Aldehyde Reductase: The Role of C-Terminal Residues in Defining Substrate and Cofactor Specificities
The only major structural difference between aldehyde reductase, a primarily NADPH-dependent aldo–keto reductase, and aldose reductase, a dually coenzyme-specific (NADPH/NADH) member of the same superfamily, is an additional eight amino acid residues in the substrate/inhibitor binding site (C-termin...
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| Veröffentlicht in: | Archives of biochemistry and biophysics 1998-07, Vol.355 (2), p.137-144 |
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| creator | Rees-Milton, Karen J. Jia, Zongchao Green, Nancy C. Bhatia, Mohit El-Kabbani, Ossama Flynn, T.Geoffrey |
| description | The only major structural difference between aldehyde reductase, a primarily NADPH-dependent aldo–keto reductase, and aldose reductase, a dually coenzyme-specific (NADPH/NADH) member of the same superfamily, is an additional eight amino acid residues in the substrate/inhibitor binding site (C-terminal region) of aldehyde reductase. On the premise that this segment defines the substrate specificity of the enzyme, a mutant of aldehyde reductase lacking residues 306–313 was constructed. In contrast to wild-type enzyme, the mutant enzyme reduced a narrower range of aldehydes and the new substrate specificity was not similar to aldose reductase as might have been predicted. A major change in coenzyme specificity was observed, however, the mutant enzyme being distinctly NADH preferring(Km, NADH= 35 μM, compared to |
| doi_str_mv | 10.1006/abbi.1998.0721 |
| format | Article |
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On the premise that this segment defines the substrate specificity of the enzyme, a mutant of aldehyde reductase lacking residues 306–313 was constructed. In contrast to wild-type enzyme, the mutant enzyme reduced a narrower range of aldehydes and the new substrate specificity was not similar to aldose reductase as might have been predicted. A major change in coenzyme specificity was observed, however, the mutant enzyme being distinctly NADH preferring(Km, NADH= 35 μM, compared to <5 mM for wild-type andKm, NADPH= 670 μM, compared to 35 μM for wild type). Upon analyzing coordinates of aldehyde and aldose reductase, we found that deletion of residues 306–313 may have created a truncated enzyme that retained the three-dimensional structural features of the enzyme's C-terminal segment. The change in substrate specificity could be explained by the new alignment of amino acids. The reversal of coenzyme specificity appeared to be due to a significant backbone shift initiated by the formation of a strong hydrogen bond between Tyr319 and Val300. A similar bond exists in aldose reductase (Tyr309-Ala299). It appears, therefore, that as far as coenzyme specificity is concerned, deletion of residues 306–313 has converted aldehyde reductase into an aldose reductase-like enzyme.</description><identifier>ISSN: 0003-9861</identifier><identifier>EISSN: 1096-0384</identifier><identifier>DOI: 10.1006/abbi.1998.0721</identifier><identifier>PMID: 9675019</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>aldehyde reductase ; Aldehyde Reductase - genetics ; Aldehyde Reductase - metabolism ; Aldehyde Reductase - physiology ; aldose reductase ; Amino Acid Sequence ; Amino Acid Substitution - genetics ; Animals ; Base Sequence ; C-terminus ; Kidney ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; NAD - metabolism ; NADP - metabolism ; Oxidation-Reduction ; Peptide Fragments - genetics ; Peptide Fragments - metabolism ; Peptide Fragments - physiology ; Sequence Homology, Amino Acid ; Structure-Activity Relationship ; substrate specificity ; Substrate Specificity - genetics ; Swine</subject><ispartof>Archives of biochemistry and biophysics, 1998-07, Vol.355 (2), p.137-144</ispartof><rights>1998 Academic Press</rights><rights>Copyright 1998 Academic Press.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c339t-fd9e1cd5113a6bf344aa24f93d98d9c498fd808e49318556f6fe26e4ef113b923</citedby><cites>FETCH-LOGICAL-c339t-fd9e1cd5113a6bf344aa24f93d98d9c498fd808e49318556f6fe26e4ef113b923</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1006/abbi.1998.0721$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9675019$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rees-Milton, Karen J.</creatorcontrib><creatorcontrib>Jia, Zongchao</creatorcontrib><creatorcontrib>Green, Nancy C.</creatorcontrib><creatorcontrib>Bhatia, Mohit</creatorcontrib><creatorcontrib>El-Kabbani, Ossama</creatorcontrib><creatorcontrib>Flynn, T.Geoffrey</creatorcontrib><title>Aldehyde Reductase: The Role of C-Terminal Residues in Defining Substrate and Cofactor Specificities</title><title>Archives of biochemistry and biophysics</title><addtitle>Arch Biochem Biophys</addtitle><description>The only major structural difference between aldehyde reductase, a primarily NADPH-dependent aldo–keto reductase, and aldose reductase, a dually coenzyme-specific (NADPH/NADH) member of the same superfamily, is an additional eight amino acid residues in the substrate/inhibitor binding site (C-terminal region) of aldehyde reductase. On the premise that this segment defines the substrate specificity of the enzyme, a mutant of aldehyde reductase lacking residues 306–313 was constructed. In contrast to wild-type enzyme, the mutant enzyme reduced a narrower range of aldehydes and the new substrate specificity was not similar to aldose reductase as might have been predicted. A major change in coenzyme specificity was observed, however, the mutant enzyme being distinctly NADH preferring(Km, NADH= 35 μM, compared to <5 mM for wild-type andKm, NADPH= 670 μM, compared to 35 μM for wild type). Upon analyzing coordinates of aldehyde and aldose reductase, we found that deletion of residues 306–313 may have created a truncated enzyme that retained the three-dimensional structural features of the enzyme's C-terminal segment. The change in substrate specificity could be explained by the new alignment of amino acids. The reversal of coenzyme specificity appeared to be due to a significant backbone shift initiated by the formation of a strong hydrogen bond between Tyr319 and Val300. A similar bond exists in aldose reductase (Tyr309-Ala299). It appears, therefore, that as far as coenzyme specificity is concerned, deletion of residues 306–313 has converted aldehyde reductase into an aldose reductase-like enzyme.</description><subject>aldehyde reductase</subject><subject>Aldehyde Reductase - genetics</subject><subject>Aldehyde Reductase - metabolism</subject><subject>Aldehyde Reductase - physiology</subject><subject>aldose reductase</subject><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution - genetics</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>C-terminus</subject><subject>Kidney</subject><subject>Kinetics</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutagenesis, Site-Directed</subject><subject>NAD - metabolism</subject><subject>NADP - metabolism</subject><subject>Oxidation-Reduction</subject><subject>Peptide Fragments - genetics</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptide Fragments - physiology</subject><subject>Sequence Homology, Amino Acid</subject><subject>Structure-Activity Relationship</subject><subject>substrate specificity</subject><subject>Substrate Specificity - genetics</subject><subject>Swine</subject><issn>0003-9861</issn><issn>1096-0384</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kF1LwzAUhoMoc05vvRPyB1qTJs0S70b9hIHg5nVIkxMX6dqRdML-vS0b3nl1eHk_ODwI3VKSU0LEvanrkFOlZE7mBT1DU0qUyAiT_BxNCSEsU1LQS3SV0jchlHJRTNBEiXlJqJoit2gcbA4O8Ae4ve1Ngge83gyyawB3HlfZGuI2tKYZEim4PSQcWvwIPrSh_cKrfZ36aHrApnW46ryxfRfxagc2-GBDHyBdowtvmgQ3pztDn89P6-o1W76_vFWLZWYZU33mnQJqXUkpM6L2jHNjCu4Vc0o6ZbmS3kkigStGZVkKLzwUAjj4oVGrgs1Qfty1sUspgte7GLYmHjQleqSlR1p6pKVHWkPh7ljY7estuL_4Cc_gy6MPw9c_AaJONkBrwYUItteuC_9N_wKvN3lG</recordid><startdate>19980715</startdate><enddate>19980715</enddate><creator>Rees-Milton, Karen J.</creator><creator>Jia, Zongchao</creator><creator>Green, Nancy C.</creator><creator>Bhatia, Mohit</creator><creator>El-Kabbani, Ossama</creator><creator>Flynn, T.Geoffrey</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>19980715</creationdate><title>Aldehyde Reductase: The Role of C-Terminal Residues in Defining Substrate and Cofactor Specificities</title><author>Rees-Milton, Karen J. ; Jia, Zongchao ; Green, Nancy C. ; Bhatia, Mohit ; El-Kabbani, Ossama ; Flynn, T.Geoffrey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c339t-fd9e1cd5113a6bf344aa24f93d98d9c498fd808e49318556f6fe26e4ef113b923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>aldehyde reductase</topic><topic>Aldehyde Reductase - genetics</topic><topic>Aldehyde Reductase - metabolism</topic><topic>Aldehyde Reductase - physiology</topic><topic>aldose reductase</topic><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution - genetics</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>C-terminus</topic><topic>Kidney</topic><topic>Kinetics</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutagenesis, Site-Directed</topic><topic>NAD - metabolism</topic><topic>NADP - metabolism</topic><topic>Oxidation-Reduction</topic><topic>Peptide Fragments - genetics</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptide Fragments - physiology</topic><topic>Sequence Homology, Amino Acid</topic><topic>Structure-Activity Relationship</topic><topic>substrate specificity</topic><topic>Substrate Specificity - genetics</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rees-Milton, Karen J.</creatorcontrib><creatorcontrib>Jia, Zongchao</creatorcontrib><creatorcontrib>Green, Nancy C.</creatorcontrib><creatorcontrib>Bhatia, Mohit</creatorcontrib><creatorcontrib>El-Kabbani, Ossama</creatorcontrib><creatorcontrib>Flynn, T.Geoffrey</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Archives of biochemistry and biophysics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rees-Milton, Karen J.</au><au>Jia, Zongchao</au><au>Green, Nancy C.</au><au>Bhatia, Mohit</au><au>El-Kabbani, Ossama</au><au>Flynn, T.Geoffrey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aldehyde Reductase: The Role of C-Terminal Residues in Defining Substrate and Cofactor Specificities</atitle><jtitle>Archives of biochemistry and biophysics</jtitle><addtitle>Arch Biochem Biophys</addtitle><date>1998-07-15</date><risdate>1998</risdate><volume>355</volume><issue>2</issue><spage>137</spage><epage>144</epage><pages>137-144</pages><issn>0003-9861</issn><eissn>1096-0384</eissn><abstract>The only major structural difference between aldehyde reductase, a primarily NADPH-dependent aldo–keto reductase, and aldose reductase, a dually coenzyme-specific (NADPH/NADH) member of the same superfamily, is an additional eight amino acid residues in the substrate/inhibitor binding site (C-terminal region) of aldehyde reductase. On the premise that this segment defines the substrate specificity of the enzyme, a mutant of aldehyde reductase lacking residues 306–313 was constructed. In contrast to wild-type enzyme, the mutant enzyme reduced a narrower range of aldehydes and the new substrate specificity was not similar to aldose reductase as might have been predicted. A major change in coenzyme specificity was observed, however, the mutant enzyme being distinctly NADH preferring(Km, NADH= 35 μM, compared to <5 mM for wild-type andKm, NADPH= 670 μM, compared to 35 μM for wild type). Upon analyzing coordinates of aldehyde and aldose reductase, we found that deletion of residues 306–313 may have created a truncated enzyme that retained the three-dimensional structural features of the enzyme's C-terminal segment. The change in substrate specificity could be explained by the new alignment of amino acids. The reversal of coenzyme specificity appeared to be due to a significant backbone shift initiated by the formation of a strong hydrogen bond between Tyr319 and Val300. A similar bond exists in aldose reductase (Tyr309-Ala299). It appears, therefore, that as far as coenzyme specificity is concerned, deletion of residues 306–313 has converted aldehyde reductase into an aldose reductase-like enzyme.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>9675019</pmid><doi>10.1006/abbi.1998.0721</doi><tpages>8</tpages></addata></record> |
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| subjects | aldehyde reductase Aldehyde Reductase - genetics Aldehyde Reductase - metabolism Aldehyde Reductase - physiology aldose reductase Amino Acid Sequence Amino Acid Substitution - genetics Animals Base Sequence C-terminus Kidney Kinetics Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed NAD - metabolism NADP - metabolism Oxidation-Reduction Peptide Fragments - genetics Peptide Fragments - metabolism Peptide Fragments - physiology Sequence Homology, Amino Acid Structure-Activity Relationship substrate specificity Substrate Specificity - genetics Swine |
| title | Aldehyde Reductase: The Role of C-Terminal Residues in Defining Substrate and Cofactor Specificities |
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