ArticleBMC structural biology2010
Molecular modeling of the reductase domain to elucidate the reaction mechanism of reduction of peptidyl thioester into its corresponding alcohol in non-ribosomal peptide synthetases.
Article in BMC structural biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 45 citations in OpenAlex.
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- Identification of Novel Rotihibin Analogues inMicrobiology spectrum · 2021Article
- Cyanochelins, an Overlooked Class of Widely Distributed Cyanobacterial Siderophores, Discovered by Silent Gene Cluster Awakening.Applied and environmental microbiology · 2021Article
- Biosynthesis of depsipeptides, or Depsi: The peptides with varied generations.Protein science : a publication of the Protein Society · 2020Review
- Engineering carboxylic acid reductase for selective synthesis of medium-chain fatty alcohols in yeast.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Natural products from thioester reductase containing biosynthetic pathways.Natural product reports · 2018Review
- DHSpred: support-vector-machine-based human DNase I hypersensitive sites prediction using the optimal features selected by random forest.Oncotarget · 2018Article
- AIPpred: Sequence-Based Prediction of Anti-inflammatory Peptides Using Random Forest.Frontiers in pharmacology · 2018Article
- PVP-SVM: Sequence-Based Prediction of Phage Virion Proteins Using a Support Vector Machine.Frontiers in microbiology · 2018Article
- iBCE-EL: A New Ensemble Learning Framework for Improved Linear B-Cell Epitope Prediction.Frontiers in immunology · 2018Article
- PIP-EL: A New Ensemble Learning Method for Improved Proinflammatory Peptide Predictions.Frontiers in immunology · 2018Article
- MLACP: machine-learning-based prediction of anticancer peptides.Oncotarget · 2017Article
- Modification ofDrug target insights · 2017Article
- Analysis of the Sequences, Structures, and Functions of Product-Releasing Enzyme Domains in Fungal Polyketide Synthases.Frontiers in microbiology · 2017Article
- Mining for Nonribosomal Peptide Synthetase and Polyketide Synthase Genes Revealed a High Level of Diversity in the Sphagnum Bog Metagenome.Applied and environmental microbiology · 2015Article
- Endogenous cross-talk of fungal metabolites.Frontiers in microbiology · 2014Review
- Article
- Distribution of amino acids in functional sites of proteins with high melting temperature.Bioinformation · 2012Article
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4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNonribosomal peptide synthetases (NRPSs) are multienzymatic, multidomain megasynthases involved in the biosynthesis of pharmaceutically important nonribosomal peptides. The peptaibol synthetase from Trichoderma virens (TPS) is an important member of the NRPS family that exhibits antifungal properties. The majority of the NRPSs terminate peptide synthesis with the thioesterase (TE) domain, which either hydrolyzes the thioester linkage, releasing the free peptic acid, or catalyzes the intramolecular macrocyclization to produce a macrolactone product. TPS is an important NRPS that does not encompass a TE domain, but rather a reductase domain (R domain) to release the mature peptide product reductively with the aid of a NADPH cofactor. However, the catalytic mechanism of the reductase domain has not yet been elucidated.
resultsWe present here a three-dimensional (3D) model of the reductase domain based on the crystal structure of vestitone reductase (VR). VR belongs to the short-chain dehydrogenase/reductase (SDR) superfamily and is responsible for the nicotinamide dinucleotide phosphate (NADPH)-dependent reduction of the substrate into its corresponding secondary alcohol product. The binding sites of the probable linear substrates, alamethicin, trichotoxin, antiamoebin I, chrysopermin C and gramicidin, were identified within the modeled R domain using multiple docking approaches. The docking results of the ligand in the active site of the R domain showed that reductase side chains have a high affinity towards ligand binding, while the thioester oxygen of each substrate forms a hydrogen bond with the OH group of Tyr176 and the thiol group of the substrate is closer to the Glu220. The modeling and docking studies revealed the reaction mechanism of reduction of thioester into a primary alcohol.
conclusionPeptaibol biosynthesis incorporates a single R domain, which appears to catalyze the four-electron reduction reaction of a peptidyl carrier protein (PCP)-bound peptide to its corresponding primary alcohol. Analysis of R domains present in the non-redundant (nr) database of the NCBI showed that the R domain always resides in the last NRPS module and is involved in either a two or four-electron reduction reaction.
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