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Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function
Identifying novel metabolites and characterizing their biological functions are major challenges of the post-genomic era. X-ray crystallography can reveal unanticipated ligands which persist through purification and crystallization. These adventitious protein:ligand complexes provide insights into n...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895326/ https://www.ncbi.nlm.nih.gov/pubmed/23676670 http://dx.doi.org/10.1038/nature12180 |
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author | Kim, Jungwook Xiao, Hui Bonanno, Jeffrey B. Kalyanaraman, Chakrapani Brown, Shoshana Tang, Xiangying Al-Obaidi, Nawar F. Patskovsky, Yury Babbitt, Patricia C. Jacobson, Matthew P. Lee, Young-Sam Almo, Steven C. |
author_facet | Kim, Jungwook Xiao, Hui Bonanno, Jeffrey B. Kalyanaraman, Chakrapani Brown, Shoshana Tang, Xiangying Al-Obaidi, Nawar F. Patskovsky, Yury Babbitt, Patricia C. Jacobson, Matthew P. Lee, Young-Sam Almo, Steven C. |
author_sort | Kim, Jungwook |
collection | PubMed |
description | Identifying novel metabolites and characterizing their biological functions are major challenges of the post-genomic era. X-ray crystallography can reveal unanticipated ligands which persist through purification and crystallization. These adventitious protein:ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosylmethionine (Cx-SAM), its biosynthetic pathway and its role in tRNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand in the catalytic site consistent with Cx-SAM. Mechanistic analyses demonstrated an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine (ho5U) into 5-oxyacetyl uridine (cmo5U) at the wobble position of multiple tRNAs in Gram negative bacteria(1), resulting in expanded codon-recognition properties(2,3). CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches for identifying ligands in the context of their physiologically relevant macromolecular binding partners and for aiding in functional assignment. |
format | Online Article Text |
id | pubmed-3895326 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-38953262014-01-18 Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function Kim, Jungwook Xiao, Hui Bonanno, Jeffrey B. Kalyanaraman, Chakrapani Brown, Shoshana Tang, Xiangying Al-Obaidi, Nawar F. Patskovsky, Yury Babbitt, Patricia C. Jacobson, Matthew P. Lee, Young-Sam Almo, Steven C. Nature Article Identifying novel metabolites and characterizing their biological functions are major challenges of the post-genomic era. X-ray crystallography can reveal unanticipated ligands which persist through purification and crystallization. These adventitious protein:ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosylmethionine (Cx-SAM), its biosynthetic pathway and its role in tRNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand in the catalytic site consistent with Cx-SAM. Mechanistic analyses demonstrated an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine (ho5U) into 5-oxyacetyl uridine (cmo5U) at the wobble position of multiple tRNAs in Gram negative bacteria(1), resulting in expanded codon-recognition properties(2,3). CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches for identifying ligands in the context of their physiologically relevant macromolecular binding partners and for aiding in functional assignment. 2013-05-15 2013-06-06 /pmc/articles/PMC3895326/ /pubmed/23676670 http://dx.doi.org/10.1038/nature12180 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Kim, Jungwook Xiao, Hui Bonanno, Jeffrey B. Kalyanaraman, Chakrapani Brown, Shoshana Tang, Xiangying Al-Obaidi, Nawar F. Patskovsky, Yury Babbitt, Patricia C. Jacobson, Matthew P. Lee, Young-Sam Almo, Steven C. Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function |
title | Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function |
title_full | Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function |
title_fullStr | Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function |
title_full_unstemmed | Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function |
title_short | Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function |
title_sort | structure-guided discovery of carboxy-sam as a novel metabolite modulating trna function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895326/ https://www.ncbi.nlm.nih.gov/pubmed/23676670 http://dx.doi.org/10.1038/nature12180 |
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