Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates
Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and...
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| Veröffentlicht in: | Journal of Biological Chemistry 2004-04, Vol.279 (17), p.18034-18045 |
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| container_title | Journal of Biological Chemistry |
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| creator | Cheong, Cheom-Gil Wolan, Dennis W. Greasley, Samantha E. Horton, Patricia A. Beardsley, G. Peter Wilson, Ian A. |
| description | Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent Ki values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 Å with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn431′ in the reaction mechanism along with previously identified key catalytic residues Lys266 and His267. Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates. |
| doi_str_mv | 10.1074/jbc.M313691200 |
| format | Article |
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Peter ; Wilson, Ian A.</creator><creatorcontrib>Cheong, Cheom-Gil ; Wolan, Dennis W. ; Greasley, Samantha E. ; Horton, Patricia A. ; Beardsley, G. Peter ; Wilson, Ian A. ; Stanford Linear Accelerator Center, Menlo Park, CA (US)Stanford Synchrotron Radiation Laboratory (US)</creatorcontrib><description>Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent Ki values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 Å with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn431′ in the reaction mechanism along with previously identified key catalytic residues Lys266 and His267. Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M313691200</identifier><identifier>PMID: 14966129</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Anions ; Binding Sites ; Catalytic Domain ; CRYSTAL STRUCTURE ; Crystallography, X-Ray ; Electrons ; Enzyme Inhibitors - pharmacology ; ENZYMES ; Humans ; Hydrogen Bonding ; Hydroxymethyl and Formyl Transferases - chemistry ; Kinetics ; MATERIALS SCIENCE ; Models, Chemical ; Models, Molecular ; Molecular Sequence Data ; Multienzyme Complexes - chemistry ; Nucleotide Deaminases - chemistry ; PARTICLE ACCELERATORS ; Protein Binding ; Protein Conformation ; Sequence Homology, Amino Acid ; STANFORD LINEAR ACCELERATOR CENTER ; STANFORD SYNCHROTRON RADIATION LABORATORY ; Substrate Specificity ; Sulfonamides - pharmacology ; SYNCHROTRON RADIATION ; Tetrahydrofolates - pharmacology</subject><ispartof>Journal of Biological Chemistry, 2004-04, Vol.279 (17), p.18034-18045</ispartof><rights>2004 © 2004 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-f04eb19257e19755ba0a44435d018d41417c4118353456888464564ff435ee993</citedby><cites>FETCH-LOGICAL-c435t-f04eb19257e19755ba0a44435d018d41417c4118353456888464564ff435ee993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,885,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14966129$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/831814$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheong, Cheom-Gil</creatorcontrib><creatorcontrib>Wolan, Dennis W.</creatorcontrib><creatorcontrib>Greasley, Samantha E.</creatorcontrib><creatorcontrib>Horton, Patricia A.</creatorcontrib><creatorcontrib>Beardsley, G. Peter</creatorcontrib><creatorcontrib>Wilson, Ian A.</creatorcontrib><creatorcontrib>Stanford Linear Accelerator Center, Menlo Park, CA (US)Stanford Synchrotron Radiation Laboratory (US)</creatorcontrib><title>Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates</title><title>Journal of Biological Chemistry</title><addtitle>J Biol Chem</addtitle><description>Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent Ki values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 Å with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn431′ in the reaction mechanism along with previously identified key catalytic residues Lys266 and His267. Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.</description><subject>Amino Acid Sequence</subject><subject>Anions</subject><subject>Binding Sites</subject><subject>Catalytic Domain</subject><subject>CRYSTAL STRUCTURE</subject><subject>Crystallography, X-Ray</subject><subject>Electrons</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>ENZYMES</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>Hydroxymethyl and Formyl Transferases - chemistry</subject><subject>Kinetics</subject><subject>MATERIALS SCIENCE</subject><subject>Models, Chemical</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Multienzyme Complexes - chemistry</subject><subject>Nucleotide Deaminases - chemistry</subject><subject>PARTICLE ACCELERATORS</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Sequence Homology, Amino Acid</subject><subject>STANFORD LINEAR ACCELERATOR CENTER</subject><subject>STANFORD SYNCHROTRON RADIATION LABORATORY</subject><subject>Substrate Specificity</subject><subject>Sulfonamides - pharmacology</subject><subject>SYNCHROTRON RADIATION</subject><subject>Tetrahydrofolates - pharmacology</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUFv1DAQhSMEotvClSMyEuKWrWfjbJzjEpW2UisqWiRuluNMGleOvdgObfq7-IF4tSv1hC8jj7_3NOOXZR-ALoFW7PShVcvrAop1DStKX2ULoLzIixJ-vc4WlK4gr1clP8qOQ3ig6bAa3mZHwOr1Glb1Ivvb-DlEacht9JOKk8dAXE8uplFa8lX3k1VRO5uAM_s8j0g2o7ZOj7qTz85gznIlfeueZOog-aFbZydl0MXd9c5LG3rnx9nIgKeX1zekmZVxw9x5t2sRbUnjxq3BJ_Ko40BuXEQbye1kemdnkytno9RW23uysVH3SRUxvMve9NIEfH-oJ9nPb2d3zUV-9f38stlc5YoVZcx7yrCFtH-FUFdl2UoqGUtPHQXeMWBQKQbAi7Jg5Zpzztapsr5PCGJdFyfZp72vC1GLoHRENaSRLKooeAEcWGK-7Jmtd78nDFGMOig0Rlp0UxBV8k8oJHC5B5V3IXjsxdbrUfpZABW7LEXKUrxkmQQfD85TO2L3gh_CS8DnPTDo--FRexStdmrAUayqWkAlgNNiNyHfY5i-6o9Gv9sErcIuSdIindP_G-EfOkO8Cw</recordid><startdate>20040423</startdate><enddate>20040423</enddate><creator>Cheong, Cheom-Gil</creator><creator>Wolan, Dennis W.</creator><creator>Greasley, Samantha E.</creator><creator>Horton, Patricia A.</creator><creator>Beardsley, G. Peter</creator><creator>Wilson, Ian A.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20040423</creationdate><title>Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates</title><author>Cheong, Cheom-Gil ; Wolan, Dennis W. ; Greasley, Samantha E. ; Horton, Patricia A. ; Beardsley, G. Peter ; Wilson, Ian A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-f04eb19257e19755ba0a44435d018d41417c4118353456888464564ff435ee993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Amino Acid Sequence</topic><topic>Anions</topic><topic>Binding Sites</topic><topic>Catalytic Domain</topic><topic>CRYSTAL STRUCTURE</topic><topic>Crystallography, X-Ray</topic><topic>Electrons</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>ENZYMES</topic><topic>Humans</topic><topic>Hydrogen Bonding</topic><topic>Hydroxymethyl and Formyl Transferases - chemistry</topic><topic>Kinetics</topic><topic>MATERIALS SCIENCE</topic><topic>Models, Chemical</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Multienzyme Complexes - chemistry</topic><topic>Nucleotide Deaminases - chemistry</topic><topic>PARTICLE ACCELERATORS</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Sequence Homology, Amino Acid</topic><topic>STANFORD LINEAR ACCELERATOR CENTER</topic><topic>STANFORD SYNCHROTRON RADIATION LABORATORY</topic><topic>Substrate Specificity</topic><topic>Sulfonamides - pharmacology</topic><topic>SYNCHROTRON RADIATION</topic><topic>Tetrahydrofolates - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheong, Cheom-Gil</creatorcontrib><creatorcontrib>Wolan, Dennis W.</creatorcontrib><creatorcontrib>Greasley, Samantha E.</creatorcontrib><creatorcontrib>Horton, Patricia A.</creatorcontrib><creatorcontrib>Beardsley, G. Peter</creatorcontrib><creatorcontrib>Wilson, Ian A.</creatorcontrib><creatorcontrib>Stanford Linear Accelerator Center, Menlo Park, CA (US)Stanford Synchrotron Radiation Laboratory (US)</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>Journal of Biological Chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheong, Cheom-Gil</au><au>Wolan, Dennis W.</au><au>Greasley, Samantha E.</au><au>Horton, Patricia A.</au><au>Beardsley, G. Peter</au><au>Wilson, Ian A.</au><aucorp>Stanford Linear Accelerator Center, Menlo Park, CA (US)Stanford Synchrotron Radiation Laboratory (US)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates</atitle><jtitle>Journal of Biological Chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-04-23</date><risdate>2004</risdate><volume>279</volume><issue>17</issue><spage>18034</spage><epage>18045</epage><pages>18034-18045</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent Ki values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 Å with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn431′ in the reaction mechanism along with previously identified key catalytic residues Lys266 and His267. Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>14966129</pmid><doi>10.1074/jbc.M313691200</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of Biological Chemistry, 2004-04, Vol.279 (17), p.18034-18045 |
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| subjects | Amino Acid Sequence Anions Binding Sites Catalytic Domain CRYSTAL STRUCTURE Crystallography, X-Ray Electrons Enzyme Inhibitors - pharmacology ENZYMES Humans Hydrogen Bonding Hydroxymethyl and Formyl Transferases - chemistry Kinetics MATERIALS SCIENCE Models, Chemical Models, Molecular Molecular Sequence Data Multienzyme Complexes - chemistry Nucleotide Deaminases - chemistry PARTICLE ACCELERATORS Protein Binding Protein Conformation Sequence Homology, Amino Acid STANFORD LINEAR ACCELERATOR CENTER STANFORD SYNCHROTRON RADIATION LABORATORY Substrate Specificity Sulfonamides - pharmacology SYNCHROTRON RADIATION Tetrahydrofolates - pharmacology |
| title | Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates |
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