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cryptic biosynthesis

Xiaoli Yan, Benyin Zhang, Wenya Tian, Qi Dai, Xiaoqin Zheng, Ke Hu, Xinxin Liu, Zixin Deng, Xudong Qu
Natural product discovery is pivot for drug development, however, this endeavor is often challenged by the wide inactivation or silence of natural products biosynthetic pathways. We recently developed a highly efficient approach to activate cryptic/silenced biosynthetic pathways through augmentation of the phosphopantetheinylation of carrier proteins. By applying this approach in the Streptomyces alboniger NRRL B-1832, we herein identified three cryptic nucleosides products, including one known puromycin A and two new derivatives (puromycin B and C)...
March 2018: Synthetic and Systems Biotechnology
Tao Zhang, Jun Wan, Zhajun Zhan, Jian Bai, Bingyu Liu, Youcai Hu
Fungal genomes carry many gene clusters seemingly capable of natural products biosynthesis, yet most clusters remain cryptic or down-regulated. Genome mining revealed an unconventional paraherquonin-like meroterpenoid biosynthetic gene cluster in the chromosome of Neosartorya glabra . The cryptic or down-regulated pathway was activated by constitutive expression of pathway-specific regulator gene berA encoded within ber biosynthetic gene cluster. Chemical analysis of mutant Ng -OE: berA extracts enabled the isolation of four berkeleyacetal congeners, in which two of them are new...
May 2018: Acta Pharmaceutica Sinica. B
Shotaro Hoshino, Masahiro Ozeki, Chin Piow Wong, Huiping Zhang, Fumiaki Hayashi, Takayoshi Awakawa, Hiroyuki Morita, Hiroyasu Onaka, Ikuro Abe
Mycolic acid-containing bacteria (MACB) are known to activate cryptic natural product biosynthesis in co-cultures with actinobacteria. We cultured Actinosynnema mirum NBRC 14064, a producer of the mono-cyclic polyene macrolactam mirilactam A (6), with the MACB Tsukamurella pulmonis TP-B0596. As a result, three novel compounds (mirilactams C-E, 1-3) were produced in the co-culture conditions. Compounds 1-3 were likely derived from 6 by epoxidation and subsequent spontaneous cyclization. The chemical structures and stereochemistries of 1-3 were determined by spectroscopic analyses (NMR and MS), conformational searches in the optimized potentials for liquid simulations-3 (OPLS3) force field, and calculations of electronic circular dichroism (ECD)...
2018: Chemical & Pharmaceutical Bulletin
Adriana Becerril, Susana Álvarez, Alfredo F Braña, Sergio Rico, Margarita Díaz, Ramón I Santamaría, José A Salas, Carmen Méndez
Sequencing of Streptomyces genomes has revealed they harbor a high number of biosynthesis gene cluster (BGC), which uncovered their enormous potentiality to encode specialized metabolites. However, these metabolites are not usually produced under standard laboratory conditions. In this manuscript we report the activation of BGCs for antimycins, carotenoids, germicidins and desferrioxamine compounds in Streptomyces argillaceus, and the identification of the encoded compounds. This was achieved by following different strategies, including changing the growth conditions, heterologous expression of the cluster and inactivating the adpAa or overexpressing the abrC3 global regulatory genes...
2018: PloS One
Yan Liu, Haoxin Wang, Rentai Song, Jining Chen, Tianhong Li, Yaoyao Li, Liangcheng Du, Yuemao Shen
Polycyclic tetramate macrolactams (PoTeMs) are a growing class of natural products with distinct structure and diverse biological activities. By promoter engineering and heterologous expression of the cryptic cbm gene cluster, four new PoTeMs, combamides A-E (1-4), were identified. Additionally, two new derivatives, combamides E (5) and F (6), were generated via combinatorial biosynthesis. Together, our findings provide a sound base for expanding the structure diversities of PoTeMs through genome mining and combinatorial biosynthesis...
May 24, 2018: Organic Letters
Linan Xie, Liwen Zhang, Chen Wang, Xiaojing Wang, Ya-Ming Xu, Hefen Yu, Ping Wu, Shenglan Li, Lida Han, A A Leslie Gunatilaka, Xiaoyi Wei, Min Lin, István Molnár, Yuquan Xu
Glycosylation is a prominent strategy to optimize the pharmacokinetic and pharmacodynamic properties of drug-like small-molecule scaffolds by modulating their solubility, stability, bioavailability, and bioactivity. Glycosyltransferases applicable for "sugarcoating" various small-molecule acceptors have been isolated and characterized from plants and bacteria, but remained cryptic from filamentous fungi until recently, despite the frequent use of some fungi for whole-cell biocatalytic glycosylations...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Helga U van der Heul, Bohdan L Bilyk, Kenneth J McDowall, Ryan F Seipke, Gilles P van Wezel
Covering: 2000 to 2018The antimicrobial activity of many of their natural products has brought prominence to the Streptomycetaceae, a family of Gram-positive bacteria that inhabit both soil and aquatic sediments. In the natural environment, antimicrobial compounds are likely to limit the growth of competitors, thereby offering a selective advantage to the producer, in particular when nutrients become limited and the developmental programme leading to spores commences. The study of the control of this secondary metabolism continues to offer insights into its integration with a complex lifecycle that takes multiple cues from the environment and primary metabolism...
May 3, 2018: Natural Product Reports
Alexandra Pitt, Johanna Schmidt, Elke Lang, William B Whitman, Tanja Woyke, Martin W Hahn
Strain AP-Melu-1000-B4 was isolated from a lake located in the mountains of the Mediterranean island of Corsica (France). Phenotypic, chemotaxonomic and genomic traits were investigated. Phylogenetic analyses based on 16S rRNA gene sequencing referred the strain to the cryptic species complex PnecC within the genus Polynucleobacter. The strain encoded genes for biosynthesis of proteorhodopsin and retinal. When pelleted by centrifugation the strain showed an intense rose colouring. Major fatty acids were C16 : 1ω7c, C16 : 0, C18 : 1ω7c and summed feature 2 (C16 : 1 isoI and C14 : 0-3OH)...
June 2018: International Journal of Systematic and Evolutionary Microbiology
Laura Di Sante, Armanda Pugnaloni, Francesca Biavasco, Eleonora Giovanetti, Carla Vignaroli
The multicellular behavior designated "red dry and rough" (rdar) morphotype-characterized by production of extracellular matrix mainly comprising curli fimbriae and cellulose-is a potential survival strategy of Escherichia coli outside the host. This study documents the ability of Escherichia cryptic clades, which have recently been recognized as new lineages genetically divergent from E. coli, to grow in unfavorable conditions through expression of distinct phenotypes. Growth under low-temperature and nutrient-poor conditions induced the rdar morphotype in all cryptic clade strains tested, especially after preincubation in broth supplemented with uracil...
May 2018: Microbiological Research
Martin Klapper, Daniel Braga, Gerald Lackner, Rosa Herbst, Pierre Stallforth
Chemical and biochemical analyses of one of the most basic nonribosomal peptide synthetases (NRPS) from a Pseudomonas fluorescens strain revealed its striking plasticity. Determination of the potential substrate scope enabled us to anticipate novel secondary metabolites that could subsequently be isolated and tested for their bioactivities. Detailed analyses of the monomodular pyreudione synthetase showed that the biosynthesis of the bacterial pyreudione alkaloids does not require additional biosynthetic enzymes...
March 13, 2018: Cell Chemical Biology
Suhui Ye, Alfredo F Braña, Javier González-Sabín, Francisco Morís, Carlos Olano, José A Salas, Carmen Méndez
Argimycins P are a recently identified family of polyketide alkaloids encoded by the cryptic gene cluster arp of Streptomyces argillaceus . These compounds contain either a piperideine ring, or a piperidine ring which may be fused to a five membered ring, and a polyene side chain, which is bound in some cases to an N -acetylcysteine moiety. The arp cluster consists of 11 genes coding for structural proteins, two for regulatory proteins and one for a hypothetical protein. Herein, we have characterized the post-piperideine ring biosynthesis steps of argimycins P through the generation of mutants in arp genes, the identification and characterization of compounds accumulated by those mutants, and cross-feeding experiments between mutants...
2018: Frontiers in Microbiology
Yi He, Bin Wang, Wanping Chen, Russell J Cox, Jingren He, Fusheng Chen
High throughput genome sequencing has revealed a multitude of potential secondary metabolites biosynthetic pathways that remain cryptic. Pathway reconstruction coupled with genetic engineering via heterologous expression enables discovery of novel compounds, elucidation of biosynthetic pathways, and optimization of product yields. Apart from Escherichia coli and yeast, fungi, especially Aspergillus spp., are well known and efficient heterologous hosts. This review summarizes recent advances in heterologous expression of microbial secondary metabolite biosynthesis in Aspergillus spp...
February 5, 2018: Biotechnology Advances
Jianxiong Wang, Wen Li, Haoxin Wang, Chunhua Lu
Overexpression of the pathway-specific positive regulator gene mas13 activated the cryptic gene cluster mas, resulting in the isolation of nine novel pentaketide ansamycins, namely, microansamycins A-I (1-9). These results not only revealed a biosynthetic gene cluster of pentaketide ansamycins for the first time but also presented an unprecedented scenario of diverse post-PKS modifications in ansamycin biosynthesis.
February 16, 2018: Organic Letters
Johanna Mattay, Stefanie Houwaart, Wolfgang Hüttel
Echinocandins are antifungal nonribosomal hexapeptides produced by fungi. Two of the amino acids are hydroxy-l-prolines: trans -4-hydroxy-l-proline and, in most echinocandin structures, ( trans -2,3)-3-hydroxy-( trans -2,4)-4-methyl-l-proline. In the case of echinocandin biosynthesis by Glarea lozoyensis , both amino acids are found in pneumocandin A0 , while in pneumocandin B0 the latter residue is replaced by trans -3-hydroxy-l-proline (3-Hyp). We have recently reported that all three amino acids are generated by the 2-oxoglutarate-dependent proline hydroxylase GloF...
April 1, 2018: Applied and Environmental Microbiology
Yang Hai, Yi Tang
Truncated iterative polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) megasynthases in which only the C domain is present are widespread in fungi, yet nearly all members have unknown functions. Bioinformatics analysis showed that the C domains of such PKS-C enzymes are noncanonical due to substitution at the second histidine in the active site HHxxxDG motif. Here, we used genome mining strategy to characterize a cryptic PKS-C hybrid from Talaromyces wortmanii and discovered the products are reduced long-chain polyketides amidated with a specific ω-amino acid 5-aminopentanoic acid (5PA)...
January 23, 2018: Journal of the American Chemical Society
Dian Anggraini Suroto, Shigeru Kitani, Masayoshi Arai, Haruo Ikeda, Takuya Nihira
Phthoxazolin A, an oxazole-containing polyketide, has a broad spectrum of anti-oomycete activity and herbicidal activity. We recently identified phthoxazolin A as a cryptic metabolite of Streptomyces avermitilis that produces the important anthelmintic agent avermectin. Even though genome data of S. avermitilis is publicly available, no plausible biosynthetic gene cluster for phthoxazolin A is apparent in the sequence data. Here, we identified and characterized the phthoxazolin A (ptx) biosynthetic gene cluster through genome sequencing, comparative genomic analysis, and gene disruption...
2018: PloS One
Li Zhang, Kunling Teng, Jian Wang, Zheng Zhang, Jie Zhang, Shutao Sun, Lili Li, Xiaopan Yang, Jin Zhong
Cerecidins are small lantibiotics from Bacillus cereus that were obtained using a semi- in vitro biosynthesis strategy and showed prominent antimicrobial activities against certain Gram-positive bacteria. However, the parental strain B. cereus As 1.1846 is incapable of producing cerecidins, most probably due to the transcriptional repression of the cerecidin gene cluster. Located in the cerecidin gene cluster, cerR encodes a putative response regulator protein that belongs to the LuxR family transcriptional regulators...
March 1, 2018: Applied and Environmental Microbiology
Frank Surup, Konrad Viehrig, Shwan Rachid, Alberto Plaza, Christine K Maurer, Rolf W Hartmann, Rolf Müller
Analysis of the genome sequence of the myxobacterium Chondromyces crocatus Cm c5 revealed the presence of numerous cryptic megasynthetase gene clusters, one of which we here assign to two previously unknown chlorinated metabolites by a comparative gene inactivation and secondary metabolomics approach. Structure elucidation of these compounds revealed a unique cyclic depsipeptide skeleton featuring β- and δ-amide bonds of aspartic acid and 3-methyl ornithine moieties, respectively. Insights into their biosynthesis were obtained by targeted gene inactivation and feeding experiments employing isotope-labeled precursors...
January 19, 2018: ACS Chemical Biology
Navid Adnani, Marc G Chevrette, Srikar N Adibhatla, Fan Zhang, Qing Yu, Doug R Braun, Justin Nelson, Scott W Simpkins, Bradon R McDonald, Chad L Myers, Jeff S Piotrowski, Christopher J Thompson, Cameron R Currie, Lingjun Li, Scott R Rajski, Tim S Bugni
Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such "cryptic" or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions...
December 15, 2017: ACS Chemical Biology
Jie Shi Chua, Balagurunathan Kuberan
Glycosaminoglycans (GAGs) are polysaccharides ubiquitously found on cell surfaces and in the extracellular matrix (ECM). They regulate numerous cellular signaling events involved in many developmental and pathophysiological processes. GAGs are composed of complex sequences of repeating disaccharide units, each of which can carry many different modifications. The tremendous structural variations account for their ability to bind many proteins and thus, for their numerous functions. Although the sequence of GAG biosynthetic events and the enzymes involved mostly were deduced a decade ago, the emergence of tissue or cell specific GAGs from a nontemplate driven process remains an enigma...
October 23, 2017: Accounts of Chemical Research
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