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Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites

Thousands of biochemical reactions with characterized activities are “orphan,” meaning they cannot be assigned to a specific enzyme, leaving gaps in metabolic pathways. Novel reactions predicted by pathway-generation tools also lack associated sequences, limiting protein engineering applications. As...

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Detalles Bibliográficos
Autores principales: Hadadi, Noushin, MohammadiPeyhani, Homa, Miskovic, Ljubisa, Seijo, Marianne, Hatzimanikatis, Vassily
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462048/
https://www.ncbi.nlm.nih.gov/pubmed/30910961
http://dx.doi.org/10.1073/pnas.1818877116
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author Hadadi, Noushin
MohammadiPeyhani, Homa
Miskovic, Ljubisa
Seijo, Marianne
Hatzimanikatis, Vassily
author_facet Hadadi, Noushin
MohammadiPeyhani, Homa
Miskovic, Ljubisa
Seijo, Marianne
Hatzimanikatis, Vassily
author_sort Hadadi, Noushin
collection PubMed
description Thousands of biochemical reactions with characterized activities are “orphan,” meaning they cannot be assigned to a specific enzyme, leaving gaps in metabolic pathways. Novel reactions predicted by pathway-generation tools also lack associated sequences, limiting protein engineering applications. Associating orphan and novel reactions with known biochemistry and suggesting enzymes to catalyze them is a daunting problem. We propose the method BridgIT to identify candidate genes and catalyzing proteins for these reactions. This method introduces information about the enzyme binding pocket into reaction-similarity comparisons. BridgIT assesses the similarity of two reactions, one orphan and one well-characterized nonorphan reaction, using their substrate reactive sites, their surrounding structures, and the structures of the generated products to suggest enzymes that catalyze the most-similar nonorphan reactions as candidates for also catalyzing the orphan ones. We performed two large-scale validation studies to test BridgIT predictions against experimental biochemical evidence. For the 234 orphan reactions from the Kyoto Encyclopedia of Genes and Genomes (KEGG) 2011 (a comprehensive enzymatic-reaction database) that became nonorphan in KEGG 2018, BridgIT predicted the exact or a highly related enzyme for 211 of them. Moreover, for 334 of 379 novel reactions in 2014 that were later cataloged in KEGG 2018, BridgIT predicted the exact or highly similar enzymes. BridgIT requires knowledge about only four connecting bonds around the atoms of the reactive sites to correctly annotate proteins for 93% of analyzed enzymatic reactions. Increasing to seven connecting bonds allowed for the accurate identification of a sequence for nearly all known enzymatic reactions.
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spelling pubmed-64620482019-04-16 Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites Hadadi, Noushin MohammadiPeyhani, Homa Miskovic, Ljubisa Seijo, Marianne Hatzimanikatis, Vassily Proc Natl Acad Sci U S A PNAS Plus Thousands of biochemical reactions with characterized activities are “orphan,” meaning they cannot be assigned to a specific enzyme, leaving gaps in metabolic pathways. Novel reactions predicted by pathway-generation tools also lack associated sequences, limiting protein engineering applications. Associating orphan and novel reactions with known biochemistry and suggesting enzymes to catalyze them is a daunting problem. We propose the method BridgIT to identify candidate genes and catalyzing proteins for these reactions. This method introduces information about the enzyme binding pocket into reaction-similarity comparisons. BridgIT assesses the similarity of two reactions, one orphan and one well-characterized nonorphan reaction, using their substrate reactive sites, their surrounding structures, and the structures of the generated products to suggest enzymes that catalyze the most-similar nonorphan reactions as candidates for also catalyzing the orphan ones. We performed two large-scale validation studies to test BridgIT predictions against experimental biochemical evidence. For the 234 orphan reactions from the Kyoto Encyclopedia of Genes and Genomes (KEGG) 2011 (a comprehensive enzymatic-reaction database) that became nonorphan in KEGG 2018, BridgIT predicted the exact or a highly related enzyme for 211 of them. Moreover, for 334 of 379 novel reactions in 2014 that were later cataloged in KEGG 2018, BridgIT predicted the exact or highly similar enzymes. BridgIT requires knowledge about only four connecting bonds around the atoms of the reactive sites to correctly annotate proteins for 93% of analyzed enzymatic reactions. Increasing to seven connecting bonds allowed for the accurate identification of a sequence for nearly all known enzymatic reactions. National Academy of Sciences 2019-04-09 2019-03-25 /pmc/articles/PMC6462048/ /pubmed/30910961 http://dx.doi.org/10.1073/pnas.1818877116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Hadadi, Noushin
MohammadiPeyhani, Homa
Miskovic, Ljubisa
Seijo, Marianne
Hatzimanikatis, Vassily
Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites
title Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites
title_full Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites
title_fullStr Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites
title_full_unstemmed Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites
title_short Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites
title_sort enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462048/
https://www.ncbi.nlm.nih.gov/pubmed/30910961
http://dx.doi.org/10.1073/pnas.1818877116
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