Histidine triad nucleotide‐binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A
Human histidine triad nucleotide‐binding protein 2 (hHINT2) is an important player in human mitochondrial bioenergetics, but little is known about its catalytic capabilities or its nucleotide phosphoramidate prodrug (proTide)‐activating activity akin to the cytosolic isozyme hHINT1. Here, a similar...
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| Veröffentlicht in: | FEBS letters 2020-05, Vol.594 (10), p.1497-1505 |
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| description | Human histidine triad nucleotide‐binding protein 2 (hHINT2) is an important player in human mitochondrial bioenergetics, but little is known about its catalytic capabilities or its nucleotide phosphoramidate prodrug (proTide)‐activating activity akin to the cytosolic isozyme hHINT1. Here, a similar substrate specificity profile (kcat/Km) for model phosphoramidate substrates was found for hHINT2 but with higher kcat and Km values when compared with hHINT1. A broader pH range for maximum catalytic activity was determined for hHINT2 (pK1 = 6.76 ± 0.16, pK2 = 8.41 ± 0.07). In addition, the known hHINT1‐microphthalmia‐inducing transcription factor‐regulating molecule Ap4A was found to have no detectable binding to HINT1 nor HINT2 by isothermal titration calorimetry. These results demonstrate that despite differences in their sequence and localization, HINT1 and HINT2 have similar nucleotide substrate specificities, which should be considered in future proTide design and in studies of their natural function. |
| doi_str_mv | 10.1002/1873-3468.13745 |
| format | Article |
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Here, a similar substrate specificity profile (kcat/Km) for model phosphoramidate substrates was found for hHINT2 but with higher kcat and Km values when compared with hHINT1. A broader pH range for maximum catalytic activity was determined for hHINT2 (pK1 = 6.76 ± 0.16, pK2 = 8.41 ± 0.07). In addition, the known hHINT1‐microphthalmia‐inducing transcription factor‐regulating molecule Ap4A was found to have no detectable binding to HINT1 nor HINT2 by isothermal titration calorimetry. 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Here, a similar substrate specificity profile (kcat/Km) for model phosphoramidate substrates was found for hHINT2 but with higher kcat and Km values when compared with hHINT1. A broader pH range for maximum catalytic activity was determined for hHINT2 (pK1 = 6.76 ± 0.16, pK2 = 8.41 ± 0.07). In addition, the known hHINT1‐microphthalmia‐inducing transcription factor‐regulating molecule Ap4A was found to have no detectable binding to HINT1 nor HINT2 by isothermal titration calorimetry. These results demonstrate that despite differences in their sequence and localization, HINT1 and HINT2 have similar nucleotide substrate specificities, which should be considered in future proTide design and in studies of their natural function.</description><subject>Ap4A</subject><subject>Biocatalysis</subject><subject>Calorimetry</subject><subject>Dinucleoside Phosphates</subject><subject>hHINT1</subject><subject>hHINT2</subject><subject>Histidine - metabolism</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Mitochondrial Proteins - chemistry</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Nerve Tissue Proteins - chemistry</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>pH profile</subject><subject>phosphoramidate</subject><subject>proTide</subject><subject>Substrate Specificity</subject><issn>0014-5793</issn><issn>1873-3468</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUbtuFDEUtRCILAs1HXJJM4lfY4_LJUrYSFHShNryjq8TI-_MYnuEtssn0PN3fAme3bAtle3j89C9B6GPlJxTQtgF7RRvuJDdOeVKtK_Q4oS8RgtCqGhapfkZepfzd1LfHdVv0RmnWhMu1QL9XodcggsD4JKCdXiY-ghjheDP869NGOrXI96lsUAYMl7f3D1QbAd3uDGcn2wCnMM2RJtwnja5JFsqsoM--NCHEiAf-DGUEgFb78MQyh77MeHyNGsfBxvnkJp0ysarnVi9R2-8jRk-vJxL9O366uFy3dzef725XN02Pe_atvGcKcYFEy2lxFrlPThmHVOO99YTIZkApzutWkI19ER2goFslSRWg3acL9Hno28d88cEuZhtyD3EaAcYp2yqedVKWVOW6OJI7dOYcwJvdilsbdobSszciJn3b-b9m0MjVfHpxXzabMGd-P8qqAR5JPwMEfb_8zPXV1_Y0fkvCriYMA</recordid><startdate>202005</startdate><enddate>202005</enddate><creator>Strom, Alexander</creator><creator>Tong, Cher Ling</creator><creator>Wagner, Carston R.</creator><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><orcidid>https://orcid.org/0000-0001-7927-719X</orcidid></search><sort><creationdate>202005</creationdate><title>Histidine triad nucleotide‐binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A</title><author>Strom, Alexander ; Tong, Cher Ling ; Wagner, Carston R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3855-f327234245110aa7ffed2ad27d3caf04624ed98975019ec06842e65760a9e9d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Ap4A</topic><topic>Biocatalysis</topic><topic>Calorimetry</topic><topic>Dinucleoside Phosphates</topic><topic>hHINT1</topic><topic>hHINT2</topic><topic>Histidine - metabolism</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Mitochondrial Proteins - chemistry</topic><topic>Mitochondrial Proteins - metabolism</topic><topic>Nerve Tissue Proteins - chemistry</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>pH profile</topic><topic>phosphoramidate</topic><topic>proTide</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Strom, Alexander</creatorcontrib><creatorcontrib>Tong, Cher Ling</creatorcontrib><creatorcontrib>Wagner, Carston R.</creatorcontrib><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><jtitle>FEBS letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Strom, Alexander</au><au>Tong, Cher Ling</au><au>Wagner, Carston R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histidine triad nucleotide‐binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A</atitle><jtitle>FEBS letters</jtitle><addtitle>FEBS Lett</addtitle><date>2020-05</date><risdate>2020</risdate><volume>594</volume><issue>10</issue><spage>1497</spage><epage>1505</epage><pages>1497-1505</pages><issn>0014-5793</issn><eissn>1873-3468</eissn><abstract>Human histidine triad nucleotide‐binding protein 2 (hHINT2) is an important player in human mitochondrial bioenergetics, but little is known about its catalytic capabilities or its nucleotide phosphoramidate prodrug (proTide)‐activating activity akin to the cytosolic isozyme hHINT1. Here, a similar substrate specificity profile (kcat/Km) for model phosphoramidate substrates was found for hHINT2 but with higher kcat and Km values when compared with hHINT1. A broader pH range for maximum catalytic activity was determined for hHINT2 (pK1 = 6.76 ± 0.16, pK2 = 8.41 ± 0.07). In addition, the known hHINT1‐microphthalmia‐inducing transcription factor‐regulating molecule Ap4A was found to have no detectable binding to HINT1 nor HINT2 by isothermal titration calorimetry. These results demonstrate that despite differences in their sequence and localization, HINT1 and HINT2 have similar nucleotide substrate specificities, which should be considered in future proTide design and in studies of their natural function.</abstract><cop>England</cop><pmid>31990367</pmid><doi>10.1002/1873-3468.13745</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-7927-719X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Ap4A Biocatalysis Calorimetry Dinucleoside Phosphates hHINT1 hHINT2 Histidine - metabolism Humans Hydrogen-Ion Concentration Mitochondrial Proteins - chemistry Mitochondrial Proteins - metabolism Nerve Tissue Proteins - chemistry Nerve Tissue Proteins - metabolism pH profile phosphoramidate proTide Substrate Specificity |
| title | Histidine triad nucleotide‐binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A |
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