibitory activity of the parent DDATHF analog as an inhibitor of the target enzyme, the first-order rate constants for FPGS were found to be predictive of the potency of tumor cell growth inhibition for most of the compounds in this structural series.
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_77468743</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>77468743</sourcerecordid><originalsourceid>FETCH-LOGICAL-h236t-69294ee755a782e536b9e4218a7472274277cfb1ce61fc66f816bdf668c4550d3</originalsourceid><addsrcrecordid>eNotkE1LxDAURYMo4zj6E4RudGUhSfPVpYhfMOBCBXchbZNpJGlrkiL11xud2by3OOddePcIrBHFqIQIoWOwhhCzUtT04xScxfgJISJUwBVYcUZRxdga2Ne5iSmopIs46dYa29q0FKMpvPJeOauGwoxucVMeOzcn5f_dZUi9TirqTENBbxAsO9tp9ZNpjuuXLoz57s9Vg3LjLp6DE6Nc1BeHvQHvD_dvd0_l9uXx-e52W_a4YqlkNa6J1pxSxQXWtGJNrQlGQnHCMeYEc96aBrWaIdMyZgRiTWcYEy2hFHbVBlzvc6cwfs06JultbLVzatDjHCXnhAlOqixeHsS58bqTU7BehUUeusn8as97u-u_bdBy6lXwqh3zO4skQmJZYVb9AprpcB8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>77468743</pqid></control><display><type>article</type><title>Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Habeck, L L ; Mendelsohn, L G ; Shih, C ; Taylor, E C ; Colman, P D ; Gossett, L S ; Leitner, T A ; Schultz, R M ; Andis, S L ; Moran, R G</creator><creatorcontrib>Habeck, L L ; Mendelsohn, L G ; Shih, C ; Taylor, E C ; Colman, P D ; Gossett, L S ; Leitner, T A ; Schultz, R M ; Andis, S L ; Moran, R G</creatorcontrib><description>The metabolism of 5,10-dideazatetrahydrofolate (DDATHF [lometrexol]) to polyglutamate derivatives by folylpoly-gamma-glutamate synthetase (FPGS) plays a central role in the activity of this compound as an antineoplastic agent. The availability of a series of DDATHF derivatives differing in structure throughout the molecule has allowed a study of the structural requirements for substrate activity with mouse liver and hog liver FPGS. Kinetics of the polyglutamation reaction in vitro have been related to the potency of these compounds as inhibitors of the growth of human CEM leukemic cells. The structure-activity relationships for enzyme from both sources were nearly identical. FPGS from both species showed a broad acceptance for structural changes in the pyridopyrimidine ring, in the phenyl group, and in the intermediate bridge region, with structural changes in these regions being reflected in changes in Km for FPGS but much more modest alterations in Vmax. The data suggested that the phenyl ring was not contributing to any pi-pi hydrophobic interactions. It appeared to function primarily in maintaining a favorable distance between the pyridopyrimidine ring and the glutamate side chain. The lowest Km values were found for DDATHF analogs in which there were small alterations at the 10 position, e.g., 5-deazatetrahydrofolate, 10-methyl-DDATHF, and 10-formyl-5-deazatetrahydrofolate; the first-order rate constants for these substrates were the highest in this series, an indication of the efficiency of polyglutamation at low substrate concentrations. After correction for the intrinsic inhibitory activity of the parent DDATHF analog as an inhibitor of the target enzyme, the first-order rate constants for FPGS were found to be predictive of the potency of tumor cell growth inhibition for most of the compounds in this structural series.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 7651366</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Acyltransferases - antagonists &amp; inhibitors ; Animals ; Cell Division - drug effects ; Hydroxymethyl and Formyl Transferases ; Kinetics ; Leukemia - pathology ; Liver - enzymology ; Mice ; Peptide Synthases - metabolism ; Phosphoribosylglycinamide Formyltransferase ; Substrate Specificity ; Swine ; Tetrahydrofolates - chemistry ; Tetrahydrofolates - metabolism ; Tetrahydrofolates - pharmacology ; Tumor Cells, Cultured</subject><ispartof>Molecular pharmacology, 1995-08, Vol.48 (2), p.326-333</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7651366$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Habeck, L L</creatorcontrib><creatorcontrib>Mendelsohn, L G</creatorcontrib><creatorcontrib>Shih, C</creatorcontrib><creatorcontrib>Taylor, E C</creatorcontrib><creatorcontrib>Colman, P D</creatorcontrib><creatorcontrib>Gossett, L S</creatorcontrib><creatorcontrib>Leitner, T A</creatorcontrib><creatorcontrib>Schultz, R M</creatorcontrib><creatorcontrib>Andis, S L</creatorcontrib><creatorcontrib>Moran, R G</creatorcontrib><title>Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>The metabolism of 5,10-dideazatetrahydrofolate (DDATHF [lometrexol]) to polyglutamate derivatives by folylpoly-gamma-glutamate synthetase (FPGS) plays a central role in the activity of this compound as an antineoplastic agent. The availability of a series of DDATHF derivatives differing in structure throughout the molecule has allowed a study of the structural requirements for substrate activity with mouse liver and hog liver FPGS. Kinetics of the polyglutamation reaction in vitro have been related to the potency of these compounds as inhibitors of the growth of human CEM leukemic cells. The structure-activity relationships for enzyme from both sources were nearly identical. FPGS from both species showed a broad acceptance for structural changes in the pyridopyrimidine ring, in the phenyl group, and in the intermediate bridge region, with structural changes in these regions being reflected in changes in Km for FPGS but much more modest alterations in Vmax. The data suggested that the phenyl ring was not contributing to any pi-pi hydrophobic interactions. It appeared to function primarily in maintaining a favorable distance between the pyridopyrimidine ring and the glutamate side chain. The lowest Km values were found for DDATHF analogs in which there were small alterations at the 10 position, e.g., 5-deazatetrahydrofolate, 10-methyl-DDATHF, and 10-formyl-5-deazatetrahydrofolate; the first-order rate constants for these substrates were the highest in this series, an indication of the efficiency of polyglutamation at low substrate concentrations. After correction for the intrinsic inhibitory activity of the parent DDATHF analog as an inhibitor of the target enzyme, the first-order rate constants for FPGS were found to be predictive of the potency of tumor cell growth inhibition for most of the compounds in this structural series.</description><subject>Acyltransferases - antagonists &amp; inhibitors</subject><subject>Animals</subject><subject>Cell Division - drug effects</subject><subject>Hydroxymethyl and Formyl Transferases</subject><subject>Kinetics</subject><subject>Leukemia - pathology</subject><subject>Liver - enzymology</subject><subject>Mice</subject><subject>Peptide Synthases - metabolism</subject><subject>Phosphoribosylglycinamide Formyltransferase</subject><subject>Substrate Specificity</subject><subject>Swine</subject><subject>Tetrahydrofolates - chemistry</subject><subject>Tetrahydrofolates - metabolism</subject><subject>Tetrahydrofolates - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNotkE1LxDAURYMo4zj6E4RudGUhSfPVpYhfMOBCBXchbZNpJGlrkiL11xud2by3OOddePcIrBHFqIQIoWOwhhCzUtT04xScxfgJISJUwBVYcUZRxdga2Ne5iSmopIs46dYa29q0FKMpvPJeOauGwoxucVMeOzcn5f_dZUi9TirqTENBbxAsO9tp9ZNpjuuXLoz57s9Vg3LjLp6DE6Nc1BeHvQHvD_dvd0_l9uXx-e52W_a4YqlkNa6J1pxSxQXWtGJNrQlGQnHCMeYEc96aBrWaIdMyZgRiTWcYEy2hFHbVBlzvc6cwfs06JultbLVzatDjHCXnhAlOqixeHsS58bqTU7BehUUeusn8as97u-u_bdBy6lXwqh3zO4skQmJZYVb9AprpcB8</recordid><startdate>19950801</startdate><enddate>19950801</enddate><creator>Habeck, L L</creator><creator>Mendelsohn, L G</creator><creator>Shih, C</creator><creator>Taylor, E C</creator><creator>Colman, P D</creator><creator>Gossett, L S</creator><creator>Leitner, T A</creator><creator>Schultz, R M</creator><creator>Andis, S L</creator><creator>Moran, R G</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19950801</creationdate><title>Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs</title><author>Habeck, L L ; Mendelsohn, L G ; Shih, C ; Taylor, E C ; Colman, P D ; Gossett, L S ; Leitner, T A ; Schultz, R M ; Andis, S L ; Moran, R G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h236t-69294ee755a782e536b9e4218a7472274277cfb1ce61fc66f816bdf668c4550d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Acyltransferases - antagonists &amp; inhibitors</topic><topic>Animals</topic><topic>Cell Division - drug effects</topic><topic>Hydroxymethyl and Formyl Transferases</topic><topic>Kinetics</topic><topic>Leukemia - pathology</topic><topic>Liver - enzymology</topic><topic>Mice</topic><topic>Peptide Synthases - metabolism</topic><topic>Phosphoribosylglycinamide Formyltransferase</topic><topic>Substrate Specificity</topic><topic>Swine</topic><topic>Tetrahydrofolates - chemistry</topic><topic>Tetrahydrofolates - metabolism</topic><topic>Tetrahydrofolates - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Habeck, L L</creatorcontrib><creatorcontrib>Mendelsohn, L G</creatorcontrib><creatorcontrib>Shih, C</creatorcontrib><creatorcontrib>Taylor, E C</creatorcontrib><creatorcontrib>Colman, P D</creatorcontrib><creatorcontrib>Gossett, L S</creatorcontrib><creatorcontrib>Leitner, T A</creatorcontrib><creatorcontrib>Schultz, R M</creatorcontrib><creatorcontrib>Andis, S L</creatorcontrib><creatorcontrib>Moran, R G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Habeck, L L</au><au>Mendelsohn, L G</au><au>Shih, C</au><au>Taylor, E C</au><au>Colman, P D</au><au>Gossett, L S</au><au>Leitner, T A</au><au>Schultz, R M</au><au>Andis, S L</au><au>Moran, R G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1995-08-01</date><risdate>1995</risdate><volume>48</volume><issue>2</issue><spage>326</spage><epage>333</epage><pages>326-333</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>The metabolism of 5,10-dideazatetrahydrofolate (DDATHF [lometrexol]) to polyglutamate derivatives by folylpoly-gamma-glutamate synthetase (FPGS) plays a central role in the activity of this compound as an antineoplastic agent. The availability of a series of DDATHF derivatives differing in structure throughout the molecule has allowed a study of the structural requirements for substrate activity with mouse liver and hog liver FPGS. Kinetics of the polyglutamation reaction in vitro have been related to the potency of these compounds as inhibitors of the growth of human CEM leukemic cells. The structure-activity relationships for enzyme from both sources were nearly identical. FPGS from both species showed a broad acceptance for structural changes in the pyridopyrimidine ring, in the phenyl group, and in the intermediate bridge region, with structural changes in these regions being reflected in changes in Km for FPGS but much more modest alterations in Vmax. The data suggested that the phenyl ring was not contributing to any pi-pi hydrophobic interactions. It appeared to function primarily in maintaining a favorable distance between the pyridopyrimidine ring and the glutamate side chain. The lowest Km values were found for DDATHF analogs in which there were small alterations at the 10 position, e.g., 5-deazatetrahydrofolate, 10-methyl-DDATHF, and 10-formyl-5-deazatetrahydrofolate; the first-order rate constants for these substrates were the highest in this series, an indication of the efficiency of polyglutamation at low substrate concentrations. After correction for the intrinsic inhibitory activity of the parent DDATHF analog as an inhibitor of the target enzyme, the first-order rate constants for FPGS were found to be predictive of the potency of tumor cell growth inhibition for most of the compounds in this structural series.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>7651366</pmid><tpages>8</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0026-895X
ispartof Molecular pharmacology, 1995-08, Vol.48 (2), p.326-333
issn 0026-895X
1521-0111
language eng
recordid cdi_proquest_miscellaneous_77468743
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
subjects Acyltransferases - antagonists & inhibitors
Animals
Cell Division - drug effects
Hydroxymethyl and Formyl Transferases
Kinetics
Leukemia - pathology
Liver - enzymology
Mice
Peptide Synthases - metabolism
Phosphoribosylglycinamide Formyltransferase
Substrate Specificity
Swine
Tetrahydrofolates - chemistry
Tetrahydrofolates - metabolism
Tetrahydrofolates - pharmacology
Tumor Cells, Cultured
title Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T15%3A40%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Substrate%20specificity%20of%20mammalian%20folylpolyglutamate%20synthetase%20for%205,10-dideazatetrahydrofolate%20analogs&rft.jtitle=Molecular%20pharmacology&rft.au=Habeck,%20L%20L&rft.date=1995-08-01&rft.volume=48&rft.issue=2&rft.spage=326&rft.epage=333&rft.pages=326-333&rft.issn=0026-895X&rft.eissn=1521-0111&rft_id=info:doi/&rft_dat=%3Cproquest_pubme%3E77468743%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=77468743&rft_id=info:pmid/7651366&rfr_iscdi=true