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Cyclodipeptide synthase

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https://www.readbyqxmd.com/read/29574613/expanding-tryptophan-containing-cyclodipeptide-synthase-spectrum-by-identification-of-nine-members-from-streptomyces-strains
#1
Jing Liu, Huili Yu, Shu-Ming Li
Cyclodipeptide synthases (CDPSs) comprise normally 200-300 amino acid residues and are mainly found in bacteria. They hijack aminoacyl-tRNAs from the ribosomal machinery for cyclodipeptide formation. In this study, nine new CDPS genes from eight Streptomyces strains were cloned into pET28a vector and expressed in Escherichia coli. Structural elucidation of the isolated products led to the identification of one cyclo-L-Trp-L-Leu, two cyclo-L-Trp-L-Pro, and three cyclo-L-Trp-L-Trp synthases. Other three CDPSs produce cyclo-L-Trp-L-Ala or cyclo-L-Trp-L-Tyr as the major cyclodipeptide...
March 24, 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29505829/structural-basis-for-partition-of-the-cyclodipeptide-synthases-into-two-subfamilies
#2
Gabrielle Bourgeois, Jérôme Seguin, Morgan Babin, Pascal Belin, Mireille Moutiez, Yves Mechulam, Muriel Gondry, Emmanuelle Schmitt
Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides that can be further used for the synthesis of diketopiperazines. It was shown that CDPSs fall into two subfamilies, NYH and XYP, characterized by the presence of specific sequence signatures. However, current understanding of CDPSs only comes from studies of enzymes from the NYH subfamily. The present study reveals the crystal structures of three CDPSs from the XYP subfamily. Comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold...
March 2, 2018: Journal of Structural Biology
https://www.readbyqxmd.com/read/29500259/discovery-and-biosynthesis-of-the-antibiotic-bicyclomycin-in-distant-bacterial-classes
#3
Natalia M Vior, Rodney Lacret, Govind Chandra, Siobhán Dorai-Raj, Martin Trick, Andrew W Truman
Bicyclomycin (BCM) is a clinically promising antibiotic that is biosynthesised by Streptomyces cinnamoneus DSM 41675. BCM is structurally characterized by a core cyclo(L-Ile-L-Leu) 2,5-diketopiperazine (DKP) that is extensively oxidized. Here, we identify the BCM biosynthetic gene cluster, which shows that the core of BCM is biosynthesised by a cyclodipeptide synthase and the oxidative modifications are introduced by five 2-oxoglutarate-dependent dioxygenases and one cytochrome P450 monooxygenase. The discovery of the gene cluster enabled the identification of BCM pathways encoded in the genomes of hundreds of Pseudomonas aeruginosa isolates distributed globally, and heterologous expression of the pathway from P...
March 2, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29483897/a-comprehensive-overview-of-the-cyclodipeptide-synthase-family-enriched-with-the-characterization-of-32-new-enzymes
#4
Muriel Gondry, Isabelle B Jacques, Robert Thai, Morgan Babin, Nicolas Canu, Jérôme Seguin, Pascal Belin, Jean-Luc Pernodet, Mireille Moutiez
Cyclodipeptide synthases (CDPSs) use as substrates two amino acids activated as aminoacyl-tRNAs to synthesize cyclodipeptides in secondary metabolites biosynthetic pathways. Since the first description of a CDPS in 2002, the number of putative CDPSs in databases has increased exponentially, reaching around 800 in June 2017. They are likely to be involved in numerous biosynthetic pathways but the diversity of their products is still under-explored. Here, we describe the activity of 32 new CDPSs, bringing the number of experimentally characterized CDPSs to about 100...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29377457/non-canonical-amino-acid-incorporation-into-2-5-diketopiperazines-by-cyclodipeptide-synthases
#5
Nicolas Canu, Pascal Belin, Robert Thai, Isabelle Correia, Olivier Lequin, Jérôme Seguin, Mireille Moutiez, Muriel Gondry
The manipulation of natural product biosynthetic pathways is a powerful means of expanding the chemical diversity of bioactive molecules. 2,5-diketopiperazines (2,5-DKPs) have been widely developed by medicinal chemists, but their biological production is yet to be exploited. We introduce here an in vivo method to incorporate non-canonical amino acids (ncAAs) into 2,5-DKPs using cyclodipeptide synthases (CDPSs), the enzymes responsible for scaffold assembly in many 2,5-DKP biosynthetic pathways. CDPSs use aminoacyl-tRNAs as substrates...
January 29, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29334896/global-analysis-of-prokaryotic-trna-derived-cyclodipeptide-biosynthesis
#6
Michael A Skinnider, Chad W Johnston, Nishanth J Merwin, Chris A Dejong, Nathan A Magarvey
BACKGROUND: Among naturally occurring small molecules, tRNA-derived cyclodipeptides are a class that have attracted attention for their diverse and desirable biological activities. However, no tools are available to link cyclodipeptide synthases identified within prokaryotic genome sequences to their chemical products. Consequently, it is unclear how many genetically encoded cyclodipeptides represent novel products, and which producing organisms should be targeted for discovery. RESULTS: We developed a pipeline for identification and classification of cyclodipeptide biosynthetic gene clusters and prediction of aminoacyl-tRNA substrates and complete chemical structures...
January 15, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29194897/a-six-oxidase-cascade-for-tandem-c-h-bond-activation-revealed-by-reconstitution-of-bicyclomycin-biosynthesis
#7
Song Meng, Wei Han, Juan Zhao, Xiao-Hong Jian, Hai-Xue Pan, Gong-Li Tang
As a commercial antibiotic, bicyclomycin (BCM) is currently the only known natural product targeting the transcription termination factor rho. It belongs to a family of highly functionalized diketopiperazine (DKP) alkaloids and bears a unique O-bridged bicyclo[4.2.2]piperazinedione ring system, a C1 triol, and terminal exo-methylene groups. We have identified and characterized the BCM biosynthetic pathway by heterologous biotransformations, in vitro biochemical assays, and one-pot enzymatic synthesis. A tRNA-dependent cyclodipeptide synthase guides the heterodimerization of leucine and isoleucine to afford the DKP precursor; subsequently, six redox enzymes, including five α-ketoglutarate/Fe2+ -dependent dioxygenases and one cytochrome P450 monooxygenase, regio- and stereoselectively install four hydroxy groups (primary, secondary, and two tertiary), an exo-methylene moiety, and a medium-sized bridged ring through the functionalization of eight unactivated C-H bonds...
January 15, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29065531/cyclodipeptides-an-overview-of-their-biosynthesis-and-biological-activity
#8
REVIEW
Awdhesh Kumar Mishra, Jaehyuk Choi, Seong-Jin Choi, Kwang-Hyun Baek
Cyclodipeptides (CDP) represent a diverse family of small, highly stable, cyclic peptides that are produced as secondary functional metabolites or side products of protein metabolism by bacteria, fungi, and animals. They are widespread in nature, and exhibit a broad variety of biological and pharmacological activities. CDP synthases (CDPSs) and non-ribosomal peptide synthetases (NRPSs) catalyze the biosynthesis of the CDP core structure, which is further modified by tailoring enzymes often associated with CDP biosynthetic gene clusters...
October 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29064250/mutations-of-residues-in-pocket-p1-of-a-cyclodipeptide-synthase-strongly-increase-product-formation
#9
Kirsten Brockmeyer, Shu-Ming Li
Expression of a cyclodipeptide synthase gene from Nocardiopsis prasina (CDPS-Np) in Escherichia coli resulted in the formation of cyclo-(l-Tyr-l-Tyr) (1) as the minor and cyclo-(l-Tyr-l-Phe) (2) as the major products. Site-directed mutagenesis revealed a strong influence on product accumulation of the amino acid residues in pocket P1. An 8-fold increase in product formation for 1 and 10-fold for 2 were detected in the double mutant T82V_Y196F compared with the wild type.
November 22, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/29053243/identification-of-the-biosynthetic-pathway-for-the-antibiotic-bicyclomycin
#10
Jon B Patteson, Wenlong Cai, Rachel A Johnson, Kevin C Santa Maria, Bo Li
Diketopiperazines (DKPs) make up a large group of natural products with diverse structures and biological activities. Bicyclomycin is a broad-spectrum DKP antibiotic with unique structure and function: it contains a highly oxidized bicyclic [4.2.2] ring and is the only known selective inhibitor of the bacterial transcription termination factor, Rho. Here, we identify the biosynthetic gene cluster for bicyclomycin containing six iron-dependent oxidases. We demonstrate that the DKP core is made by a tRNA-dependent cyclodipeptide synthase, and hydroxylations on two unactivated sp3 carbons are performed by two mononuclear iron, α-ketoglutarate-dependent hydroxylases...
January 9, 2018: Biochemistry
https://www.readbyqxmd.com/read/28060488/aminoacyl-trna-utilizing-enzymes-in-natural-product-biosynthesis
#11
REVIEW
Mireille Moutiez, Pascal Belin, Muriel Gondry
Aminoacyl-tRNAs were long thought to be involved solely in ribosome-dependent protein synthesis and essential primary metabolism processes, such as targeted protein degradation and peptidoglycan synthesis. About 10 years ago, an aminoacyl-tRNA-dependent enzyme involved in the biosynthesis of the antibiotic valanimycin was discovered in a Streptomyces strain. Far from being an isolated case, this discovery has been followed by the description of an increasing number of aminoacyl-tRNA-dependent enzymes involved in secondary metabolism...
April 26, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/27900439/non-ribosomal-peptide-synthases-from-pseudomonas-aeruginosa-play-a-role-in-cyclodipeptide-biosynthesis-quorum-sensing-regulation-and-root-development-in-a-plant-host
#12
Omar González, Randy Ortíz-Castro, César Díaz-Pérez, Alma L Díaz-Pérez, Viridiana Magaña-Dueñas, José López-Bucio, Jesús Campos-García
Diverse molecules mediate cross-kingdom communication between bacteria and their eukaryotic partners and determine pathogenic or symbiotic relationships. N-acyl-L-homoserine lactone-dependent quorum-sensing signaling represses the biosynthesis of bacterial cyclodipeptides (CDPs) that act as auxin signal mimics in the host plant Arabidopsis thaliana. In this work, we performed bioinformatics, biochemical, and plant growth analyses to identify non-ribosomal peptide synthase (NRPS) proteins of Pseudomonas aeruginosa, which are involved in CDP synthesis...
April 2017: Microbial Ecology
https://www.readbyqxmd.com/read/27780756/spectrophotometric-assays-for-monitoring-trna-aminoacylation-and-aminoacyl-trna-hydrolysis-reactions
#13
REVIEW
Eric A First, Charles J Richardson
Aminoacyl-tRNA synthetases play a central role in protein synthesis, catalyzing the attachment of amino acids to their cognate tRNAs. Here, we describe a spectrophotometric assay for tyrosyl-tRNA synthetase in which the Tyr-tRNA product is cleaved, regenerating the tRNA substrate. As tRNA is the limiting substrate in the assay, recycling it substantially increases the sensitivity of the assay while simultaneously reducing its cost. The tRNA aminoacylation reaction is monitored spectrophotometrically by coupling the production of AMP to the conversion of NAD+ to NADH...
January 15, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/26641496/two-distinct-cyclodipeptide-synthases-from-a-marine-actinomycete-catalyze-biosynthesis-of-the-same-diketopiperazine-natural-product
#14
Elle D James, Bryan Knuckley, Norah Alqahtani, Suheel Porwal, Jisun Ban, Jonathan A Karty, Rajesh Viswanathan, Amy L Lane
Diketopiperazine natural products are structurally diverse and offer many biological activities. Cyclodipeptide synthases (CDPSs) were recently unveiled as a novel enzyme family that employs aminoacyl-tRNAs as substrates for 2,5-diketopiperazine assembly. Here, the Nocardiopsis sp. CMB-M0232 genome is predicted to encode two CDPSs, NozA and NcdA. Metabolite profiles from E. coli expressing these genes and assays with purified recombinant enzymes revealed that NozA and NcdA catalyze cyclo(l-Trp-l-Trp) (1) biosynthesis from tryptophanyl-tRNA and do not accept other aromatic aminoacyl-tRNA substrates...
July 15, 2016: ACS Synthetic Biology
https://www.readbyqxmd.com/read/26369300/nocardiopsis-species-a-potential-source-of-bioactive-compounds
#15
REVIEW
T Bennur, A Ravi Kumar, S S Zinjarde, V Javdekar
Members of the genus Nocardiopsis are an ecologically versatile and biotechnologically important group of Actinomycetes. Most of the isolates are halotolerant or halophilic and they prevail in soils, marine environments or hypersaline locations. To aid their survival under these conditions, they mainly produce extremozymes, compatible solutes, surfactants and bioactive compounds. The current review details the bioactive compounds obtained for this genus. Important antimicrobial agents obtained from this genus include polyketides, phenzines, quinoline alkaloids, terphenyls, proteins, thiopeptides and amines...
January 2016: Journal of Applied Microbiology
https://www.readbyqxmd.com/read/26236937/analysis-of-51-cyclodipeptide-synthases-reveals-the-basis-for-substrate-specificity
#16
Isabelle B Jacques, Mireille Moutiez, Jerzy Witwinowski, Emmanuelle Darbon, Cécile Martel, Jérôme Seguin, Emmanuel Favry, Robert Thai, Alain Lecoq, Steven Dubois, Jean-Luc Pernodet, Muriel Gondry, Pascal Belin
Cyclodipeptide synthases (CDPSs) constitute a family of peptide bond-forming enzymes that use aminoacyl-tRNAs for the synthesis of cyclodipeptides. Here, we describe the activity of 41 new CDPSs. We also show that CDPSs can be classified into two main phylogenetically distinct subfamilies characterized by specific functional subsequence signatures, named NYH and XYP. All 11 previously characterized CDPSs belong to the NYH subfamily, suggesting that further special features may be yet to be discovered in the other subfamily...
September 2015: Nature Chemical Biology
https://www.readbyqxmd.com/read/26022437/synergism-between-genome-sequencing-tandem-mass-spectrometry-and-bio-inspired-synthesis-reveals-insights-into-nocardioazine-b-biogenesis
#17
Norah Alqahtani, Suheel K Porwal, Elle D James, Dana M Bis, Jonathan A Karty, Amy L Lane, Rajesh Viswanathan
Marine actinomycete-derived natural products continue to inspire chemical and biological investigations. Nocardioazines A and B (3 and 4), from Nocardiopsis sp. CMB-M0232, are structurally unique alkaloids featuring a 2,5-diketopiperazine (DKP) core functionalized with indole C3-prenyl as well as indole C3- and N-methyl groups. The logic of their assembly remains cryptic. Bioinformatics analyses of the Nocardiopsis sp. CMB-M0232 draft genome afforded the noz cluster, split across two regions of the genome, and encoding putative open reading frames with roles in nocardioazine biosynthesis, including cyclodipeptide synthase (CDPS), prenyltransferase, methyltransferase, and cytochrome P450 homologs...
July 14, 2015: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/25284085/unravelling-the-mechanism-of-non-ribosomal-peptide-synthesis-by-cyclodipeptide-synthases
#18
Mireille Moutiez, Emmanuelle Schmitt, Jérôme Seguin, Robert Thai, Emmanuel Favry, Pascal Belin, Yves Mechulam, Muriel Gondry
Cyclodipeptide synthases form cyclodipeptides from two aminoacyl transfer RNAs. They use a ping-pong mechanism that begins with transfer of the aminoacyl moiety of the first aminoacyl tRNA onto a conserved serine, yielding an aminoacyl enzyme. Combining X-ray crystallography, site-directed mutagenesis and affinity labelling of the cyclodipeptide synthase AlbC, we demonstrate that the covalent intermediate reacts with the aminoacyl moiety of the second aminoacyl tRNA, forming a dipeptidyl enzyme, and identify the aminoacyl-binding sites of the aminoacyl tRNAs...
2014: Nature Communications
https://www.readbyqxmd.com/read/25196600/the-trna-dependent-biosynthesis-of-modified-cyclic-dipeptides
#19
REVIEW
Tobias W Giessen, Mohamed A Marahiel
In recent years it has become apparent that aminoacyl-tRNAs are not only crucial components involved in protein biosynthesis, but are also used as substrates and amino acid donors in a variety of other important cellular processes, ranging from bacterial cell wall biosynthesis and lipid modification to protein turnover and secondary metabolite assembly. In this review, we focus on tRNA-dependent biosynthetic pathways that generate modified cyclic dipeptides (CDPs). The essential peptide bond-forming catalysts responsible for the initial generation of a CDP-scaffold are referred to as cyclodipeptide synthases (CDPSs) and use loaded tRNAs as their substrates...
2014: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/24782519/specificity-determinants-for-the-two-trna-substrates-of-the-cyclodipeptide-synthase-albc-from-streptomyces-noursei
#20
Mireille Moutiez, Jérôme Seguin, Matthieu Fonvielle, Pascal Belin, Isabelle Béatrice Jacques, Emmanuel Favry, Michel Arthur, Muriel Gondry
Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNA substrates in a sequential ping-pong mechanism to form a cyclodipeptide. The crystal structures of three CDPSs have been determined and all show a Rossmann-fold domain similar to the catalytic domain of class-I aminoacyl-tRNA synthetases (aaRSs). Structural features and mutational analyses however suggest that CDPSs and aaRSs interact differently with their tRNA substrates. We used AlbC from Streptomyces noursei that mainly produces cyclo(l-Phe-l-Leu) to investigate the interaction of a CDPS with its substrates...
June 2014: Nucleic Acids Research
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