Bacillus subtilis produces many chemlcally-dwerse seconaary metaDolltes or interest to chemists ano biologlsts. Based on this, this review gives a detailed overview of the natural components produced by B. subtilis in...Bacillus subtilis produces many chemlcally-dwerse seconaary metaDolltes or interest to chemists ano biologlsts. Based on this, this review gives a detailed overview of the natural components produced by B. subtilis including cyclic lipopeptides, polypeptides, proteins （enzymes）, and non-peptide products. Their structures, bioactive ac- tivities and the relevant variants as novel lead structures for drug discovery are also described. The challenging effects of fermentation metabolites, isolation and purification, as well as the overproduction of bioactive com- pounds from B. subtilis by metabolic engineering, ＇~ere also highlighted. Systematically exploring biosynthetic routes and the functions of secondary metabolites from 13. subtilis may not only be beneficial in improving yields of the products, but also in helping them to be used in food industry and public medical service on a large-scale.展开更多
Tetronate antibiotics, a growing family of natural products featuring a characteristic tetronic acid moiety, are of importance and of particular interest for their typical structures, especially the spirotetronate str...Tetronate antibiotics, a growing family of natural products featuring a characteristic tetronic acid moiety, are of importance and of particular interest for their typical structures, especially the spirotetronate structure, and corresponding versatile biolog- ical activities. Considerable efforts have persistently performed since the first tetronate was isolated, to elucidate the biosyn- thesis of natural tetronate products, by isotope-labeled feeding experiments, genetical characterization of biosynthetic gene clusters, and biochemical reconstitution of key enzymatic catalyzed reactions. Accordingly, the biosynthesis of spirotetronates has been gradually determined, including biosynthesis of a polyketide-derived backbone for spirotetronate aglycone, incorpo- ration of a glycerol-derived three-carbon unit into tetronic acid moiety, formation of mature aglycone via Diels-AIder-like re- action, and decorations of aglycone with various deoxysugar moieties. In this paper, the biosynthetic investigations of natural tetronates are well documented and a common biosynthetic route for this group of natural products is summarized accordingly.展开更多
Natural products are often secondary metabolites in living organisms with a wide variety of biological activities. The diversification of their structures, aiming to the search for biologically active small molecules ...Natural products are often secondary metabolites in living organisms with a wide variety of biological activities. The diversification of their structures, aiming to the search for biologically active small molecules by expanding chemical and functional spaces, is a major area of current interest in synthetic chemistry. However, developing synthetic accessibility and efficiency often faces challenges associated with structural complexity. Synthetic biology has recently emerged and is promising to accomplish complex molecules; by contrast, the application to structural diversification of natural products relies on the understanding, development and utilization of compatible biosynthetic machinery. Here, we review the strategies primarily concerning the artificial evolution of microbial natural products whose biosynthesis features template enzymology, including ribosomaUy synthesized and post-translationally modified peptides as well as the assembly line-resultant polyketides, non-ribosomal peptides and hybrids. The establishment of these approaches largely facilitates the expansion of the molecular diversity and utility through bioengineering at different stages/levels of biosynthetic pathways.展开更多
Metalloproteins have inspired chemists for many years to synthesize artificial catalysts that mimic native enzymes.As a complementary approach to studying native enzymes or making synthetic models,biosynthetic approac...Metalloproteins have inspired chemists for many years to synthesize artificial catalysts that mimic native enzymes.As a complementary approach to studying native enzymes or making synthetic models,biosynthetic approach using small and stable proteins to model native enzymes has offered advantages of incorporating non-covalent secondary sphere interactions under physiological conditions.However,most biosynthetic models are restricted to natural amino acids.To overcome this limitation,incorporating unnatural amino acids into the biosynthetic models has shown promises.In this review,we summarize first synthetic,semisynthetic and biological methods of incorporates unnatural amino acids(UAAs)into proteins,followed by progress made in incorporating UAAs into both native metalloproteins and their biosynthetic models to fine-tune functional properties beyond native enzymes or their variants containing natural amino acids,such as reduction potentials of azurin,O_2 reduction rates and percentages of product formation of HCO models in Mb,the rate of radical transport in ribonucleotide reductase(RNR)and the proton and electron transfer pathways in photosystemⅡ(PSⅡ).We also discuss how this endeavour has allowed systematic investigations of precise roles of conserved residues in metalloproteins,such as Metl21 in azurin,Tyr244 that is cross-linked to one of the three His ligands to CuB in HCO,Tyr122,356,730 and 731 in RNR and TyrZ in PSⅡ.These examples have demonstrated that incorporating UAAs has provided a new dimension in our efforts to mimic native enzymes and in providing deeper insights into structural features responsible high enzymatic activity and reaction mechanisms,making it possible to design highly efficient artificial catalysts with similar or even higher activity than native enzymes.展开更多
基金Supported by the National Natural Science Foundation of China(21376215)the National Science and Technology Major Project of New Drug,China(2012ZX09103101-075)+2 种基金the Innovative Research Platform co-constructed by Zhejiang University and Taizhou City,and the Science and Technology Project of Zhejiang Province(2014C33174)the Major State Basic Research Development Program of China(2011CB710803)the National High-Tech Research and Development Program of China(2012AA022302)
文摘Bacillus subtilis produces many chemlcally-dwerse seconaary metaDolltes or interest to chemists ano biologlsts. Based on this, this review gives a detailed overview of the natural components produced by B. subtilis including cyclic lipopeptides, polypeptides, proteins （enzymes）, and non-peptide products. Their structures, bioactive ac- tivities and the relevant variants as novel lead structures for drug discovery are also described. The challenging effects of fermentation metabolites, isolation and purification, as well as the overproduction of bioactive com- pounds from B. subtilis by metabolic engineering, ＇~ere also highlighted. Systematically exploring biosynthetic routes and the functions of secondary metabolites from 13. subtilis may not only be beneficial in improving yields of the products, but also in helping them to be used in food industry and public medical service on a large-scale.
基金supported by the Research Fund for the Doctoral Program of Higher Education of Chinathe Research and Development Program of Hubei Province,and the China Postdoctoral Science Foundation(2012M521461)
文摘Tetronate antibiotics, a growing family of natural products featuring a characteristic tetronic acid moiety, are of importance and of particular interest for their typical structures, especially the spirotetronate structure, and corresponding versatile biolog- ical activities. Considerable efforts have persistently performed since the first tetronate was isolated, to elucidate the biosyn- thesis of natural tetronate products, by isotope-labeled feeding experiments, genetical characterization of biosynthetic gene clusters, and biochemical reconstitution of key enzymatic catalyzed reactions. Accordingly, the biosynthesis of spirotetronates has been gradually determined, including biosynthesis of a polyketide-derived backbone for spirotetronate aglycone, incorpo- ration of a glycerol-derived three-carbon unit into tetronic acid moiety, formation of mature aglycone via Diels-AIder-like re- action, and decorations of aglycone with various deoxysugar moieties. In this paper, the biosynthetic investigations of natural tetronates are well documented and a common biosynthetic route for this group of natural products is summarized accordingly.
基金supported by the National Natural Science Foundation of China (81402831, 21520102004, 31430005, 21472231)Science and Technology Commission of Shanghai Municipality (Shanghai, China) (14JC1407700, 15JC1400400) of China
文摘Natural products are often secondary metabolites in living organisms with a wide variety of biological activities. The diversification of their structures, aiming to the search for biologically active small molecules by expanding chemical and functional spaces, is a major area of current interest in synthetic chemistry. However, developing synthetic accessibility and efficiency often faces challenges associated with structural complexity. Synthetic biology has recently emerged and is promising to accomplish complex molecules; by contrast, the application to structural diversification of natural products relies on the understanding, development and utilization of compatible biosynthetic machinery. Here, we review the strategies primarily concerning the artificial evolution of microbial natural products whose biosynthesis features template enzymology, including ribosomaUy synthesized and post-translationally modified peptides as well as the assembly line-resultant polyketides, non-ribosomal peptides and hybrids. The establishment of these approaches largely facilitates the expansion of the molecular diversity and utility through bioengineering at different stages/levels of biosynthetic pathways.
基金supported by the US National Science Foundation(CHE-1413328)the Major State Basic Research Program of China(2015CB856203)+1 种基金the National Natural Science Foundation of China (21325211,31500641)theTianjinMunicipalGrant(13ZCZDSY04800, 14ZCZDSY00059,14JCYBJC43400)
文摘Metalloproteins have inspired chemists for many years to synthesize artificial catalysts that mimic native enzymes.As a complementary approach to studying native enzymes or making synthetic models,biosynthetic approach using small and stable proteins to model native enzymes has offered advantages of incorporating non-covalent secondary sphere interactions under physiological conditions.However,most biosynthetic models are restricted to natural amino acids.To overcome this limitation,incorporating unnatural amino acids into the biosynthetic models has shown promises.In this review,we summarize first synthetic,semisynthetic and biological methods of incorporates unnatural amino acids(UAAs)into proteins,followed by progress made in incorporating UAAs into both native metalloproteins and their biosynthetic models to fine-tune functional properties beyond native enzymes or their variants containing natural amino acids,such as reduction potentials of azurin,O_2 reduction rates and percentages of product formation of HCO models in Mb,the rate of radical transport in ribonucleotide reductase(RNR)and the proton and electron transfer pathways in photosystemⅡ(PSⅡ).We also discuss how this endeavour has allowed systematic investigations of precise roles of conserved residues in metalloproteins,such as Metl21 in azurin,Tyr244 that is cross-linked to one of the three His ligands to CuB in HCO,Tyr122,356,730 and 731 in RNR and TyrZ in PSⅡ.These examples have demonstrated that incorporating UAAs has provided a new dimension in our efforts to mimic native enzymes and in providing deeper insights into structural features responsible high enzymatic activity and reaction mechanisms,making it possible to design highly efficient artificial catalysts with similar or even higher activity than native enzymes.
