scholarly journals A 3-hydroxy-3-methylglutaryl-CoA synthase-based probe for the discovery of the acyltransferase-less type I polyketide synthases

2019 ◽  
Author(s):  
Haoyu Liang ◽  
Lin Jiang ◽  
Qiyun Jiang ◽  
Jie Shi ◽  
Jingxi Xiang ◽  
...  
Keyword(s):  
Natural Products ◽  
Network Analysis ◽  
In Silico ◽  
Genome Mining ◽  
Evolutionary Relationship ◽  
Soil Samples ◽  
Polyketide Synthases ◽  
Type I ◽  
Mining Sequence ◽  
Tailoring Enzymes

ABSTRACTAcyltransferase (AT)-less type I polyketide synthases (PKSs) produce complex natural products due to the presence of many unique tailoring enzymes. The 3-hydroxy-3-methylglutaryl coenzyme A synthases (HCSs) are responsible for β-alkylation of the growing polyketide intermediates in AT-less type I PKSs. In this study, we discovered a large group of HCSs, closely associated with the characterized and orphan AT-less type I PKSs through in silico genome mining, sequence and genome neighborhood network analysis. Using HCS-based probes, the survey of 1207 inhouse strains and 18 soil samples from different geological locations revealed the vast diversity of HCS-containing AT-less type I PKSs. The presence of HCSs in many AT-less type I PKSs suggests their co-evolutionary relationship. Our study should inspire future efforts to discover new polyketide natural products from AT-less type I PKSs.

scholarly journals Discovery of Two Native Baeyer-Villiger Monooxygenases for Asymmetric Synthesis of Bulky Chiral Sulfoxides

2018 ◽  
Vol 84 (14) ◽  
Author(s):  
Yan Zhang ◽  
Feng Liu ◽  
Na Xu ◽  
Yin-Qi Wu ◽  
Yu-Cong Zheng ◽  
...  
Keyword(s):  
Genome Mining ◽  
Evolutionary Relationship ◽  
Type I ◽  
Content Type ◽  
Asymmetric Oxidation ◽  
Chiral Sulfoxides ◽  
The Family ◽  
Typical Type ◽  
Main Action ◽  
Villiger Oxidation

ABSTRACT Two Baeyer-Villiger monooxygenases (BVMOs), designated Bo BVMO and Am BVMO, were discovered from Bradyrhizobium oligotrophicum and Aeromicrobium marinum , respectively. Both monooxygenases displayed novel features for catalyzing the asymmetric sulfoxidation of bulky and pharmaceutically relevant thioethers. Evolutionary relationship and sequence analysis revealed that the two BVMOs belong to the family of typical type I BVMOs and the subtype ethionamide monooxygenase. Both BVMOs are active toward medium- and long-chain aliphatic ketones as well as various thioether substrates but are ineffective toward cyclohexanone, aromatic ketones, and other typical BVMO substrates. Bo BVMO and Am BVMO showed the highest activities (0.117 and 0.025 U/mg protein, respectively) toward thioanisole among the tested substrates. Furthermore, these BVMOs exhibited distinct activity and excellent stereoselectivity toward bulky and prochiral prazole thioethers, which is a unique feature of this family of BVMOs. No native enzyme has been reported for the asymmetric sulfoxidation of bulky prazole thioethers into chiral sulfoxides. The identification of Bo BVMO and Am BVMO provides an important scaffold for discovering enzymes capable of asymmetrically oxidizing bulky thioether substrates by genome mining. IMPORTANCE Baeyer-Villiger monooxygenases (BVMOs) are valuable enzyme catalysts that are an alternative to the chemical Baeyer-Villiger oxidation reaction. Although BVMOs display broad substrate ranges, no native enzymes were reported to have activity toward the asymmetric oxidation of bulky prazole-like thioether substrates. Herein, we report the discovery of two type I BVMOs from Bradyrhizobium oligotrophicum ( Bo BVMO) and Aeromicrobium marinum ( Am BVMO) which are able to catalyze the asymmetric sulfoxidation of bulky prazole thioethers (proton pump inhibitors [PPIs], a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production). Efficient catalysis of omeprazole oxidation by Bo BVMO was developed, indicating that this enzyme is a promising biocatalyst for the synthesis of bulky and pharmaceutically relevant chiral sulfoxide drugs. These results demonstrate that the newly identified enzymes are suitable templates for the discovery of more and better thioether-converting BVMOs.

Expanding the Natural Products Heterologous Expression Repertoire in the Model Cyanobacterium Anabaena sp. Strain PCC 7120: Production of Pendolmycin and Teleocidin B-4

2019 ◽  
Author(s):  
Patrick Videau ◽  
Kaitlyn Wells ◽  
Arun Singh ◽  
Jessie Eiting ◽  
Philip Proteau ◽  
...  
Keyword(s):  
Natural Products ◽  
Genome Mining ◽  
Gene Clusters ◽  
Combinatorial Biosynthesis ◽  
Test Case ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Cyanobacterium Anabaena ◽  
Anabaena Sp ◽  
Pcc 7120

Cyanobacteria are prolific producers of natural products and genome mining has shown that many orphan biosynthetic gene clusters can be found in sequenced cyanobacterial genomes. New tools and methodologies are required to investigate these biosynthetic gene clusters and here we present the use of <i>Anabaena </i>sp. strain PCC 7120 as a host for combinatorial biosynthesis of natural products using the indolactam natural products (lyngbyatoxin A, pendolmycin, and teleocidin B-4) as a test case. We were able to successfully produce all three compounds using codon optimized genes from Actinobacteria. We also introduce a new plasmid backbone based on the native <i>Anabaena</i>7120 plasmid pCC7120ζ and show that production of teleocidin B-4 can be accomplished using a two-plasmid system, which can be introduced by co-conjugation.

In-silico Analyses of Natural Products on Leishmania Enzyme Targets

2015 ◽  
Vol 15 (3) ◽  
pp. 253-269 ◽  
Author(s):  
L. Scotti ◽  
H. Ishiki ◽  
F.J.B. Mendonca ◽  
M.S. Silva ◽  
M.T. Scotti
Keyword(s):  
Natural Products ◽  
In Silico ◽  
In Silico Analyses

scholarly journals Towards Prediction of Metabolic Products of Polyketide Synthases: An In Silico Analysis

2009 ◽  
Vol 5 (4) ◽  
pp. e1000351 ◽  
Author(s):  
Gitanjali Yadav ◽  
Rajesh S. Gokhale ◽  
Debasisa Mohanty
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Polyketide Synthases ◽  
Metabolic Products ◽  
Silico Analysis

scholarly journals In Silico Screening of Natural Products Isolated from Mexican Herbal Medicines against COVID-19

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 216
Author(s):  
Nadia A. Rivero-Segura ◽  
Juan C. Gomez-Verjan
Keyword(s):  
Natural Products ◽  
In Silico ◽  
Herbal Medicines ◽  
In Silico Screening ◽  
Docking Analysis ◽  
Physiologically Based Pharmacokinetic ◽  
Important Challenge ◽  
Emodin Anthrone ◽  
Therapeutic Tools ◽  
Vaccine Distribution

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for all countries. In this sense, research for novel molecules becomes essential to develop treatments against the SARS-CoV-2 virus. In this context, Mexican natural products have proven to be quite useful for drug development; therefore, in the present study, we perform an in silico screening of 100 compounds isolated from the most commonly used Mexican plants, against the SARS-CoV-2 virus. As results, we identify ten compounds that meet leadlikeness criteria (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin). According to the docking analysis, only three compounds target the key proteins of SARS-CoV-2 (quercetin, riolozatrione and cichoriin), but only one appears to be safe (cichoriin). ADME (absorption, distribution, metabolism and excretion) properties and the physiologically based pharmacokinetic (PBPK) model show that cichoriin reaches higher lung levels (100 mg/Kg, IV); therefore, it may be considered in developing therapeutic tools.

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