Structure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidin
Abstract The general control non-repressible 5 (GCN5)-related N-acetyltransferase (GNAT) SbzI, in the biosynthesis of the sulfonamide antibiotic altemicidin, catalyzes the transfer of the 2-sulfamoylacetyl (2-SA) moiety onto 6-azatetrahydroindane dinucleotide. While most GNAT superfamily utilize acy...
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| Format: | Article |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55265-z |
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| author | Yuhao Zhu Takahiro Mori Masayuki Karasawa Kohei Shirai Wenjiao Cheng Tohru Terada Takayoshi Awakawa Ikuro Abe |
| author_facet | Yuhao Zhu Takahiro Mori Masayuki Karasawa Kohei Shirai Wenjiao Cheng Tohru Terada Takayoshi Awakawa Ikuro Abe |
| author_sort | Yuhao Zhu |
| collection | DOAJ |
| description | Abstract The general control non-repressible 5 (GCN5)-related N-acetyltransferase (GNAT) SbzI, in the biosynthesis of the sulfonamide antibiotic altemicidin, catalyzes the transfer of the 2-sulfamoylacetyl (2-SA) moiety onto 6-azatetrahydroindane dinucleotide. While most GNAT superfamily utilize acyl-coenzyme A (acyl-CoA) as substrates, SbzI recognizes a carrier-protein (CP)-tethered 2-SA substrate. Moreover, SbzI is the only naturally occurring enzyme that catalyzes the direct incorporation of sulfonamide, a valuable pharmacophore in medicinal chemistry. Here, we present the structure-function analysis and structure-based engineering of SbzI. The crystal structure of SbzI in complex with the CP SbzG, along with cross-linking and isothermal titration calorimetry analyses of their variants, revealed the structural basis for CP recognition by the GNAT SbzI. Furthermore, docking simulation, molecular dynamics simulation, and mutagenesis studies indicated the intimate structural details of the unique reaction mechanism of SbzI, which does not utilize a general base residue in contrast to other typical GNATs. These findings facilitated rational engineering of the enzyme to expand the substrate range and to generate azaindane dinucleotide derivatives. |
| format | Article |
| id | doaj-art-146e742081b445ed9062f44ea6d4351d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-146e742081b445ed9062f44ea6d4351d2025-01-05T12:35:46ZengNature PortfolioNature Communications2041-17232024-12-0115111310.1038/s41467-024-55265-zStructure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidinYuhao Zhu0Takahiro Mori1Masayuki Karasawa2Kohei Shirai3Wenjiao Cheng4Tohru Terada5Takayoshi Awakawa6Ikuro Abe7Graduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Agricultural and Life Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Agricultural and Life Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoGraduate School of Pharmaceutical Sciences, The University of TokyoAbstract The general control non-repressible 5 (GCN5)-related N-acetyltransferase (GNAT) SbzI, in the biosynthesis of the sulfonamide antibiotic altemicidin, catalyzes the transfer of the 2-sulfamoylacetyl (2-SA) moiety onto 6-azatetrahydroindane dinucleotide. While most GNAT superfamily utilize acyl-coenzyme A (acyl-CoA) as substrates, SbzI recognizes a carrier-protein (CP)-tethered 2-SA substrate. Moreover, SbzI is the only naturally occurring enzyme that catalyzes the direct incorporation of sulfonamide, a valuable pharmacophore in medicinal chemistry. Here, we present the structure-function analysis and structure-based engineering of SbzI. The crystal structure of SbzI in complex with the CP SbzG, along with cross-linking and isothermal titration calorimetry analyses of their variants, revealed the structural basis for CP recognition by the GNAT SbzI. Furthermore, docking simulation, molecular dynamics simulation, and mutagenesis studies indicated the intimate structural details of the unique reaction mechanism of SbzI, which does not utilize a general base residue in contrast to other typical GNATs. These findings facilitated rational engineering of the enzyme to expand the substrate range and to generate azaindane dinucleotide derivatives.https://doi.org/10.1038/s41467-024-55265-z |
| spellingShingle | Yuhao Zhu Takahiro Mori Masayuki Karasawa Kohei Shirai Wenjiao Cheng Tohru Terada Takayoshi Awakawa Ikuro Abe Structure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidin Nature Communications |
| title | Structure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidin |
| title_full | Structure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidin |
| title_fullStr | Structure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidin |
| title_full_unstemmed | Structure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidin |
| title_short | Structure-function analysis of carrier protein-dependent 2-sulfamoylacetyl transferase in the biosynthesis of altemicidin |
| title_sort | structure function analysis of carrier protein dependent 2 sulfamoylacetyl transferase in the biosynthesis of altemicidin |
| url | https://doi.org/10.1038/s41467-024-55265-z |
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