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Discovery of new enzymes and metabolic pathways by using structure and genome context

Suwen Zhao, Ritesh Kumar, Ayano Sakai, Matthew W. Vetting, B. McKay Wood, Shoshana Brown, Jeffery B. Bonanno, Brandan S. Hillerich, Ronald D. Seidel, Patricia C. Babbitt, Steven C. Almo, Jonathan V. Sweedler (+3 others)
2013 Nature  
We, and others 2 , are developing computation-guided strategies for functional discovery using "metabolite docking" to 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: . wrote the paper.  ...  Acknowledgments This research was supported by cooperative agreements from the US National Institutes of Health (U54GM093342) (U54GM074945 and U54GM094662).  ... 
doi:10.1038/nature12576 pmid:24056934 pmcid:PMC3966649 fatcat:ccvtzckdcnajbfz7j6vowccc34

Metabolic pathway analysis in trypanosomes and malaria parasites

2002 Philosophical Transactions of the Royal Society of London. Biological Sciences  
Analysis of metabolic pathways provides a useful conceptual framework for the identification of potential drug targets and also for improving our understanding of microbial responses to nutritional, chemical  ...  Identification of novel drug targets is required for the development of new classes of drugs to overcome drug resistance and replace less efficacious treatments.  ...  Figure 2 . 2 Metabolic pathway analysis for: (a) whole genome; (b) generic metabolome; (c) context-specific metabolome. Individual metabolites are indicated by circles and enzymes by lozenges.  ... 
doi:10.1098/rstb.2001.1040 pmid:11839187 pmcid:PMC1692913 fatcat:iuxkooyasrax5bahm3q7l3c3pq

Genomic Enzymology: Web Tools for Leveraging Protein Family Sequence–Function Space and Genome Context to Discover Novel Functions

John A. Gerlt
2017 Biochemistry  
However, many novel enzymes with interesting mechanisms participate in uncharacterized small-molecule metabolic pathways; their discovery and functional characterization also can be accomplished by leveraging  ...  Web tools that allow identification of biosynthetic gene clusters are widely used by the natural products/synthetic biology community, thereby facilitating the discovery of novel natural products and the  ...  We suggested the term genomic enzymology to describe the expansive strategy of using protein families and genome context to focus studies of enzyme mechanisms, discover new functions, and more accurately  ... 
doi:10.1021/acs.biochem.7b00614 pmid:28826221 pmcid:PMC5569362 fatcat:t6awgzfi6jdafp62pfzxfl2t5e

Tools and strategies for discovering novel enzymes and metabolic pathways

John A. Gerlt
2016 Perspectives in Science  
and EFI-GNT web tools can be used to discover new enzyme functions and new metabolic pathways.  ...  and in vivo metabolic functions of uncharacterized enzymes.  ...  Now, a much larger informational context is available, allowing enzymologists to include the genomic context (sequence families, structures, and functions) relevant to study of their favourite enzyme,  ... 
doi:10.1016/j.pisc.2016.07.001 fatcat:wb3maa5ep5hlxii25qqjn7537a

Metabolomic strategies for the identification of new enzyme functions and metabolic pathways

G. A. Prosser, G. Larrouy-Maumus, L. P. S. de Carvalho
2014 EMBO Reports  
This review discusses state-of-the-art metabolomic approaches and highlights recent examples of their use for enzyme annotation, discovery of new metabolic pathways, and gene assignment of orphan metabolic  ...  of novel enzymatic activities and metabolic pathways.  ...  (ii) Which organisms have a large number of orphan enzymes and are therefore good models for the discovery of new enzymatic functions and new metabolic pathways?  ... 
doi:10.15252/embr.201338283 pmid:24829223 pmcid:PMC4197876 fatcat:lomvgjmptvgfvfaifknpjrysmq

Leveraging structure for enzyme function prediction: methods, opportunities, and challenges

Matthew P. Jacobson, Chakrapani Kalyanaraman, Suwen Zhao, Boxue Tian
2014 TIBS -Trends in Biochemical Sciences. Regular ed  
We discuss opportunities to systematically elucidate protein domains of unknown function, orphan enzyme activities, deadend metabolites, and pathways in secondary metabolism.  ...  Successful application of these approaches has led to the identification of novel metabolites, enzyme activities, and biochemical pathways.  ...  Acknowledgments This work was part of the Enzyme Function Initiative supported by the National Institutes of Health Grant U54 GM093342. We thank John Gerlt (U. Illinois) for helpful discussions.  ... 
doi:10.1016/j.tibs.2014.05.006 pmid:24998033 pmcid:PMC4117707 fatcat:m7rk4bs2p5b5plq2qpxq4a547a

Missing genes in metabolic pathways: a comparative genomics approach

A Osterman
2003 Current Opinion in Chemical Biology  
The new techniques of genome context analysischromosomal gene clustering, protein fusions, occurrence profiles and shared regulatory sites -infer functional coupling between genes.  ...  where one of the four techniques of genome context analysis provided the key evidence for a specific functional prediction followed by experimental verification.  ...  Combining multiple new techniques in comparative genomics is often referred to as genome context analysis; it is the focus of many recent reviews and original research papers (some of them are listed in  ... 
doi:10.1016/s1367-5931(03)00027-9 pmid:12714058 fatcat:x2uvsb3hknfytjwjwoj4hzmdku

Constructing de Novo Biosynthetic Pathways for Chemical Synthesis inside Living Cells

Amy M. Weeks, Michelle C. Y. Chang
2011 Biochemistry  
metabolic pathways for the production of new and exotic molecular targets in genetically tractable microbes.  ...  However, the development of commercially viable processes for these engineered pathways is currently limited by our ability to quickly identify or engineer enzymes with the correct reaction and substrate  ...  and the possible annotation of new enzymes and metabolic pathways.  ... 
doi:10.1021/bi200416g pmid:21591680 pmcid:PMC3768262 fatcat:uxbtpnwpuzenbos5axfsqs3q6q

How to Find "Missing" Genes

John A Gerlt
2003 Chemistry and Biology  
laboratory has used this approach to both discover previously unknown metabolic pathways and to verify novel functions of enzymes in these pathways (these novel Assigning function to "new" proteins is  ...  ., the example of this strategy was the identification of the same function may be catalyzed by unrelated se- enzymes in the human pathway for coenzyme A biosynquences and structures [2].  ...  Genome Biol 1, REwith the quinolinate biosynthesis enzymes identified by VIEWS0005. 2. Galperin, M.Y., Walker, D.R., and Koonin, E.V. (1998).  ... 
doi:10.1016/j.chembiol.2003.12.008 pmid:14700618 fatcat:rqtbx3saanbqhhuif3b2gtp2v4

Nature's Chemists: The Discovery and Engineering of Phytochemical Biosynthesis

Kaouthar Eljounaidi, Benjamin R. Lichman
2020 Frontiers in Chemistry  
In this review we highlight the methods that are used to elucidate natural product biosynthetic pathways, including the approaches leading to proposing the sequence of enzymatic steps, selecting enzyme  ...  Plants are suitable heterologous systems for the production of valuable phytochemicals as they are autotrophic, derive energy and carbon from photosynthesis, and have similar cellular context to native  ...  AUTHOR CONTRIBUTIONS KE conceived of the manuscript and wrote the first draft. Both authors prepared figures, edited text, and approved the manuscript for submission.  ... 
doi:10.3389/fchem.2020.596479 pmid:33240856 pmcid:PMC7680914 fatcat:w5jeb2whurhptkwxgxwv7uh34a

Bioinformatics of thymidine metabolism in Trypanosoma evansi: exploring nucleoside deoxyribosyltransferase (NDRT) as a drug target

Kandeel M.
2021 Tropical biomedicine  
Its zoonotic importance and increasing evidence of drug resistance necessitate the discovery of new drug targets.  ...  In this study, the thymidine metabolic pathways in camel and T. evansi were compared by analyzing their metabolic maps, protein sequences, domain and motif contents, phylogenetic relationships, and 3D  ...  MATERIALS AND METHODS Construction of the metabolic map The Kyoto Encyclopedia of Genes and Genomes (KEGG) website was used to retrieve the thymidine pathway maps.  ... 
doi:10.47665/tb.38.3.071 pmid:34508338 fatcat:rm6ocx57dfgj3aqagybp62r3bu

Metabolic pathways in the post-genome era

Jason A. Papin, Nathan D. Price, Sharon J. Wiback, David A. Fell, Bernhard O. Palsson
2003 TIBS -Trends in Biochemical Sciences. Regular ed  
Metabolic pathways are a central paradigm in biology. Historically, they have been defined on the basis of their step-by-step discovery.  ...  However, the genomescale metabolic networks now being reconstructed from annotation of genome sequences demand new network-based definitions of pathways to facilitate analysis of their capabilities and  ...  Metabolic pathways are a central paradigm in biology. Historically, they have been defined on the basis of their step-by-step discovery.  ... 
doi:10.1016/s0968-0004(03)00064-1 pmid:12765837 fatcat:lkklaphb7bcppgw6647ayueqkq

Genome evolution reveals biochemical networks and functional modules

C. von Mering, E. M. Zdobnov, S. Tsoka, F. D. Ciccarelli, J. B. Pereira-Leal, C. A. Ouzounis, P. Bork
2003 Proceedings of the National Academy of Sciences of the United States of America  
We found as many as 74% of the known metabolic enzymes clustering together in modules, with an average pathway specificity of at least 84%.  ...  In Escherichia coli, the predicted modules can be benchmarked by comparison to known metabolic pathways.  ...  We thank members of the Bork group for helpful discussions, in particular Jan Korbel and Tobias Doerks for sharing expertise in specific predictions. This work was supported by the U.  ... 
doi:10.1073/pnas.2136809100 pmid:14673105 pmcid:PMC307584 fatcat:hkqm4ga4wre5tbnrttuh5kcxc4

An Atypical Orphan Carbohydrate-NRPS Genomic Island Encodes a Novel Lytic Transglycosylase

Xun Guo, Jason M. Crawford
2014 Chemistry and Biology  
The example presented here supports the notion that targeting select genomic islands with reduced reliance on known protein homologies could enhance the discovery of new metabolic chemistry and biology  ...  Microbial genome sequencing platforms have produced a deluge of orphan biosynthetic pathways suspected of biosynthesizing new small molecules with pharmacological relevance.  ...  Using protein structure as a guide combined with genome context, computational predictions, and experimental data provide powerful platforms for the discovery of new enzymes (Bastard et al., 2014; Zhao  ... 
doi:10.1016/j.chembiol.2014.07.025 pmid:25219963 pmcid:PMC4224617 fatcat:qlgplhdovbezxjpapunkufywie

The Tripod for Bacterial Natural Product Discovery: Genome Mining, Silent Pathway Induction, and Mass Spectrometry-Based Molecular Networking

Daniela B. B. Trivella, Rafael de Felicio
2018 mSystems  
In our opinion, these three approaches—genome mining, silent pathway induction, and MS-based molecular networking—compose the tripod for modern bacterial natural product discovery and will be discussed  ...  Particularly, bacterial secondary metabolites are in the spotlight due to advances in genome sequencing and mining, as well as for the potential of biosynthetic pathway manipulation to awake silent (cryptic  ...  ACKNOWLEDGMENT We thank Marjorie Bruder for careful reading and helpful feedback on the manuscript.  ... 
doi:10.1128/msystems.00160-17 pmid:29629418 pmcid:PMC5881025 fatcat:mql436cmmfgndb24hzymgap7iy
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