16 results on '"Qingfei Zheng"'
Search Results
2. Bufospirostenin A and Bufogargarizin C, Steroids with Rearranged Skeletons from the Toad Bufo bufo gargarizans
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Ruibo Wu, Nanhao Chen, Tong Yu, Qingfei Zheng, Hai-Yan Tian, Wen-Cai Ye, Li-Jun Ruan, Lei Wang, Xiao-Qi Zhang, and Ren-Wang Jiang
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China ,Stereochemistry ,Pharmaceutical Science ,Toad ,Bufadienolide ,01 natural sciences ,Bufo bufo ,Analytical Chemistry ,chemistry.chemical_compound ,biology.animal ,Drug Discovery ,Animals ,Nuclear Magnetic Resonance, Biomolecular ,Pharmacology ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Cycloheptatriene ,Bufogargarizin C ,0104 chemical sciences ,Bufanolides ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Molecular Medicine ,Bufo bufo gargarizans - Abstract
Bufospirostenin A (1) and bufogargarizin C (2), two novel steroids with rearranged A/B rings, were isolated from the toad Bufo bufo gargarizans. Compound 1 represents the first spirostanol found in animals. Compound 2 is an unusual bufadienolide with a cycloheptatriene B ring. Their structures were elucidated by spectroscopic analysis, single crystal X-ray diffraction analysis, and computational calculations.
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- 2017
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3. Isolation and identification of<scp>l</scp>/<scp>d</scp>-lactate-conjugated bufadienolides from toad eggs revealing lactate racemization in amphibians
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Hai-Yan Tian, Ren-Wang Jiang, Wen-Cai Ye, Xiuyong Huang, Lei Wang, Si-fan Luo, Yong Wang, Shi-Wen Zhou, and Qingfei Zheng
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Cell Survival ,Stereochemistry ,Molecular Conformation ,Antineoplastic Agents ,Bufadienolide ,Toad ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Bufo bufo ,Amphibians ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,biology.animal ,Lactate racemase ,Animals ,Humans ,Structure–activity relationship ,Lactic Acid ,Physical and Theoretical Chemistry ,Cytotoxicity ,Cell Proliferation ,Ovum ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,biology ,010405 organic chemistry ,Organic Chemistry ,0104 chemical sciences ,Bufanolides ,Enzyme ,chemistry ,Acyltransferase ,Drug Screening Assays, Antitumor ,Lactate racemization - Abstract
Three pairs of bufadienolide l/d-lactate epimers (1-6) were isolated from the eggs of the toad Bufo bufo gargarizans. The structures were elucidated by using spectroscopic methods, X-ray diffraction analysis and a modified Mosher's method. Compounds 1-6 represent the first occurrence of lactate-conjugated bufadienolides in nature, and illustrate the existence of an enzyme-controlled epimerization from l- to d-lactate in amphibians. The biosynthetic pathways, in which two key enzymes might be involved (i.e., lactate racemase and acyltransferase), were proposed. In addition, the biological assays revealed that compounds 1-4 are potent cytotoxic agents against human gastric cancer cells BGC-823 and human lung cancer cells A549 with IC50 values in a range of 8.0 to 80.0 nM.
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- 2017
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4. A linear hydroxymethyl tetramate undergoes an acetylation–elimination process for exocyclic methylene formation in the biosynthetic pathway of pyrroindomycins
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Wen Liu, Qingfei Zheng, Zhenhua Tian, Peng Sun, Dandan Chen, and Zhuhua Wu
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Biological Products ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Acetylation ,010402 general chemistry ,Polyene ,Methylation ,01 natural sciences ,Biochemistry ,Streptomyces ,Biosynthetic Pathways ,0104 chemical sciences ,Serine ,chemistry.chemical_compound ,Residue (chemistry) ,chemistry ,Biosynthesis ,Intramolecular force ,Moiety ,Hydroxymethyl ,Macrolides ,Physical and Theoretical Chemistry ,Methane - Abstract
We herein report the isolation and characterization of a key linear intermediate in the biosynthetic pathway of pyrroindomycins, the potent spirotetramate natural products produced by Streptomyces rugosporus. This polyene intermediate bears a γ-hydroxymethyl group that is exocyclic to the tetramate moiety, indicating that a serine residue serves as the three-carbon unit for tetramate formation and chain-elongation termination. The further conversion involves an acetylation-elimination of the exocyclic γ-hydroxymethyl group to generate a γ-methylene group, which is indispensable for intramolecular [4 + 2] cross-bridging to construct the characteristic pentacyclic core. The findings presented in this study provide new insights into the biosynthesis of pyrroindomycins, and thus suggest a common paradigm for both spirotetramates and spirotetronates in processing the exocyclic γ-hydroxymethyl group of the five-membered heterocycle.
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- 2017
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5. An α/β-hydrolase fold protein in the biosynthesis of thiostrepton exhibits a dual activity for endopeptidyl hydrolysis and epoxide ring opening/macrocyclization
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Panpan Duan, Dandan Chen, Wen Liu, Qingfei Zheng, Rijing Liao, and Shoufeng Wang
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Signal peptide ,Hydrolases ,Stereochemistry ,Peptide ,010402 general chemistry ,01 natural sciences ,Thiostrepton ,Substrate Specificity ,chemistry.chemical_compound ,Bacterial Proteins ,Biosynthesis ,Catalytic Domain ,Catalytic triad ,Hydrolase ,Moiety ,Bond cleavage ,chemistry.chemical_classification ,Multidisciplinary ,010405 organic chemistry ,Hydrolysis ,fungi ,Biological Sciences ,Streptomyces ,Anti-Bacterial Agents ,Biosynthetic Pathways ,0104 chemical sciences ,chemistry ,Fermentation - Abstract
Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of the QA moiety, i.e., by fluorination or methylation, we have recently designed and biosynthesized biologically more active TSR analogs. Using these analogs as chemical probes, we uncovered an unusual indirect mechanism of TSR-type thiopeptides, which are able to act against intracellular pathogens through host autophagy induction in addition to direct targeting of bacterial ribosome. Herein, we report the accumulation of 6'-fluoro-7', 8'-epoxy-TSR, a key intermediate in the preparation of the analog 6'-fluoro-TSR. This unexpected finding led to unveiling of the TSR maturation process, which involves an unusual dual activity of TsrI, an α/β-hydrolase fold protein, for cascade C-N bond cleavage and formation during side-ring system construction. These two functions of TsrI rely on the same catalytic triad, Ser72-His200-Asp191, which first mediates endopeptidyl hydrolysis that occurs selectively between the residues Met-1 and Ile1 for removal of the leader peptide and then triggers epoxide ring opening for closure of the QA-containing side-ring system in a regio- and stereo-specific manner. The former reaction likely requires the formation of an acyl-Ser72 enzyme intermediate; in contrast, the latter is independent of Ser72. Consequently, C-6' fluorination of QA lowers the reactivity of the epoxide intermediate and, thereby, allows the dissection of the TsrI-associated enzymatic process that proceeds rapidly and typically is difficult to be realized during TSR biosynthesis.
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- 2016
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6. Molecular engineering of thiostrepton via single 'base'-based mutagenesis to generate side ring-derived variants
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Dandan Chen, Qingfei Zheng, Panpan Duan, Shoufeng Wang, Zhi Lin, and Wen Liu
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Mutation ,010405 organic chemistry ,Stereochemistry ,fungi ,Organic Chemistry ,Mutagenesis ,Regioselectivity ,010402 general chemistry ,medicine.disease_cause ,Ring (chemistry) ,01 natural sciences ,Thiostrepton ,0104 chemical sciences ,Molecular engineering ,chemistry.chemical_compound ,chemistry ,Biosynthesis ,medicine ,Moiety - Abstract
The quinaldic acid (QA) moiety in the side ring of thiostrepton (TSR), which can be modified regioselectively via precursor-directed mutational biosynthesis, was proven to be biologically relevant but tunable, affecting TSR's outstanding antibacterial activities. In this study, we sought to obtain TSR derivatives with varying amino acid residues connected to the QA moiety. The generation of these TSR derivatives relied on single “base”-based mutagenesis, and six new TSR-type compounds were obtained. Moreover, the simultaneous mutation of Ile1 and Ala2 in the TSR side ring resulted in a naturally occurring compound, siomycin (SIO), together with a new component, SIO-Dha2Ser. The anti-infection assays indicated that all of these new compounds could act as both antimicrobial agents and autophagy inducers, and these two kinds of activities can also be separated via regioselective modifications on the TSR side ring.
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- 2016
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7. Concurrent modifications of the C-terminus and side ring of thiostrepton and their synergistic effects with respect to improving antibacterial activities
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Yunsong Yu, Qingfei Zheng, Shoufeng Wang, Wen Liu, Jianfeng Wang, and Dandan Chen
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Strain (chemistry) ,010405 organic chemistry ,Chemistry ,Quinaldic acid ,Stereochemistry ,C-terminus ,fungi ,Organic Chemistry ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Thiostrepton ,0104 chemical sciences ,chemistry.chemical_compound ,Biosynthesis ,Streptomyces laurentii - Abstract
The double-mutant strain Streptomyces laurentii ΔtsrB/T was designed and constructed based on a recent understanding regarding the structure–activity relationship of thiostrepton (TSR) against prokaryotic pathogens. Five new C-terminally methylated TSR (CmTSR) derivatives that varied in the side-ring structure were obtained via the chemical feeding of quinaldic acid (QA) analogs. These derivatives provide new insights into the tolerance of QA incorporation in TSR biosynthesis. Certain members of the tested TSR derivatives, meanwhile, exhibited much better antibacterial activities than all currently known thiopeptide antibiotics.
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- 2016
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8. Target-oriented design and biosynthesis of thiostrepton-derived thiopeptide antibiotics with improved pharmaceutical properties
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Renxiao Wang, Qingye Li, Shoufeng Wang, Zhixiong Zhao, Jianfeng Wang, Qingfei Zheng, Wen Liu, and Yunsong Yu
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chemistry.chemical_compound ,chemistry ,Biosynthesis ,medicine.drug_class ,Stereochemistry ,Bacterial ribosome ,Organic Chemistry ,Antibiotics ,medicine ,Rational design ,Combinatorial chemistry ,Ribosome ,Thiostrepton - Abstract
Thiostrepton is a potent archetypal thiopeptide antibiotic. According to its mechanism known to target bacterial ribosome, we show here a rational design upon modeling of this molecule into the ribosome complex and an effective biosynthesis of new thiopeptide antibiotics through regioselective modifications. The resulting derivatives exhibit a series of anticipated and unanticipated pharmaceutical advantages, including improvement in activity against a number of drug-resistant pathogens and in water solubility that has largely affected the clinical use of thiostrepton.
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- 2015
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9. Structural Insights into a Flavin-Dependent [4 + 2] Cyclase that Catalyzes trans-Decalin Formation in Pyrroindomycin Biosynthesis
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Lifeng Pan, Qingfei Zheng, Yukang Gong, Dandan Chen, Zhixiong Zhao, Yujiao Guo, Zixuan Zhou, Zhuhua Wu, and Wen Liu
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Models, Molecular ,Stereochemistry ,Dinitrocresols ,Clinical Biochemistry ,Flavin group ,Biology ,Naphthalenes ,010402 general chemistry ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Cyclase ,Mixed Function Oxygenases ,chemistry.chemical_compound ,Protein structure ,Decalin ,Oxidoreductase ,Drug Discovery ,Molecular Biology ,Pharmacology ,chemistry.chemical_classification ,Flavin adenine dinucleotide ,Molecular Structure ,010405 organic chemistry ,Polyene ,0104 chemical sciences ,chemistry ,Hydroxybenzoate ,Biocatalysis ,Molecular Medicine ,Macrolides - Abstract
Summary Here, we provide structural insights into PyrE3, a flavin-dependent [4 + 2] cyclase that catalyzes trans -decalin formation in the biosynthesis of pyrroindomycins. PyrE3 shares an architecture/domain organization head-to-tail similarity with the members of the family of para -hydroxybenzoate hydroxylase (pHBH)-fold monooxygenases, and possesses a flavin adenine dinucleotide (FAD)-binding domain, a middle domain, and a C-terminal thioredoxin-like domain. The FAD-binding domain forms a central hub of the protein structure, and binds with FAD in a "closed" conformation of pHBH-fold family monooxygenases known for their highly dynamic catalytic processes. FAD plays an essential structural role in PyrE3, where it is amenable to redox change; however, redox change has little effect on [4 + 2] cyclization activity. PyrE3 appears to selectively accommodate a tetramate-containing, linear polyene intermediate in a highly positively charged pocket, which is located at the interface between the FAD-binding domain and the middle domain, and can accelerate trans -decalin formation likely through an endo -selective [4 + 2] transition state.
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- 2017
10. Discovery and efficient synthesis of a biologically active alkaloid inspired by thiostrepton biosynthesis
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Wen Liu, Shoufeng Wang, and Qingfei Zheng
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chemistry.chemical_classification ,Stereochemistry ,Quinaldic acid ,Alkaloid ,Organic Chemistry ,Peptide ,Biological activity ,Biochemistry ,Thiostrepton ,chemistry.chemical_compound ,chemistry ,Biosynthesis ,Drug Discovery - Abstract
Thiostrepton, a natural peptide macrocycle, is of great interest due to its structural complexity and numerous biological activities, including anti-bacterial, anti-tumor, and anti-plasmodial activities. The quinaldic acid (QA) moiety-containing side ring (loop 2) was proven to play an important role in carrying out these functions. Previously, we proposed biosynthetic logic for thiostrepton loop 2 and demonstrated the formation mechanism of QA. Herein, we report the discovery and efficient synthesis of a biologically active alkaloid, that is, a key intermediate involved in the thiostrepton biosynthetic pathway. A chemo-enzymatic method was performed to synthesize the molecule, and a series of analogs were prepared for bioassays, which included the examination of anti-bacterial and anti-tumor activities.
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- 2014
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11. Insight into bicyclic thiopeptide biosynthesis benefited from development of a uniform approach for molecular engineering and production improvement
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Qingfei Zheng, Heng Guo, Yeming Li, Jiang Wang, Wen Liu, Jiequn Wu, and Yi Yu
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chemistry.chemical_classification ,chemistry.chemical_compound ,Residue (chemistry) ,chemistry ,Biosynthesis ,Bicyclic molecule ,Stereochemistry ,Peptide ,General Chemistry ,Nosiheptide ,Thiostrepton ,Amino acid ,Molecular engineering - Abstract
The ribosomal origin of thiopeptide antibiotics, a class of sulfur-rich and highly modified poly(thi)azolyl natural products, has recently been uncovered and features complex post-translational modifications (PTMs) of a precursor peptide. Based on molecular engineering and production improvement, we report insight into the biosynthesis of two bicyclic thiopeptide compounds, thiostrepton and nosiheptide. The PTMs of thiostrepton tolerate variations in the first two amino acids of the core peptide part of the precursor peptide: (1) the mutation of Ile1 to Val had no apparent effect on molecular maturation, suggesting that attachment of the quinaldic moiety at position 1 is not residue-dependent for the construction of the side ring system; and (2) the change of Ala2 to Ser led exclusively to the production of an analog that bears a corresponding dehydroamino acid residue, indicating that dehydration at position 2 is site-selective or that the oxazoline formed by cyclodehydration is inaccessible for maturation. For nosiheptide biosynthesis in particular, we provide the first structural evidence that construction of the specific side ring system precedes formation of the common central heterocycle domain and therefore propose that formation of a characteristic thiopeptide framework interweaves both common and specific PTMs that are interdependent. The above efforts benefited from the development of a uniform approach to examine the effectiveness for trans expression of gene encoding precursor peptides and associated PTM capacity. This approach is independent of knowledge regarding organism-specific regulatory mechanisms and potentially applicable to other systems that produce ribosomally synthesized peptide natural products.
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- 2014
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12. Precursor-Directed Mutational Biosynthesis Facilitates the Functional Assignment of Two Cytochromes P450 in Thiostrepton Biosynthesis
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Rijing Liao, Shoufeng Wang, Qingfei Zheng, and Wen Liu
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Quinaldic acid ,Stereochemistry ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Thiostrepton ,chemistry.chemical_compound ,Biosynthesis ,Cytochrome P-450 Enzyme System ,Mutant strain ,medicine ,Moiety ,Gene ,Mutation ,biology ,010405 organic chemistry ,fungi ,Cytochrome P450 ,General Medicine ,0104 chemical sciences ,chemistry ,biology.protein ,Molecular Medicine - Abstract
Side-ring-modified thiostrepton (TSR) derivatives that vary in their quinaldic acid (QA) substitution possess more potent biological activities and better pharmaceutical properties than the parent compound. In this work, we sought to introduce fluorine onto C-7′ or C-8′ of the TSR QA moiety via precursor-directed mutational biosynthesis to obtain new TSR variants. Unexpectedly, instead of the target product, the exogenous chemical feeding of 7-F-QA into the ΔtsrT mutant strain resulted in a unique TSR analog with an incomplete side-ring structure and an unoxidized QA moiety (1). Accordingly, two cytochrome P450 genes, tsrP and tsrR, were in-frame deleted to elucidate the candidate responsible for the monooxidation of the QA moiety in TSR. The unfluorinated analog of compound 1 that was thus isolated from ΔtsrP (2) and the abolishment of TSR production in ΔtsrR revealed not only the biosynthetic logic of the TSR side-ring but also the essential checkpoint in TSR maturation before macro-ring closure.
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- 2016
13. Enzyme-Dependent [4 + 2] Cycloaddition Depends on Lid-like Interaction of the N-Terminal Sequence with the Catalytic Core in PyrI4
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Lifeng Pan, Linlin Yang, Yujiao Guo, Jiequn Wu, Qingfei Zheng, Zhuhua Wu, Hualiang Jiang, Wen Liu, Hua Zhang, Huaiyu Yang, Xiaofang Cheng, Zhixiong Zhao, and Jianping Liu
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Stereochemistry ,Clinical Biochemistry ,Organic Synthesis Methods ,Crystal structure ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Drug Discovery ,Molecule ,Spiro Compounds ,Amino Acid Sequence ,Peptide Synthases ,Molecular Biology ,Nuclear Magnetic Resonance, Biomolecular ,Pharmacology ,chemistry.chemical_classification ,Cycloaddition Reaction ,010405 organic chemistry ,Alkene ,Lyase ,Cycloaddition ,0104 chemical sciences ,Enzyme ,chemistry ,Biocatalysis ,Molecular Medicine ,Macrolides ,Sequence Alignment - Abstract
The Diels-Alder [4 + 2] cycloaddition reaction is one of the most powerful and elegant organic synthesis methods for forming 6-membered molecules and has been known for nearly a century. However, whether and how enzymes catalyze this type of reaction is still not completely clear. Here we focus on PyrI4, an enzyme found in the biosynthetic pathway of pyrroindomycins where it catalyzes the formation of a spiro-conjugate via an enzyme-dependent exo-selective [4 + 2] cycloaddition reaction. We report the crystal structures of PyrI4 alone and in complex with its product. Comparative analysis of these structures, combined with biochemical analysis, lead us to propose a unique trapping mechanism whereby the lid-like action of the N-terminal tail imposes conformational constraints on the β barrel catalytic core, which enhances the proximity and polarization effects of reactive groups (1,3-diene and alkene) to drive cyclization in a regio- and stereo-specific manner. This work represents an important step toward the wider application of enzyme-catalyzed [4 + 2] cyclization for synthetic purposes.
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- 2015
14. Recent advances in understanding the enzymatic reactions of [4+2] cycloaddition and spiroketalization
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Wen Liu, Zhenhua Tian, and Qingfei Zheng
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chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Cyclohexene ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Cycloaddition ,0104 chemical sciences ,Analytical Chemistry ,Enzyme catalysis ,Catalysis ,Enzymes ,Synthetic biology ,chemistry.chemical_compound ,Enzyme ,Cyclization - Abstract
Diels-Alder-like [4+2] cycloaddition and ketalization of dihydroxy ketones are cyclization reactions with different mechanisms that produce characteristic cyclohexene and spiroketal units, respectively. Here, we review newly identified, naturally occurring '[4+2] cycloadditionases' and 'spiroketalases' and reveal several similarities between the two types of enzymes. During catalysis, these enzymes control product stereochemistry or/and enhance the transformation rate. They exhibit convergent evolution of [4+2] cycloaddition or spiroketalization activity, which is likely dependent on interactions of variable protein folds with specialized chemical structures. An understanding of these similarities is expected to allow for establishment of the underlying principles for the application and catalyst design of associated enzymatic reactions in organic chemistry and synthetic biology.
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- 2015
15. Rational Control of Polyketide Extender Units by Structure-Based Engineering of a Crotonyl-CoA Carboxylase/Reductase in Antimycin Biosynthesis
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Qingfei Zheng, Ikuro Abe, Lihan Zhang, Takayoshi Awakawa, Yan Yan, Wen Liu, and Takahiro Mori
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chemistry.chemical_classification ,Chemistry ,Stereochemistry ,Protein Conformation ,Rational design ,Mutagenesis (molecular biology technique) ,Antimycin A ,General Chemistry ,Protein engineering ,General Medicine ,Reductase ,Protein Engineering ,Catalysis ,Pyruvate carboxylase ,Polyketide ,chemistry.chemical_compound ,Biosynthesis ,Biochemistry ,Acyl-CoA Dehydrogenases ,Oxidoreductase ,Polyketides - Abstract
Bioengineering of natural product biosynthesis is a powerful approach to expand the structural diversity of bioactive molecules. However, in polyketide biosynthesis, the modification of polyketide extender units, which form the carbon skeletons, has remained challenging. Herein, we report the rational control of polyketide extender units by the structure-based engineering of a crotonyl-CoA carboxylase/reductase (CCR), in the biosynthesis of antimycin. Site-directed mutagenesis of the CCR enzyme AntE, guided by the crystal structure solved at 1.5 angstrom resolution, expanded its substrate scope to afford indolylmethylmalonyl-CoA by the V350G mutation. The mutant A182L selectively catalyzed carboxylation over the regular reduction. Furthermore, the combinatorial biosynthesis of heterocycle- and substituted arene-bearing antimycins was achieved by an engineered Streptomyces strain bearing AntE(V350G). These findings deepen our understanding of the molecular mechanisms of the CCRs, which will serve as versatile biocatalysts for the manipulation of building blocks, and set the stage for the rational design of polyketide biosynthesis.
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- 2015
16. An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins
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Peng Sun, Yan Yan, Shuaixiang Zhou, Xinying Jia, Wen Liu, Zhuhua Wu, Qingfei Zheng, Attila Mándi, Hua Zhang, Dandan Chen, Zhenhua Tian, Futao Yu, and Tibor Kurtán
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DNA, Bacterial ,Stereochemistry ,Cyclohexene ,Stereoisomerism ,Alkenes ,Catalysis ,chemistry.chemical_compound ,Természettudományok ,Cyclohexenes ,Molecule ,Intramolecular Lyases ,Kémiai tudományok ,Molecular Biology ,chemistry.chemical_classification ,Biological Products ,Molecular Structure ,Alkene ,Cell Biology ,Pyrrolidinones ,Recombinant Proteins ,Streptomyces ,Cycloaddition ,Chemistry ,Enzyme ,Models, Chemical ,chemistry ,Cyclization ,Mutation ,Stereoselectivity ,Macrolides ,Natural Products Chemistry ,Plasmids - Abstract
The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.
- Published
- 2015
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