Immune Versus Natural Selection: Antibody Aldolases with Enzymic Rates But Broader Scope
Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibodies are much more accepting of a wide range of substrates. The catalytic antibodies were prepar...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 1997-12, Vol.278 (5346), p.2085-2092 |
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| container_title | Science (American Association for the Advancement of Science) |
| container_volume | 278 |
| creator | Barbas, Carlos F. Heine, Andreas Zhong, Guofu Hoffmann, Torsten Gramatikova, Svetlana Björnestedt, Robert List, Benjamin Anderson, James Stura, Enrico A. Wilson, Ian A. Lerner, Richard A. |
| description | Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibodies are much more accepting of a wide range of substrates. The catalytic antibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple binding to chemical reactivity. This process yielded aldolase catalytic antibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody aldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reactive lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pK$_a$. |
| doi_str_mv | 10.1126/science.278.5346.2085 |
| format | Article |
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The catalytic antibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple binding to chemical reactivity. This process yielded aldolase catalytic antibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody aldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reactive lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pK$_a$.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.278.5346.2085</identifier><identifier>PMID: 9405338</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Society for the Advancement of Science</publisher><subject>Active sites ; Amino acids ; Animals ; Antibodies ; Antibodies, Catalytic - chemistry ; Antibodies, Catalytic - immunology ; Antibodies, Catalytic - metabolism ; Binding Sites ; Biochemistry ; Biological and medical sciences ; Biotechnology ; Catalysis ; Catalysts ; Catalytic antibodies ; Chemistry ; Crystallography, X-Ray ; Decarboxylation ; Enzyme synthesis ; Enzymes ; Evolution, Molecular ; Fructose-Bisphosphate Aldolase - chemistry ; Fructose-Bisphosphate Aldolase - immunology ; Fructose-Bisphosphate Aldolase - metabolism ; Fundamental and applied biological sciences. Psychology ; Glycolysis ; Hydrogen-Ion Concentration ; Immune response ; Immune response regulation ; Immune system ; Immunization ; Immunoglobulin Fab Fragments - chemistry ; Immunoglobulin Fab Fragments - immunology ; Immunoglobulin Fab Fragments - metabolism ; Ketones ; Kinetics ; Lysine - chemistry ; Lysine - metabolism ; Methods. Procedures. Technologies ; Mice ; Models, Molecular ; Molecules ; Organic Chemistry ; Physiological aspects ; Protein Conformation ; Protein engineering ; Pyridoxal - metabolism ; Reactivity ; Regulation ; Reprography ; Selection Criteria ; Selection, Genetic ; Substrate Specificity ; Synthesis</subject><ispartof>Science (American Association for the Advancement of Science), 1997-12, Vol.278 (5346), p.2085-2092</ispartof><rights>Copyright 1997 American Association for the Advancement of Science</rights><rights>1998 INIST-CNRS</rights><rights>COPYRIGHT 1997 American Association for the Advancement of Science</rights><rights>COPYRIGHT 1997 American Association for the Advancement of Science</rights><rights>Copyright American Association for the Advancement of Science Dec 19, 1997</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c656t-319f504be76b63c5743687b39e98ee92a0c4265243ec82d2110b2589d5db744e3</citedby><cites>FETCH-LOGICAL-c656t-319f504be76b63c5743687b39e98ee92a0c4265243ec82d2110b2589d5db744e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2893935$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2893935$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>315,781,785,804,2885,2886,27928,27929,58021,58254</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2116387$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9405338$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barbas, Carlos F.</creatorcontrib><creatorcontrib>Heine, Andreas</creatorcontrib><creatorcontrib>Zhong, Guofu</creatorcontrib><creatorcontrib>Hoffmann, Torsten</creatorcontrib><creatorcontrib>Gramatikova, Svetlana</creatorcontrib><creatorcontrib>Björnestedt, Robert</creatorcontrib><creatorcontrib>List, Benjamin</creatorcontrib><creatorcontrib>Anderson, James</creatorcontrib><creatorcontrib>Stura, Enrico A.</creatorcontrib><creatorcontrib>Wilson, Ian A.</creatorcontrib><creatorcontrib>Lerner, Richard A.</creatorcontrib><title>Immune Versus Natural Selection: Antibody Aldolases with Enzymic Rates But Broader Scope</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibodies are much more accepting of a wide range of substrates. 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This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pK$_a$.</description><subject>Active sites</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Catalytic - chemistry</subject><subject>Antibodies, Catalytic - immunology</subject><subject>Antibodies, Catalytic - metabolism</subject><subject>Binding Sites</subject><subject>Biochemistry</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Catalysis</subject><subject>Catalysts</subject><subject>Catalytic antibodies</subject><subject>Chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Decarboxylation</subject><subject>Enzyme synthesis</subject><subject>Enzymes</subject><subject>Evolution, Molecular</subject><subject>Fructose-Bisphosphate Aldolase - chemistry</subject><subject>Fructose-Bisphosphate Aldolase - immunology</subject><subject>Fructose-Bisphosphate Aldolase - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glycolysis</subject><subject>Hydrogen-Ion Concentration</subject><subject>Immune response</subject><subject>Immune response regulation</subject><subject>Immune system</subject><subject>Immunization</subject><subject>Immunoglobulin Fab Fragments - chemistry</subject><subject>Immunoglobulin Fab Fragments - immunology</subject><subject>Immunoglobulin Fab Fragments - metabolism</subject><subject>Ketones</subject><subject>Kinetics</subject><subject>Lysine - chemistry</subject><subject>Lysine - metabolism</subject><subject>Methods. Procedures. Technologies</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Molecules</subject><subject>Organic Chemistry</subject><subject>Physiological aspects</subject><subject>Protein Conformation</subject><subject>Protein engineering</subject><subject>Pyridoxal - metabolism</subject><subject>Reactivity</subject><subject>Regulation</subject><subject>Reprography</subject><subject>Selection Criteria</subject><subject>Selection, Genetic</subject><subject>Substrate Specificity</subject><subject>Synthesis</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqN0l2r0zAYB_AiynEe_QYeKCLixenMS9Mm3m3jOAfjDJwevAtp-nR2tM1MUnR-ejNWjkx2MXIRyPPLC0_-UXSD0Rhjkn1wuoZOw5jkfMxomo0J4uxJNMJIsEQQRJ9GI4RolnCUs-fRC-e2CIWaoFfRlUgRo5SPou-Ltu07iB_Aut7F98r3VjXxGhrQvjbdx3jS-bow5T6eNKVplAMX_6r9j_iu-7Nvax1_UT4sTXsfT61RJdh4rc0OXkbPKtU4eDXM19G3T3dfZ5-T5Wq-mE2Wic5Y5hOKRcVQWkCeFRnVLE9pxvOCChAcQBCFdEoyRlIKmpOSYIwKwrgoWVnkaQr0Onp3PHdnzc8enJdt7TQ0jerA9E7ijBAuOA7wzX9wa3rbhbdJginLc454QLdHtFENyLqrjLdKb6CD0BXTQVWH5QlBGGWUk8CTMzyMEkJrzvn3Jz4QD7_9RvXOycX6_mK6eriYTueXUj5fntDbc1SbpoENyPCJs9UJZ0eurXHOQiV3tm6V3UuM5CGwcgisDIGVh8DKQ2DDvpvhW_qihfJx15DQUH871JXTqqms6nTtHlkIRLg-D-z1kW2dN_ZfmQsqKKN_AQuo948</recordid><startdate>19971219</startdate><enddate>19971219</enddate><creator>Barbas, Carlos F.</creator><creator>Heine, Andreas</creator><creator>Zhong, Guofu</creator><creator>Hoffmann, Torsten</creator><creator>Gramatikova, Svetlana</creator><creator>Björnestedt, Robert</creator><creator>List, Benjamin</creator><creator>Anderson, James</creator><creator>Stura, Enrico A.</creator><creator>Wilson, Ian A.</creator><creator>Lerner, Richard A.</creator><general>American Society for the Advancement of Science</general><general>American Association for the Advancement of Science</general><general>The American Association for the Advancement of Science</general><scope>IQODW</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>8GL</scope><scope>IBG</scope><scope>IOV</scope><scope>ISN</scope><scope>0-V</scope><scope>3V.</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88B</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8BQ</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ALSLI</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>CJNVE</scope><scope>D1I</scope><scope>DWQXO</scope><scope>F28</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>HCIFZ</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9-</scope><scope>K9.</scope><scope>KB.</scope><scope>KR7</scope><scope>L6V</scope><scope>L7M</scope><scope>LK8</scope><scope>L~C</scope><scope>L~D</scope><scope>M0K</scope><scope>M0P</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEDU</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>7T5</scope></search><sort><creationdate>19971219</creationdate><title>Immune Versus Natural Selection: Antibody Aldolases with Enzymic Rates But Broader Scope</title><author>Barbas, Carlos F. ; Heine, Andreas ; Zhong, Guofu ; Hoffmann, Torsten ; Gramatikova, Svetlana ; Björnestedt, Robert ; List, Benjamin ; Anderson, James ; Stura, Enrico A. ; Wilson, Ian A. ; Lerner, Richard A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c656t-319f504be76b63c5743687b39e98ee92a0c4265243ec82d2110b2589d5db744e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Active sites</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antibodies, Catalytic - chemistry</topic><topic>Antibodies, Catalytic - immunology</topic><topic>Antibodies, Catalytic - metabolism</topic><topic>Binding Sites</topic><topic>Biochemistry</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Catalysis</topic><topic>Catalysts</topic><topic>Catalytic antibodies</topic><topic>Chemistry</topic><topic>Crystallography, X-Ray</topic><topic>Decarboxylation</topic><topic>Enzyme synthesis</topic><topic>Enzymes</topic><topic>Evolution, Molecular</topic><topic>Fructose-Bisphosphate Aldolase - chemistry</topic><topic>Fructose-Bisphosphate Aldolase - immunology</topic><topic>Fructose-Bisphosphate Aldolase - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glycolysis</topic><topic>Hydrogen-Ion Concentration</topic><topic>Immune response</topic><topic>Immune response regulation</topic><topic>Immune system</topic><topic>Immunization</topic><topic>Immunoglobulin Fab Fragments - chemistry</topic><topic>Immunoglobulin Fab Fragments - immunology</topic><topic>Immunoglobulin Fab Fragments - metabolism</topic><topic>Ketones</topic><topic>Kinetics</topic><topic>Lysine - chemistry</topic><topic>Lysine - metabolism</topic><topic>Methods. Procedures. Technologies</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Molecules</topic><topic>Organic Chemistry</topic><topic>Physiological aspects</topic><topic>Protein Conformation</topic><topic>Protein engineering</topic><topic>Pyridoxal - metabolism</topic><topic>Reactivity</topic><topic>Regulation</topic><topic>Reprography</topic><topic>Selection Criteria</topic><topic>Selection, Genetic</topic><topic>Substrate Specificity</topic><topic>Synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barbas, Carlos F.</creatorcontrib><creatorcontrib>Heine, Andreas</creatorcontrib><creatorcontrib>Zhong, Guofu</creatorcontrib><creatorcontrib>Hoffmann, Torsten</creatorcontrib><creatorcontrib>Gramatikova, Svetlana</creatorcontrib><creatorcontrib>Björnestedt, Robert</creatorcontrib><creatorcontrib>List, Benjamin</creatorcontrib><creatorcontrib>Anderson, James</creatorcontrib><creatorcontrib>Stura, Enrico 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The catalytic antibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple binding to chemical reactivity. This process yielded aldolase catalytic antibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody aldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reactive lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pK$_a$.</abstract><cop>Washington, DC</cop><pub>American Society for the Advancement of Science</pub><pmid>9405338</pmid><doi>10.1126/science.278.5346.2085</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 1997-12, Vol.278 (5346), p.2085-2092 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_16228981 |
| source | MEDLINE; Science Magazine; Jstor Complete Legacy |
| subjects | Active sites Amino acids Animals Antibodies Antibodies, Catalytic - chemistry Antibodies, Catalytic - immunology Antibodies, Catalytic - metabolism Binding Sites Biochemistry Biological and medical sciences Biotechnology Catalysis Catalysts Catalytic antibodies Chemistry Crystallography, X-Ray Decarboxylation Enzyme synthesis Enzymes Evolution, Molecular Fructose-Bisphosphate Aldolase - chemistry Fructose-Bisphosphate Aldolase - immunology Fructose-Bisphosphate Aldolase - metabolism Fundamental and applied biological sciences. Psychology Glycolysis Hydrogen-Ion Concentration Immune response Immune response regulation Immune system Immunization Immunoglobulin Fab Fragments - chemistry Immunoglobulin Fab Fragments - immunology Immunoglobulin Fab Fragments - metabolism Ketones Kinetics Lysine - chemistry Lysine - metabolism Methods. Procedures. Technologies Mice Models, Molecular Molecules Organic Chemistry Physiological aspects Protein Conformation Protein engineering Pyridoxal - metabolism Reactivity Regulation Reprography Selection Criteria Selection, Genetic Substrate Specificity Synthesis |
| title | Immune Versus Natural Selection: Antibody Aldolases with Enzymic Rates But Broader Scope |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-17T03%3A02%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Immune%20Versus%20Natural%20Selection:%20Antibody%20Aldolases%20with%20Enzymic%20Rates%20But%20Broader%20Scope&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Barbas,%20Carlos%20F.&rft.date=1997-12-19&rft.volume=278&rft.issue=5346&rft.spage=2085&rft.epage=2092&rft.pages=2085-2092&rft.issn=0036-8075&rft.eissn=1095-9203&rft.coden=SCIEAS&rft_id=info:doi/10.1126/science.278.5346.2085&rft_dat=%3Cgale_proqu%3EA20106382%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=213577808&rft_id=info:pmid/9405338&rft_galeid=A20106382&rft_jstor_id=2893935&rfr_iscdi=true |