Please use this identifier to cite or link to this item: https://doi.org/10.1186/1471-2148-7-78
Title: Phylogenetic analysis of condensation domains in NRPS sheds light on their functional evolution
Authors: Rausch, C
Hoof, I
Weber, T
Wohlleben, W
Huson, D.H 
Keywords: alpha amanitin
amino acid derivative
beta hydroxycarboxylic acid
beta hydroxyl fatty acid
bleomycin
cyclosporin A
cysteine
non ribosomal peptide synthase
penicillin G
peptide synthase
serine
threonine
unclassified drug
vancomycin
non ribosomal peptide synthase
non-ribosomal peptide synthase
peptide synthase
article
catalysis
cyclization
enzyme structure
enzyme synthesis
epimerization
hidden Markov model
molecular evolution
nonhuman
nonribosomal peptide synthesis
peptide analysis
phylogeny
polymerization
protein domain
protein motif
statistical model
amino acid sequence
bacterial genome
bacterium
classification
enzyme specificity
gene expression regulation
genetics
protein tertiary structure
sequence alignment
Amino Acid Motifs
Amino Acid Sequence
Bacteria
Gene Expression Regulation, Bacterial
Gene Expression Regulation, Enzymologic
Genome, Bacterial
Peptide Synthases
Phylogeny
Protein Structure, Tertiary
Sequence Alignment
Substrate Specificity
Issue Date: 2007
Citation: Rausch, C, Hoof, I, Weber, T, Wohlleben, W, Huson, D.H (2007). Phylogenetic analysis of condensation domains in NRPS sheds light on their functional evolution. BMC Evolutionary Biology 7 : 78. ScholarBank@NUS Repository. https://doi.org/10.1186/1471-2148-7-78
Rights: Attribution 4.0 International
Abstract: Background. Non-ribosomal peptide synthetases (NRPSs) are large multimodular enzymes that synthesize a wide range of biologically active natural peptide compounds, of which many are pharmacologically important. Peptide bond formation is catalyzed by the Condensation (C) domain. Various functional subtypes of the C domain exist: An LCL domain catalyzes a peptide bond between two L-amino acids, a DCL domain links an L-amino acid to a growing peptide ending with a D-amino acid, a Starter C domain (first denominated and classified as a separate subtype here) acylates the first amino acid with a ?-hydroxy-carboxylic acid (typically a ?-hydroxyl fatty acid), and Heterocyclization (Cyc) domains catalyze both peptide bond formation and subsequent cyclization of cysteine, serine or threonine residues. The homologous Epimerization (E) domain flips the chirality of the last amino acid in the growing peptide; Dual E/C domains catalyze both epimerization and condensation. Results. In this paper, we report on the reconstruction of the phylogenetic relationship of NRPS C domain subtypes and analyze in detail the sequence motifs of recently discovered subtypes (Dual E/C, DCL and Starter domains) and their characteristic sequence differences, mutually and in comparison with LCL domains. Based on their phylogeny and the comparison of their sequence motifs, LCL and Starter domains appear to be more closely related to each other than to other subtypes, though pronounced differences in some segments of the protein account for the unequal donor substrates (amino vs. ?-hydroxy-carboxylic acid). Furthermore, on the basis of phylogeny and the comparison of sequence motifs, we conclude that Dual E/C and DC L domains share a common ancestor. In the same way, the evolutionary origin of a C domain of unknown function in glycopeptide (GP) NRPSs can be determined to be an LCL domain. In the case of two GP C domains which are most similar to DCL but which have LCL activity, we postulate convergent evolution. Conclusion. We systematize all C domain subtypes including the novel Starter C domain. With our results, it will be easier to decide the subtype of unknown C domains as we provide profile Hidden Markov Models (pHMMs) for the sequence motifs as well as for the entire sequences. The determined specificity conferring positions will be helpful for the mutation of one subtype into another, e.g. turning DCL to LCL, which can be a useful step for obtaining novel products. © 2007 Rausch et al; licensee BioMed Central Ltd.
Source Title: BMC Evolutionary Biology
URI: https://scholarbank.nus.edu.sg/handle/10635/177993
ISSN: 14712148
DOI: 10.1186/1471-2148-7-78
Rights: Attribution 4.0 International
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