keyword
https://read.qxmd.com/read/38013180/-advances-in-the-biosynthesis-of-cyclodipeptide-type-natural-products-derived-from-actinomycetes
#1
JOURNAL ARTICLE
Yunhong Huang, Jinzu Li, Simin Chen, Wenhui Liu, Miaoer Wu, Du Zhu, Yunchang Xie
Cyclodipeptide (CDP) composed of two amino acids is the simplest cyclic peptide. These two amino acids form a typical diketopiperazine (DKP) ring by linking each other with peptide bonds. This characteristic stable ring skeleton is the foundation of CDP to display extensive and excellent bioactivities, which is beneficial for CDPs' pharmaceutical research and development. The natural CDP products are well isolated from actinomycetes. These bacteria can synthesize DKP backbones with nonribosomal peptide synthetase (NRPS) or cyclodipeptide synthase (CDPS)...
November 25, 2023: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
https://read.qxmd.com/read/37977732/p450-in-c-c-coupling-of-cyclodipeptides-with-nucleobases
#2
JOURNAL ARTICLE
Sina A Stierle, Lauritz Harken, Shu-Ming Li
Bacterial cytochrome P450 enzymes catalyze various and often intriguing tailoring reactions during the biosynthesis of natural products. In contrast to the majority of membrane-bound P450 enzymes from eukaryotes, bacterial P450 enzymes are soluble proteins and therefore represent excellent candidates for in vitro biochemical investigations. In particular, cyclodipeptide synthase-associated cytochrome P450 enzymes have recently gained attention due to the broad spectrum of reactions they catalyze, i.e. hydroxylation, aromatization, intramolecular C-C bond formation, dimerization, and nucleobase addition...
2023: Methods in Enzymology
https://read.qxmd.com/read/37713115/prenylation-of-dimeric-cyclo-l-trp-l-trp-by-the-promiscuous-cyclo-l-trp-l-ala-prenyltransferase-echpt1
#3
JOURNAL ARTICLE
Wen Li, Xiulan Xie, Jing Liu, Huili Yu, Shu-Ming Li
Prenyltransferases (PTs) from the dimethylallyl tryptophan synthase (DMATS) superfamily are known as efficient biocatalysts and mainly catalyze regioselective Friedel-Crafts alkylation of tryptophan and tryptophan-containing cyclodipeptides (CDPs). They can also use other unnatural aromatic compounds as substrates and play therefore a pivotal role in increasing structural diversity and biological activities of a broad range of natural and unnatural products. In recent years, several prenylated dimeric CDPs have been identified with wide range of bioactivities...
September 15, 2023: Applied Microbiology and Biotechnology
https://read.qxmd.com/read/37183364/production-of-diketopiperazine-derivatives-by-pathway-engineering-with-different-cyclodipeptide-synthases-from-various-streptomyces-strains
#4
JOURNAL ARTICLE
Sina A Stierle, Lauritz Harken, Shu-Ming Li
Cyclodipeptides from fungi and bacteria are often modified by different tailoring enzymes. They display various biological and pharmacological activities, and some derivatives are used as drugs. In a previous study, we elucidated the function of the silent guatrypmethine gene cluster from Streptomyces cinnamoneus containing a cyclodipeptide synthase (CDPS) core gene gtmA and four genes gtmB-gtmE for tailoring enzymes. The latter are used in this study for the design of modified cyclodipeptides by genetic engineering...
May 14, 2023: ACS Synthetic Biology
https://read.qxmd.com/read/37137876/unveiling-an-indole-alkaloid-diketopiperazine-biosynthetic-pathway-that-features-a-unique-stereoisomerase-and-multifunctional-methyltransferase
#5
JOURNAL ARTICLE
Garrett Deletti, Sajan D Green, Caleb Weber, Kristen N Patterson, Swapnil S Joshi, Tushar M Khopade, Mathew Coban, James Veek-Wilson, Thomas R Caulfield, Rajesh Viswanathan, Amy L Lane
The 2,5-diketopiperazines are a prominent class of bioactive molecules. The nocardioazines are actinomycete natural products that feature a pyrroloindoline diketopiperazine scaffold composed of two D-tryptophan residues functionalized by N- and C-methylation, prenylation, and diannulation. Here we identify and characterize the nocardioazine B biosynthetic pathway from marine Nocardiopsis sp. CMB-M0232 by using heterologous biotransformations, in vitro biochemical assays, and macromolecular modeling. Assembly of the cyclo-L-Trp-L-Trp diketopiperazine precursor is catalyzed by a cyclodipeptide synthase...
May 3, 2023: Nature Communications
https://read.qxmd.com/read/36702957/genome-mining-for-unknown-unknown-natural-products
#6
JOURNAL ARTICLE
Danielle A Yee, Kanji Niwa, Bruno Perlatti, Mengbin Chen, Yuqing Li, Yi Tang
Genome mining of biosynthetic pathways with no identifiable core enzymes can lead to discovery of the so-called unknown (biosynthetic route)-unknown (molecular structure) natural products. Here we focused on a conserved fungal biosynthetic pathway that lacks a canonical core enzyme and used heterologous expression to identify the associated natural product, a highly modified cyclo-arginine-tyrosine dipeptide. Biochemical characterization of the pathway led to identification of a new arginine-containing cyclodipeptide synthase (RCDPS), which was previously annotated as a hypothetical protein and has no sequence homology to non-ribosomal peptide synthetase or bacterial cyclodipeptide synthase...
January 26, 2023: Nature Chemical Biology
https://read.qxmd.com/read/36518199/active-site-remodelling-of-a-cyclodipeptide-synthase-redefines-substrate-scope
#7
JOURNAL ARTICLE
Emmajay Sutherland, Christopher John Harding, Clarissa Melo Czekster
Cyclodipeptide synthases (CDPSs) generate a wide range of cyclic dipeptides using aminoacylated tRNAs as substrates. Histidine-containing cyclic dipeptides have important biological activities as anticancer and neuroprotective molecules. Out of the 120 experimentally validated CDPS members, only two are known to accept histidine as a substrate yielding cyclo(His-Phe) and cyclo(His-Pro) as products. It is not fully understood how CDPSs select their substrates, and we must rely on bioprospecting to find new enzymes and novel bioactive cyclic dipeptides...
August 25, 2022: Communications Chemistry
https://read.qxmd.com/read/36441211/diprenylated-cyclodipeptide-production-by-changing-the-prenylation-sequence-of-the-nature-s-synthetic-machinery
#8
JOURNAL ARTICLE
Wen Li, Lindsay Coby, Jing Zhou, Shu-Ming Li
Ascomycetous fungi are often found in agricultural products and foods as contaminants. They produce hazardous mycotoxins for human and animals. On the other hand, the fungal metabolites including mycotoxins are important drug candidates and the enzymes involved in the biosynthesis of these compounds are valuable biocatalysts for production of designed compounds. One of the enzyme groups are members of the dimethylallyl tryptophan synthase superfamily, which mainly catalyze prenylations of tryptophan and tryptophan-containing cyclodipeptides (CDPs)...
November 28, 2022: Applied Microbiology and Biotechnology
https://read.qxmd.com/read/35872818/directed-evolution-of-a-cyclodipeptide-synthase-with-new-activities-via-label-free-mass-spectrometric-screening
#9
JOURNAL ARTICLE
Songya Zhang, Jing Zhu, Shuai Fan, Wenhao Xie, Zhaoyong Yang, Tong Si
Directed evolution is a powerful approach to engineer enzymes via iterative creation and screening of variant libraries. However, assay development for high-throughput mutant screening remains challenging, particularly for new catalytic activities. Mass spectrometry (MS) analysis is label-free and well suited for untargeted discovery of new enzyme products but is traditionally limited by slow speed. Here we report an automated workflow for directed evolution of new enzymatic activities via high-throughput library creation and label-free MS screening...
June 29, 2022: Chemical Science
https://read.qxmd.com/read/35436125/griseocazines-neuroprotective-multiprenylated-cyclodipeptides-identified-through-targeted-genome-mining
#10
JOURNAL ARTICLE
Jessie James Limlingan Malit, Chuanhai Wu, Xueying Tian, Wenchao Liu, Duli Huang, Herman H-Y Sung, Ling-Li Liu, Ian D Williams, Pei-Yuan Qian
Prenylation can impart pharmacological advantages to bioactive compounds. Global genome mining for prenylated cyclodipeptides identified a gczABC BGC from Streptomyces griseocarneus 132 containing a cyclodipeptide synthase and two prenyltransferase genes. Subsequent heterologous expression allowed isolation and characterization of griseocazines, which displayed potent neuroprotective activity. Further biotransformation analyses revealed that prenyltransferases GczB and GczC catalyzed the stereospecific prenylation of cWW and attached geranyl and farnesyl groups to a cyclodipeptide scaffold, respectively...
April 18, 2022: Organic Letters
https://read.qxmd.com/read/34846144/elucidation-of-the-streptoazine-biosynthetic-pathway-in-streptomyces-aurantiacus-reveals-the-presence-of-a-promiscuous-prenyltransferase-cyclase
#11
JOURNAL ARTICLE
Jing Liu, Yiling Yang, Lauritz Harken, Shu-Ming Li
Heterologous expression of a three-gene cluster from Streptomyces aurantiacus coding for a cyclodipeptide synthase, a prenyltransferase, and a methyltransferase led to the elucidation of the biosynthetic steps of streptoazine C ( 2 ). In vivo biotransformation experiments proved the high flexibility of the prenyltransferase SasB toward tryptophan-containing cyclodipeptides for regular C-3-prenylation. Furthermore, their corresponding dehydrogenated derivatives prepared by using cyclodipeptide oxidases were also used for prenylation...
November 30, 2021: Journal of Natural Products
https://read.qxmd.com/read/34662717/genome-mining-of-biosynthetic-gene-clusters-intended-for-secondary-metabolites-conservation-in-actinobacteria
#12
JOURNAL ARTICLE
Karthick Raja Arulprakasam, Dhanasekaran Dharumadurai
Evolution of genome sequencing technology, on the one hand, and advancement of computational genome mining tools, on the other hand, paves way for improvement in predicting secondary metabolites. In past, numerous efforts were made concerning genome mining for recognizing secondary metabolites within the genus, but only a negligible quantity of comparative genomic reports had carried out among species of different genera. In this study, we explored potential of 24 actinobacteria species belonging to the genera, including Streptomyces, Nocardia, Micromonospora, and Saccharomonospora, to traverse diversity and distribution of Biosynthetic Gene Clusters (BGCs)...
December 2021: Microbial Pathogenesis
https://read.qxmd.com/read/34458818/correction-bypassing-the-requirement-for-aminoacyl-trna-by-a-cyclodipeptide-synthase-enzyme
#13
Christopher J Harding, Emmajay Sutherland, Jane G Hanna, Douglas R Houston, Clarissa M Czekster
[This corrects the article DOI: 10.1039/D0CB00142B.].
June 1, 2021: RSC chemical biology
https://read.qxmd.com/read/33937777/bypassing-the-requirement-for-aminoacyl-trna-by-a-cyclodipeptide-synthase-enzyme
#14
JOURNAL ARTICLE
Christopher J Harding, Emmajay Sutherland, Jane G Hanna, Douglas R Houston, Clarissa M Czekster
Cyclodipeptide synthases (CDPSs) produce a variety of cyclic dipeptide products by utilising two aminoacylated tRNA substrates. We sought to investigate the minimal requirements for substrate usage in this class of enzymes as the relationship between CDPSs and their substrates remains elusive. Here, we investigated the Bacillus thermoamylovorans enzyme, BtCDPS, which synthesises cyclo(l-Leu-l-Leu). We systematically tested where specificity arises and, in the process, uncovered small molecules (activated amino esters) that will suffice as substrates, although catalytically poor...
January 15, 2021: RSC chemical biology
https://read.qxmd.com/read/33741615/deciphering-a-cyclodipeptide-synthase-pathway-encoding-prenylated-indole-alkaloids-in-streptomyces-leeuwenhoekii
#15
JOURNAL ARTICLE
Yuqiao Zhang, Tingting Yao, Yuechen Jiang, Huayue Li, Weicheng Yuan, Wenli Li
Cyclodipeptide synthases (CDPSs) catalyse the formation of cyclodipeptides using aminoacylated-tRNAs as substrates and have great potentials in the production of diverse 2,5-diketopiperazines (2,5-DKPs). Genome mining of Streptomyces leeuwenhoekii NRRL B-24963 revealed a two-gene locus saz encoding a CDPS SazA and a unique fused enzyme SazB harboring two domains: phytoene-synthase-like prenyltransferase (PT) and methyltransferase (MT). Heterologous expression of the saz gene(s) in Streptomyces albus J1074 led to the production of four prenylated indole alkaloids, among which streptoazines A-C (3-5) are new compounds...
March 19, 2021: Applied and Environmental Microbiology
https://read.qxmd.com/read/33625545/modifications-of-diketopiperazines-assembled-by-cyclodipeptide-synthases-with-cytochrome-p-450-enzymes
#16
REVIEW
Lauritz Harken, Shu-Ming Li
2,5-Diketopiperazines are the smallest cyclic peptides comprising two amino acids connected via two peptide bonds. They can be biosynthesized in nature by two different enzyme families, either by nonribosomal peptide synthetases or by cyclodipeptide synthases. Due to the stable scaffold of the diketopiperazine ring, they can serve as precursors for further modifications by different tailoring enzymes, such as methyltransferases, prenyltransferases, oxidoreductases like cyclodipeptide oxidases, 2-oxoglutarate-dependent monooxygenases and cytochrome P450 enzymes, leading to the formation of intriguing secondary metabolites...
February 24, 2021: Applied Microbiology and Biotechnology
https://read.qxmd.com/read/33331769/cyclodipeptide-synthases-of-the-nyh-subfamily-recognize-trna-using-an-%C3%AE-helix-enriched-with-positive-residues
#17
JOURNAL ARTICLE
Anastasia Croitoru, Morgan Babin, Hannu Myllykallio, Muriel Gondry, Alexey Aleksandrov
Cyclodipeptide synthases (CDPSs) perform nonribosomal protein synthesis using two aminoacyl-tRNA substrates to produce cyclodipeptides. At present, there are no structural details of the CDPS:tRNA interaction available. Using AlbC, a CDPS that produces cyclo(l-Phe-l-Phe), the interaction between AlbC and its Phe-tRNA substrate was investigated. Simulations of models of the AlbC:tRNA complex, proposed by rigid-body docking or homology modeling, demonstrated that interactions with residues of an AlbC α-helix, α4, significantly contribute to the free energy of binding of AlbC to tRNA...
December 17, 2020: Biochemistry
https://read.qxmd.com/read/32894164/in-vivo-characterization-of-the-activities-of-novel-cyclodipeptide-oxidases-new-tools-for-increasing-chemical-diversity-of-bioproduced-2-5-diketopiperazines-in-escherichia-coli
#18
JOURNAL ARTICLE
Fabien Le Chevalier, Isabelle Correia, Lucrèce Matheron, Morgan Babin, Mireille Moutiez, Nicolas Canu, Muriel Gondry, Olivier Lequin, Pascal Belin
BACKGROUND: Cyclodipeptide oxidases (CDOs) are enzymes involved in the biosynthesis of 2,5-diketopiperazines, a class of naturally occurring compounds with a large range of pharmaceutical activities. CDOs belong to cyclodipeptide synthase (CDPS)-dependent pathways, in which they play an early role in the chemical diversification of cyclodipeptides by introducing Cα-Cβ dehydrogenations. Although the activities of more than 100 CDPSs have been determined, the activities of only a few CDOs have been characterized...
September 7, 2020: Microbial Cell Factories
https://read.qxmd.com/read/32680846/structural-basis-of-the-interaction-between-cyclodipeptide-synthases-and-aminoacylated-trna-substrates
#19
JOURNAL ARTICLE
Gabrielle Bourgeois, Jérôme Seguin, Morgan Babin, Muriel Gondry, Yves Mechulam, Emmanuelle Schmitt
Cyclodipeptide synthases (CDPSs) catalyze the synthesis of various cyclodipeptides by using two aminoacyl-tRNA (aa-tRNA) substrates in a sequential mechanism. Here, we studied binding of phenylalanyl-tRNAPhe to the CDPS from Candidatus Glomeribacter gigasporarum (Cglo-CDPS) by gel filtration and electrophoretic mobility shift assay. We determined the crystal structure of the Cglo-CDPS:Phe-tRNAPhe complex to 5 Å resolution and further studied it in solution using small-angle X-ray scattering (SAXS). The data show that the major groove of the acceptor stem of the aa-tRNA interacts with the enzyme through the basic β2 and β7 strands of CDPSs belonging to the XYP subfamily...
July 17, 2020: RNA
https://read.qxmd.com/read/32659721/expanding-the-structural-diversity-of-drimentines-by-exploring-the-promiscuity-of-two-n-methyltransferases
#20
JOURNAL ARTICLE
Tingting Yao, Jing Liu, Enjing Jin, Zengzhi Liu, Huayue Li, Qian Che, Tianjiao Zhu, Dehai Li, Wenli Li
Methylation is envisioned as a promising way to rationally improve key pharmacokinetic characteristics of lead compounds. Although diverse tailoring enzymes are found to be clustered with cyclodipeptide synthases (CDPSs) to perform further modification reactions on the diketopiperazine (DKP) rings generating complex DKP-containing compounds, so far, a limited number of methyltransferases (MTs) co-occurring with CDPS have been experimentally characterized. Herein, we deciphered the methylation steps during drimentines (DMTs) biosynthesis with identification and characterization of DmtMT2-1 (from Streptomyces sp...
June 28, 2020: IScience
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