scholarly journals Comparative investigation into formycin A and pyrazofurin A biosynthesis reveals branch pathways for the construction of C-nucleoside scaffolds

2019 ◽  
Author(s):  
Meng Zhang ◽  
Peichao Zhang ◽  
Gudan Xu ◽  
Wenting Zhou ◽  
Yaojie Gao ◽  
...  
Keyword(s):  
Biological Activities ◽  
Bond Formation ◽  
Genome Mining ◽  
Comparative Investigation ◽  
Combinatorial Biosynthesis ◽  
Glycosidic Bond ◽  
Enzymatic Reactions ◽  
Natural Product Biosynthesis ◽  
Nucleoside Antibiotics ◽  
Chemical Structures

ABSTRACTFormycin A (FOR-A) and pyrazofurin A (PRF-A) are purine-related C-nucleoside antibiotics, in which ribose and a pyrazole-derived base are linked by a C-glycosidic bond, however, the logic underlying the biosynthesis of these molecules has remained largely unexplored. Here, we report the discovery of the pathways for FOR-A and PRF-A biosynthesis from diverse actinobacteria, and demonstrate that their biosynthesis is initiated by a lysine N6-monooxygenase. Moreover, we show that the forT and prfE (individually related to FOR-A and PRF-A biosynthesis) mutants are correspondingly capable of accumulating the unexpected pyrazole-related intermediates, compound 11 and 9a. We also decipher the enzymatic basis of ForT/PrfE for the C-glycosidic bond formation in FOR-A/PRF-A biosynthesis. To our knowledge, ForT/PrfE represents the first example of β-RFA-P (β-ribofuranosyl-aminobenzene 5’-phosphate) synthase-like enzymes governing C-nucleoside scaffold construction in natural product biosynthesis. These data establish a foundation for combinatorial biosynthesis of related purine nucleoside antibiotics, and also open the way for target-directed genome mining of PRF-A/FOR-A related antibiotics.IMPORTANCEFormycin A (FOR-A) and pyrazofurin A (PRF-A) are well known for their unusual chemical structures and remarkable biological activities. Actually, deciphering FOR-A/PRF-A biosynthesis will not only expand biochemical repertoire for novel enzymatic reactions, but also permit the target-oriented genome mining of FOR-A/PRF-A related C-nucleoside antibiotics.

scholarly journals Comparative Investigation into Formycin A and Pyrazofurin A Biosynthesis Reveals Branch Pathways for the Construction of C-Nucleoside Scaffolds

2019 ◽  
Vol 86 (2) ◽  
Author(s):  
Meng Zhang ◽  
Peichao Zhang ◽  
Gudan Xu ◽  
Wenting Zhou ◽  
Yaojie Gao ◽  
...  
Keyword(s):  
Biological Activities ◽  
Genome Mining ◽  
Gene Clusters ◽  
Combinatorial Biosynthesis ◽  
Glycosidic Bond ◽  
Enzymatic Reactions ◽  
Nucleoside Antibiotics ◽  
Enzymatic Mechanism ◽  
Chemical Structures ◽  
The Way

ABSTRACT Formycin A (FOR-A) and pyrazofurin A (PRF-A) are purine-related C-nucleoside antibiotics in which ribose and a pyrazole-derived base are linked by a C-glycosidic bond. However, the logic underlying the biosynthesis of these molecules has remained largely unexplored. Here, we report the discovery of the pathways for FOR-A and PRF-A biosynthesis from diverse actinobacteria and propose that their biosynthesis is likely initiated by a lysine N6-monooxygenase. Moreover, we show that forT and prfT (involved in FOR-A and PRF-A biosynthesis, respectively) mutants are correspondingly capable of accumulating the unexpected pyrazole-related intermediates 4-amino-3,5-dicarboxypyrazole and 3,5-dicarboxy-4-oxo-4,5-dihydropyrazole. We also decipher the enzymatic mechanism of ForT/PrfT for C-glycosidic bond formation in FOR-A/PRF-A biosynthesis. To our knowledge, ForT/PrfT represents an example of β-RFA-P (β-ribofuranosyl-aminobenzene 5ʹ-phosphate) synthase-like enzymes governing C-nucleoside scaffold construction in natural product biosynthesis. These data establish a foundation for combinatorial biosynthesis of related purine nucleoside antibiotics and also open the way for target-directed genome mining of PRF-A/FOR-A-related antibiotics. IMPORTANCE FOR-A and PRF-A are C-nucleoside antibiotics known for their unusual chemical structures and remarkable biological activities. Deciphering the enzymatic mechanism for the construction of a C-nucleoside scaffold during FOR-A/PRF-A biosynthesis will not only expand the biochemical repertoire for novel enzymatic reactions but also permit target-oriented genome mining of FOR-A/PRF-A-related C-nucleoside antibiotics. Moreover, the availability of FOR-A/PRF-A biosynthetic gene clusters will pave the way for the rational generation of designer FOR-A/PRF-A derivatives with enhanced/selective bioactivity via synthetic biology strategies.

scholarly journals Coordinated Biosynthesis of the Purine Nucleoside Antibiotics Aristeromycin and Coformycin in Actinomycetes

2018 ◽  
Vol 84 (22) ◽  
Author(s):  
Gudan Xu ◽  
Liyuan Kong ◽  
Rong Gong ◽  
Liudong Xu ◽  
Yaojie Gao ◽  
...  
Keyword(s):  
Biological Activities ◽  
Genome Mining ◽  
Combinatorial Biosynthesis ◽  
Purine Nucleoside ◽  
Enzymatic Reactions ◽  
Single Strain ◽  
Content Type ◽  
Precursor Pool ◽  
Irreversible Reaction ◽  
Chemical Structures

ABSTRACT Purine nucleoside antibiotic pairs, concomitantly produced by a single strain, are an important group of microbial natural products. Here, we report a target-directed genome mining approach to elucidate the biosynthesis of the purine nucleoside antibiotic pair aristeromycin (ARM) and coformycin (COF) in Micromonospora haikouensis DSM 45626 (a new producer for ARM and COF) and Streptomyces citricolor NBRC 13005 (a new COF producer). We also provide biochemical data that MacI and MacT function as unusual phosphorylases, catalyzing an irreversible reaction for the tailoring assembly of neplanocin A (NEP-A) and ARM. Moreover, we demonstrate that MacQ is shown to be an adenosine-specific deaminase, likely relieving the potential “excess adenosine” for producing cells. Finally, we report that MacR, an annotated IMP dehydrogenase, is actually an NADPH-dependent GMP reductase, which potentially plays a salvage role for the efficient supply of the precursor pool. Hence, these findings illustrate a fine-tuned pathway for the biosynthesis of ARM and also open the way for the rational search for purine antibiotic pairs. IMPORTANCE ARM and COF are well known for their prominent biological activities and unusual chemical structures; however, the logic of their biosynthesis has long been poorly understood. Actually, the new insights into the ARM and COF pathway will not only enrich the biochemical repertoire for interesting enzymatic reactions but may also lay a solid foundation for the combinatorial biosynthesis of this group of antibiotics via a target-directed genome mining strategy.

scholarly journals Biosynthesis of 2′-Chloropentostatin and 2′-Amino-2′-Deoxyadenosine Highlights a Single Gene Cluster Responsible for Two Independent Pathways in Actinomadura sp. Strain ATCC 39365

2017 ◽  
Vol 83 (10) ◽  
Author(s):  
Yaojie Gao ◽  
Gudan Xu ◽  
Pan Wu ◽  
Jin Liu ◽  
You-sheng Cai ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Single Gene ◽  
Combinatorial Biosynthesis ◽  
Pathway Engineering ◽  
Enzymatic Reactions ◽  
Strain Atcc ◽  
Nudix Hydrolase ◽  
Nucleoside Antibiotics ◽  
Chemical Structures ◽  
Hydrolysis Of

ABSTRACT 2′-Chloropentostatin (2′-Cl PTN, 2′-chloro-2′-deoxycoformycin) and 2′-amino-2′-deoxyadenosine (2′-amino dA) are two adenosine-derived nucleoside antibiotics coproduced by Actinomadura sp. strain ATCC 39365. 2′-Cl PTN is a potent adenosine deaminase (ADA) inhibitor featuring an intriguing 1,3-diazepine ring, as well as a chlorination at C-2′ of ribose, and 2′-amino dA is an adenosine analog showing bioactivity against RNA-type virus infection. However, the biosynthetic logic of them has remained poorly understood. Here, we report the identification of a single gene cluster (ada) essential for the biosynthesis of 2′-Cl PTN and 2′-amino dA. Further systematic genetic investigations suggest that 2′-Cl PTN and 2′-amino dA are biosynthesized by independent pathways. Moreover, we provide evidence that a predicted cation/H+ antiporter, AdaE, is involved in the chlorination step during 2′-Cl PTN biosynthesis. Notably, we demonstrate that 2′-amino dA biosynthesis is initiated by a Nudix hydrolase, AdaJ, catalyzing the hydrolysis of ATP. Finally, we reveal that the host ADA (designated ADA1), capable of converting adenosine/2′-amino dA to inosine/2′-amino dI, is not very sensitive to the powerful ADA inhibitor pentostatin. These findings provide a basis for the further rational pathway engineering of 2′-Cl PTN and 2′-amino dA production. IMPORTANCE 2′-Cl PTN/PTN and 2′-amino dA have captivated the great interests of scientists, owing to their unusual chemical structures and remarkable bioactivities. However, the precise logic for their biosynthesis has been elusive for decades. Actually, the identification and elucidation of their biosynthetic pathways not only enrich the biochemical repertoire of novel enzymatic reactions but may also lay solid foundations for the pathway engineering and combinatorial biosynthesis of this family of purine nucleoside antibiotics to generate novel hybrid analogs with improved features.

scholarly journals New insights into bacterial type II polyketide biosynthesis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 172 ◽  
Author(s):  
Zhuan Zhang ◽  
Hai-Xue Pan ◽  
Gong-Li Tang
Keyword(s):  
Biological Activities ◽  
Genome Mining ◽  
Large Family ◽  
Combinatorial Biosynthesis ◽  
Type Ii ◽  
Polyketide Biosynthesis ◽  
Aromatic Polyketides ◽  
Starting Point ◽  
Biosynthetic Engineering ◽  
Bacterial Type

Bacterial aromatic polyketides, exemplified by anthracyclines, angucyclines, tetracyclines, and pentangular polyphenols, are a large family of natural products with diverse structures and biological activities and are usually biosynthesized by type II polyketide synthases (PKSs). Since the starting point of biosynthesis and combinatorial biosynthesis in 1984–1985, there has been a continuous effort to investigate the biosynthetic logic of aromatic polyketides owing to the urgent need of developing promising therapeutic candidates from these compounds. Recently, significant advances in the structural and mechanistic identification of enzymes involved in aromatic polyketide biosynthesis have been made on the basis of novel genetic, biochemical, and chemical technologies. This review highlights the progress in bacterial type II PKSs in the past three years (2013–2016). Moreover, novel compounds discovered or created by genome mining and biosynthetic engineering are also included.

scholarly journals Biosynthesis of C-nucleoside antibiotics in actinobacteria: recent advances and future developments

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Meng Zhang ◽  
Liyuan Kong ◽  
Rong Gong ◽  
Marianna Iorio ◽  
Stefano Donadio ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Synthetic Biology ◽  
Plant Protection ◽  
Biological Activities ◽  
Genome Mining ◽  
Nucleoside Antibiotics ◽  
Future Developments ◽  
Recent Advances ◽  
Microbial Natural Products ◽  
Epidemic Diseases

AbstractEpidemic diseases and antibiotic resistance are urgent threats to global health, and human is confronted with an unprecedented dilemma to conquer them by expediting development of new natural product related drugs. C-nucleoside antibiotics, a remarkable group of microbial natural products with diverse biological activities, feature a heterocycle base linked with a ribosyl moiety via an unusual C-glycosidic bond, and have played significant roles in healthcare and for plant protection. Elucidating how nature biosynthesizes such a group of antibiotics has provided the basis for engineered biosynthesis as well as targeted genome mining of more C-nucleoside antibiotics towards improved properties. In this review, we mainly summarize the recent advances on the biosynthesis of C-nucleoside antibiotics, and we also tentatively discuss the future developments on rationally accessing C-nucleoside diversities in a more efficient and economical way via synthetic biology strategies.

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.

Design, Synthesis, Characterization and in silico molecular docking studies and in vivo anti-inflammatory Activity of Pyrazoline clubbed Thiazolinone Derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Deepak Kumar Singh ◽  
Mayank Kulshreshtha ◽  
Yogesh Kumar ◽  
Pooja A Chawla ◽  
Akash Ved ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Biological Activities ◽  
Inflammatory Activity ◽  
Standard Drug ◽  
Docking Score ◽  
Chemical Structures ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

Biotransformation of Coumarins by Filamentous Fungi: An Alternative Way for Achievement of Bioactive Analogs

2019 ◽  
Vol 16 (6) ◽  
pp. 568-577 ◽  
Author(s):  
Jainara Santos do Nascimento ◽  
João Carlos Silva Conceição ◽  
Eliane de Oliveira Silva
Keyword(s):  
Filamentous Fungi ◽  
Chemical Reactions ◽  
Biological Activities ◽  
Chemical Transformations ◽  
Chemical Structures ◽  
Pattern Structures ◽  
Pharmacological Interest ◽  
Aspergillus Sp ◽  
The Impact ◽  
Related Compounds

Coumarins are natural 1,2-benzopyrones, present in remarkable amounts as secondary metabolites in edible and medicinal plants. The low yield in the coumarins isolation from natural sources, along with the difficulties faced by the total synthesis, make them attractive for biotechnological studies. The current literature contains several reports on the biotransformation of coumarins by fungi, which can generate chemical analogs with high selectivity, using mild and eco-friendly conditions. Prompted by the enormous pharmacological interest in the coumarin-related compounds, their alimentary and chemical applications, this review covers the biotransformation of coumarins by filamentous fungi. The chemical structures of the analogs were presented and compared with those from the pattern structures. The main chemical reactions catalyzed the insertion of functional groups, and the impact on the biological activities caused by the chemical transformations were discussed. Several chemical reactions can be catalyzed by filamentous fungi in the coumarin scores, mainly lactone ring opening, C3-C4 reduction and hydroxylation. Chunninghamella sp. and Aspergillus sp. are the most common fungi used in these transformations. Concerning the substrates, the biotransformation of pyranocoumarins is a rarer process. Sometimes, the bioactivities were improved by the chemical modifications and coincidences with the mammalian metabolism were pointed out.

Anticancer Active Heterocyclic Chalcones: Recent Developments

2020 ◽  
Vol 20 ◽  
Author(s):  
Prasad Dandawate ◽  
Khursheed Ahmed ◽  
Subhash Padhye ◽  
Aamir Ahmad ◽  
Bernhard Biersack
Keyword(s):  
Histone Deacetylases ◽  
Biological Activities ◽  
Synthetic Methods ◽  
Antitumor Activities ◽  
Web Based ◽  
Chemical Structures ◽  
Recent Developments ◽  
Number Of Publications ◽  
Tubulin Polymerization Inhibitors ◽  
Dna Binding Properties

Background: Chalcones are structurally simple compounds that are easily accessible by synthetic methods. Heterocyclic chalcones have gained the interest among scientists due to their diverse biological activities. The anti-tumor activities of heterocyclic chalcones are especially remarkable and the growing number of publications dealing with this topic warrants an up-to-date compilation. Methods: Search for antitumor active heterocyclic chalcones was carried out using Pubmed and Scifinder as common web-based literature searching tools. Pertinent and current literature is covered from 2015/2016 to 2019. Chemical structures, biological activities and modes of action of anti-tumor active heterocyclic chalcones are summarized. Results: Simply prepared chalcones have emerged over the last years with promising antitumor activities. Among them is a considerable number of tubulin polymerization inhibitors. But there are also new chalcones targeting special enzymes such as histone deacetylases or with DNA-binding properties. Conclusion: This review provides a summary of recent heterocyclic chalcone derivatives with distinct anti-tumor activities.

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