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In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites

BACKGROUND: Secondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) family of enzymes constitute several classes of therapeutically important natural products like erythromycin, rapamycin, cyclosporine etc. In view of their relevance for natural p...

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Autores principales: Ansari, Mohd Zeeshan, Sharma, Jyoti, Gokhale, Rajesh S, Mohanty, Debasisa
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613160/
https://www.ncbi.nlm.nih.gov/pubmed/18950525
http://dx.doi.org/10.1186/1471-2105-9-454
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author Ansari, Mohd Zeeshan
Sharma, Jyoti
Gokhale, Rajesh S
Mohanty, Debasisa
author_facet Ansari, Mohd Zeeshan
Sharma, Jyoti
Gokhale, Rajesh S
Mohanty, Debasisa
author_sort Ansari, Mohd Zeeshan
collection PubMed
description BACKGROUND: Secondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) family of enzymes constitute several classes of therapeutically important natural products like erythromycin, rapamycin, cyclosporine etc. In view of their relevance for natural product based drug discovery, identification of novel secondary metabolite natural products by genome mining has been an area of active research. A number of different tailoring enzymes catalyze a variety of chemical modifications to the polyketide or nonribosomal peptide backbone of these secondary metabolites to enhance their structural diversity. Therefore, development of powerful bioinformatics methods for identification of these tailoring enzymes and assignment of their substrate specificity is crucial for deciphering novel secondary metabolites by genome mining. RESULTS: In this work, we have carried out a comprehensive bioinformatics analysis of methyltransferase (MT) domains present in multi functional type I PKS and NRPS proteins encoded by PKS/NRPS gene clusters having known secondary metabolite products. Based on the results of this analysis, we have developed a novel knowledge based computational approach for detecting MT domains present in PKS and NRPS megasynthases, delineating their correct boundaries and classifying them as N-MT, C-MT and O-MT using profile HMMs. Analysis of proteins in nr database of NCBI using these class specific profiles has revealed several interesting examples, namely, C-MT domains in NRPS modules, N-MT domains with significant homology to C-MT proteins, and presence of NRPS/PKS MTs in association with other catalytic domains. Our analysis of the chemical structures of the secondary metabolites and their site of methylation suggested that a possible evolutionary basis for the presence of a novel class of N-MT domains with significant homology to C-MT proteins could be the close resemblance of the chemical structures of the acceptor substrates, as in the case of pyochelin and yersiniabactin. These two classes of MTs recognize similar acceptor substrates, but transfer methyl groups to N and C positions on these substrates. CONCLUSION: We have developed a novel knowledge based computational approach for identifying MT domains present in type I PKS and NRPS multifunctional enzymes and predicting their site of methylation. Analysis of nr database using this approach has revealed presence of several novel MT domains. Our analysis has also given interesting insight into the evolutionary basis of the novel substrate specificities of these MT proteins.
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spelling pubmed-26131602009-01-01 In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites Ansari, Mohd Zeeshan Sharma, Jyoti Gokhale, Rajesh S Mohanty, Debasisa BMC Bioinformatics Research Article BACKGROUND: Secondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) family of enzymes constitute several classes of therapeutically important natural products like erythromycin, rapamycin, cyclosporine etc. In view of their relevance for natural product based drug discovery, identification of novel secondary metabolite natural products by genome mining has been an area of active research. A number of different tailoring enzymes catalyze a variety of chemical modifications to the polyketide or nonribosomal peptide backbone of these secondary metabolites to enhance their structural diversity. Therefore, development of powerful bioinformatics methods for identification of these tailoring enzymes and assignment of their substrate specificity is crucial for deciphering novel secondary metabolites by genome mining. RESULTS: In this work, we have carried out a comprehensive bioinformatics analysis of methyltransferase (MT) domains present in multi functional type I PKS and NRPS proteins encoded by PKS/NRPS gene clusters having known secondary metabolite products. Based on the results of this analysis, we have developed a novel knowledge based computational approach for detecting MT domains present in PKS and NRPS megasynthases, delineating their correct boundaries and classifying them as N-MT, C-MT and O-MT using profile HMMs. Analysis of proteins in nr database of NCBI using these class specific profiles has revealed several interesting examples, namely, C-MT domains in NRPS modules, N-MT domains with significant homology to C-MT proteins, and presence of NRPS/PKS MTs in association with other catalytic domains. Our analysis of the chemical structures of the secondary metabolites and their site of methylation suggested that a possible evolutionary basis for the presence of a novel class of N-MT domains with significant homology to C-MT proteins could be the close resemblance of the chemical structures of the acceptor substrates, as in the case of pyochelin and yersiniabactin. These two classes of MTs recognize similar acceptor substrates, but transfer methyl groups to N and C positions on these substrates. CONCLUSION: We have developed a novel knowledge based computational approach for identifying MT domains present in type I PKS and NRPS multifunctional enzymes and predicting their site of methylation. Analysis of nr database using this approach has revealed presence of several novel MT domains. Our analysis has also given interesting insight into the evolutionary basis of the novel substrate specificities of these MT proteins. BioMed Central 2008-10-25 /pmc/articles/PMC2613160/ /pubmed/18950525 http://dx.doi.org/10.1186/1471-2105-9-454 Text en Copyright © 2008 Ansari et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Ansari, Mohd Zeeshan
Sharma, Jyoti
Gokhale, Rajesh S
Mohanty, Debasisa
In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites
title In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites
title_full In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites
title_fullStr In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites
title_full_unstemmed In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites
title_short In silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites
title_sort in silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613160/
https://www.ncbi.nlm.nih.gov/pubmed/18950525
http://dx.doi.org/10.1186/1471-2105-9-454
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