3 results on '"Zhenyao Luo"'
Search Results
2. Molecular basis of regio- and stereo-specificity in biosynthesis of bacterial heterodimeric diketopiperazines
- Author
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Bostjan Kobe, Zhi Lin, Chenghai Sun, Haidong Peng, Zixin Deng, Wenlu Zhang, Xinying Jia, Wenya Tian, Zhenyao Luo, and Xudong Qu
- Subjects
Cytochrome ,Stereochemistry ,Science ,Protein domain ,General Physics and Astronomy ,Stereoisomerism ,Diketopiperazines ,Molecular Dynamics Simulation ,Biosynthesis ,Crystallography, X-Ray ,010402 general chemistry ,01 natural sciences ,Article ,General Biochemistry, Genetics and Molecular Biology ,Substrate Specificity ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Protein Domains ,Amino Acid Sequence ,Peptide sequence ,X-ray crystallography ,chemistry.chemical_classification ,Biological Products ,Multidisciplinary ,Bacteria ,Molecular Structure ,Sequence Homology, Amino Acid ,biology ,010405 organic chemistry ,Chemistry ,Tryptophan ,General Chemistry ,0104 chemical sciences ,Amino acid ,Biocatalysis ,Enzyme mechanisms ,biology.protein ,Natural product synthesis ,Dimerization - Abstract
Bacterial heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are a growing family of bioactive natural products. They are challenging to prepare by chemical routes due to the polycyclic and densely functionalized backbone. Through functional characterization and investigation, we herein identify a family of three related HTDKP-forming cytochrome P450s (NasbB, NasS1868 and NasF5053) and reveal four critical residues (Qln65, Ala86, Ser284 and Val288) that control their regio- and stereo-selectivity to generate diverse dimeric DKP frameworks. Engineering these residues can alter the specificities of the enzymes to produce diverse frameworks. Determining the crystal structures (1.70–1.47 Å) of NasF5053 (ligand-free and substrate-bound NasF5053 and its Q65I-A86G and S284A-V288A mutants) and molecular dynamics simulation finally elucidate the specificity-conferring mechanism of these residues. Our results provide a clear molecular and mechanistic basis into this family of HTDKP-forming P450s, laying a solid foundation for rapid access to the molecular diversity of HTDKP frameworks through rational engineering of the P450s., Bacterial heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are bioactive natural products that are difficult to access chemically. Here, the authors identify a family of three related HTDKP-forming cytochrome P450s and engineer key amino acid residues to produce distinct diketopiperazines frameworks.
- Published
- 2020
3. Dysregulation of transition metal ion homeostasis is the molecular basis for cadmium toxicity in Streptococcus pneumoniae
- Author
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Jacqueline R. Morey, Christopher A. McDevitt, Bart A. Eijkelkamp, Megan J. Maher, Megan L. O'Mara, Cheryl-lynn Y. Ong, Stephanie L. Begg, Alastair G. McEwan, Zhenyao Luo, Rafael M. Couñago, Bostjan Kobe, James C. Paton, Begg, Stephanie L, Eijkelkamp, Bart A, Luo, Zhenyao, Counago, Rafael M, Morey, Jacqueline R, Maher, Megan J, Ong, Cheryl-lynn Y, McEwan, Alastair G, Kobe, Bostjan, O'Mara, Megan L, Paton, James C, and McDevitt, Christopher A
- Subjects
Models, Molecular ,inorganic chemicals ,Protein Conformation ,Lipoproteins ,Immunoblotting ,Microbial metabolism ,General Physics and Astronomy ,chemistry.chemical_element ,Manganese ,Zinc ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Homeostasis ,Magnesium ,cadmium toxicity ,Adhesins, Bacterial ,030304 developmental biology ,Transition metal ion homeostasis ,0303 health sciences ,Cadmium ,Multidisciplinary ,Reverse Transcriptase Polymerase Chain Reaction ,030306 microbiology ,cadmium accumulation ,General Chemistry ,Glutathione ,Multidisciplinary Sciences ,Oxidative Stress ,Streptococcus pneumoniae ,chemistry ,Biochemistry ,13. Climate action ,Toxicity ,Crystallization ,Oxidative stress - Abstract
Cadmium is a transition metal ion that is highly toxic in biological systems. Although relatively rare in the Earth’s crust, anthropogenic release of cadmium since industrialization has increased biogeochemical cycling and the abundance of the ion in the biosphere. Despite this, the molecular basis of its toxicity remains unclear. Here we combine metal-accumulation assays, high-resolution structural data and biochemical analyses to show that cadmium toxicity, in Streptococcus pneumoniae, occurs via perturbation of first row transition metal ion homeostasis. We show that cadmium uptake reduces the millimolar cellular accumulation of manganese and zinc, and thereby increases sensitivity to oxidative stress. Despite this, high cellular concentrations of cadmium (~17 mM) are tolerated, with negligible impact on growth or sensitivity to oxidative stress, when manganese and glutathione are abundant. Collectively, this work provides insight into the molecular basis of cadmium toxicity in prokaryotes, and the connection between cadmium accumulation and oxidative stress., The molecular basis for the high toxicity of cadmium is unclear. Here, Begg et al. use the bacterium Streptococcus pneumoniae as a model system, and show that cadmium uptake increases sensitivity to oxidative stress by reducing intracellular concentrations of manganese and zinc through different mechanisms.
- Published
- 2015
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