Identification of Key Residues for Urate Specific Transport in Human Glucose Transporter 9 (hSLC2A9)
Human glucose transporter 9 (hSLC2A9) is critical in human urate homeostasis, for which very small deviations can lead to chronic or acute metabolic disorders. Human SLC2A9 is unique in that it transports hexoses as well as the organic anion, urate. This ability is in contrast to other homologous su...
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| description | Human glucose transporter 9 (hSLC2A9) is critical in human urate homeostasis, for which very small deviations can lead to chronic or acute metabolic disorders. Human SLC2A9 is unique in that it transports hexoses as well as the organic anion, urate. This ability is in contrast to other homologous sugar transporters such as glucose transporters 1 and 5 (SLC2A1 & SLC2A5) and the xylose transporter (XylE), despite the fact that these transporters have similar protein structures. Our
in silico
substrate docking study has revealed that urate and fructose bind within the same binding pocket in hSLC2A9, yet with distinct orientations, and allowed us to identify novel residues for urate binding. Our functional studies confirmed that N429 is a key residue for both urate binding and transport. We have shown that cysteine residues, C181, C301 and C459 in hSLC2A9 are also essential elements for mediating urate transport. Additional data from chimæric protein analysis illustrated that transmembrane helix 7 of hSLC2A9 is necessary for urate transport but not sufficient to allow urate transport to be induced in glucose transporter 5 (hSLC2A5). These data indicate that urate transport in hSLC2A9 involves several structural elements rather than just a unique substrate binding pocket. |
| doi_str_mv | 10.1038/srep41167 |
| format | Article |
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in silico
substrate docking study has revealed that urate and fructose bind within the same binding pocket in hSLC2A9, yet with distinct orientations, and allowed us to identify novel residues for urate binding. Our functional studies confirmed that N429 is a key residue for both urate binding and transport. We have shown that cysteine residues, C181, C301 and C459 in hSLC2A9 are also essential elements for mediating urate transport. Additional data from chimæric protein analysis illustrated that transmembrane helix 7 of hSLC2A9 is necessary for urate transport but not sufficient to allow urate transport to be induced in glucose transporter 5 (hSLC2A5). These data indicate that urate transport in hSLC2A9 involves several structural elements rather than just a unique substrate binding pocket.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep41167</identifier><identifier>PMID: 28117388</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/443/272 ; 631/45 ; Animals ; Cysteine ; Cysteine - chemistry ; Cysteine - metabolism ; Data processing ; Fructose ; Fructose - chemistry ; Fructose - metabolism ; Glucose ; Glucose transport ; Glucose Transport Proteins, Facilitative - chemistry ; Glucose Transport Proteins, Facilitative - metabolism ; Glucose transporter ; Homeostasis ; Humanities and Social Sciences ; Humans ; Metabolic disorders ; Molecular Docking Simulation ; multidisciplinary ; Protein Binding ; Protein Structure, Tertiary ; Protein transport ; Residues ; Science ; Sugar ; Uric acid ; Uric Acid - chemistry ; Uric Acid - metabolism ; Xenopus laevis ; Xylose</subject><ispartof>Scientific reports, 2017-01, Vol.7 (1), p.41167-41167, Article 41167</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Jan 2017</rights><rights>Copyright © 2017, The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-caddf879f87d1e7c8f65ef8b73cda37c3940dad2cc3fad048aa6b91082a8182d3</citedby><cites>FETCH-LOGICAL-c438t-caddf879f87d1e7c8f65ef8b73cda37c3940dad2cc3fad048aa6b91082a8182d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259734/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259734/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28117388$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Long, Wentong</creatorcontrib><creatorcontrib>Panigrahi, Rashmi</creatorcontrib><creatorcontrib>Panwar, Pankaj</creatorcontrib><creatorcontrib>Wong, Kenneth</creatorcontrib><creatorcontrib>O′Neill, Debbie</creatorcontrib><creatorcontrib>Chen, Xing-Zhen</creatorcontrib><creatorcontrib>Lemieux, M. Joanne</creatorcontrib><creatorcontrib>Cheeseman, Chris I.</creatorcontrib><title>Identification of Key Residues for Urate Specific Transport in Human Glucose Transporter 9 (hSLC2A9)</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Human glucose transporter 9 (hSLC2A9) is critical in human urate homeostasis, for which very small deviations can lead to chronic or acute metabolic disorders. Human SLC2A9 is unique in that it transports hexoses as well as the organic anion, urate. This ability is in contrast to other homologous sugar transporters such as glucose transporters 1 and 5 (SLC2A1 & SLC2A5) and the xylose transporter (XylE), despite the fact that these transporters have similar protein structures. Our
in silico
substrate docking study has revealed that urate and fructose bind within the same binding pocket in hSLC2A9, yet with distinct orientations, and allowed us to identify novel residues for urate binding. Our functional studies confirmed that N429 is a key residue for both urate binding and transport. We have shown that cysteine residues, C181, C301 and C459 in hSLC2A9 are also essential elements for mediating urate transport. Additional data from chimæric protein analysis illustrated that transmembrane helix 7 of hSLC2A9 is necessary for urate transport but not sufficient to allow urate transport to be induced in glucose transporter 5 (hSLC2A5). These data indicate that urate transport in hSLC2A9 involves several structural elements rather than just a unique substrate binding pocket.</description><subject>631/443/272</subject><subject>631/45</subject><subject>Animals</subject><subject>Cysteine</subject><subject>Cysteine - chemistry</subject><subject>Cysteine - metabolism</subject><subject>Data processing</subject><subject>Fructose</subject><subject>Fructose - chemistry</subject><subject>Fructose - metabolism</subject><subject>Glucose</subject><subject>Glucose transport</subject><subject>Glucose Transport Proteins, Facilitative - chemistry</subject><subject>Glucose Transport Proteins, Facilitative - metabolism</subject><subject>Glucose transporter</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Metabolic disorders</subject><subject>Molecular Docking Simulation</subject><subject>multidisciplinary</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>Protein transport</subject><subject>Residues</subject><subject>Science</subject><subject>Sugar</subject><subject>Uric acid</subject><subject>Uric Acid - chemistry</subject><subject>Uric Acid - metabolism</subject><subject>Xenopus laevis</subject><subject>Xylose</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNplkV1LHDEYhYNUXNG98A9IoDda2DZfM0luCrK0Kl0Q6u51yOZDI7PJNJkR_PeNrN1uayAkcB7O-x4OAGcYfcaIii8lu55h3PIDcEwQa2aEEvJh7z8B01KeUD0NkQzLIzAhAmNOhTgG9ta6OAQfjB5CijB5-MO9wJ-uBDu6An3KcJX14OB978wrB5dZx9KnPMAQ4c240RFed6NJxf2VXIYSXjzeL-bkSl6egkOvu-Kmb-8JWH3_tpzfzBZ317fzq8XMMCqGmdHWesFlvRY7boRvG-fFmlNjNeWGSoastsQY6rVFTGjdriVGgmiBBbH0BHzd-vbjeuOsqcmy7lSfw0bnF5V0UP8qMTyqh_SsGtJITlk1uHgzyOlXjT-oTSjGdZ2OLo1FYdHiFnHEeUU__oc-pTHHGq9SUjLOBSOVutxSJqdSm_K7ZTBSr_WpXX2VPd_ffkf-KasCn7ZAqVJ8cHlv5Du336lfpJs</recordid><startdate>20170124</startdate><enddate>20170124</enddate><creator>Long, Wentong</creator><creator>Panigrahi, Rashmi</creator><creator>Panwar, Pankaj</creator><creator>Wong, Kenneth</creator><creator>O′Neill, Debbie</creator><creator>Chen, Xing-Zhen</creator><creator>Lemieux, M. Joanne</creator><creator>Cheeseman, Chris I.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170124</creationdate><title>Identification of Key Residues for Urate Specific Transport in Human Glucose Transporter 9 (hSLC2A9)</title><author>Long, Wentong ; Panigrahi, Rashmi ; Panwar, Pankaj ; Wong, Kenneth ; O′Neill, Debbie ; Chen, Xing-Zhen ; Lemieux, M. Joanne ; Cheeseman, Chris I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-caddf879f87d1e7c8f65ef8b73cda37c3940dad2cc3fad048aa6b91082a8182d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>631/443/272</topic><topic>631/45</topic><topic>Animals</topic><topic>Cysteine</topic><topic>Cysteine - chemistry</topic><topic>Cysteine - metabolism</topic><topic>Data processing</topic><topic>Fructose</topic><topic>Fructose - chemistry</topic><topic>Fructose - metabolism</topic><topic>Glucose</topic><topic>Glucose transport</topic><topic>Glucose Transport Proteins, Facilitative - chemistry</topic><topic>Glucose Transport Proteins, Facilitative - metabolism</topic><topic>Glucose transporter</topic><topic>Homeostasis</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Metabolic disorders</topic><topic>Molecular Docking Simulation</topic><topic>multidisciplinary</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Protein transport</topic><topic>Residues</topic><topic>Science</topic><topic>Sugar</topic><topic>Uric acid</topic><topic>Uric Acid - chemistry</topic><topic>Uric Acid - metabolism</topic><topic>Xenopus laevis</topic><topic>Xylose</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Long, Wentong</creatorcontrib><creatorcontrib>Panigrahi, Rashmi</creatorcontrib><creatorcontrib>Panwar, Pankaj</creatorcontrib><creatorcontrib>Wong, Kenneth</creatorcontrib><creatorcontrib>O′Neill, Debbie</creatorcontrib><creatorcontrib>Chen, Xing-Zhen</creatorcontrib><creatorcontrib>Lemieux, M. 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Joanne</au><au>Cheeseman, Chris I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Key Residues for Urate Specific Transport in Human Glucose Transporter 9 (hSLC2A9)</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-01-24</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>41167</spage><epage>41167</epage><pages>41167-41167</pages><artnum>41167</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Human glucose transporter 9 (hSLC2A9) is critical in human urate homeostasis, for which very small deviations can lead to chronic or acute metabolic disorders. Human SLC2A9 is unique in that it transports hexoses as well as the organic anion, urate. This ability is in contrast to other homologous sugar transporters such as glucose transporters 1 and 5 (SLC2A1 & SLC2A5) and the xylose transporter (XylE), despite the fact that these transporters have similar protein structures. Our
in silico
substrate docking study has revealed that urate and fructose bind within the same binding pocket in hSLC2A9, yet with distinct orientations, and allowed us to identify novel residues for urate binding. Our functional studies confirmed that N429 is a key residue for both urate binding and transport. We have shown that cysteine residues, C181, C301 and C459 in hSLC2A9 are also essential elements for mediating urate transport. Additional data from chimæric protein analysis illustrated that transmembrane helix 7 of hSLC2A9 is necessary for urate transport but not sufficient to allow urate transport to be induced in glucose transporter 5 (hSLC2A5). These data indicate that urate transport in hSLC2A9 involves several structural elements rather than just a unique substrate binding pocket.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28117388</pmid><doi>10.1038/srep41167</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/443/272 631/45 Animals Cysteine Cysteine - chemistry Cysteine - metabolism Data processing Fructose Fructose - chemistry Fructose - metabolism Glucose Glucose transport Glucose Transport Proteins, Facilitative - chemistry Glucose Transport Proteins, Facilitative - metabolism Glucose transporter Homeostasis Humanities and Social Sciences Humans Metabolic disorders Molecular Docking Simulation multidisciplinary Protein Binding Protein Structure, Tertiary Protein transport Residues Science Sugar Uric acid Uric Acid - chemistry Uric Acid - metabolism Xenopus laevis Xylose |
| title | Identification of Key Residues for Urate Specific Transport in Human Glucose Transporter 9 (hSLC2A9) |
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