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cryptic biosynthesis

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 7, 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 substituted 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...
January 19, 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 LuxR-family transcriptional regulators...
December 15, 2017: 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...
December 8, 2017: ACS Chemical Biology
Navid Adnani, Marc 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...
November 9, 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
Jingjing Xu, Jihui Zhang, Jiming Zhuo, Yue Li, Yuqing Tian, Huarong Tan
Genome sequencing analysis has revealed at least 35 clusters of likely biosynthetic genes for secondary metabolites in Streptomyces ansochromogenes. Disruption of adpA encoding a global regulator (AdpA) resulted in the failure of nikkomycin production, whereas other antibacterial activities against Staphylococcus aureus, Bacillus cereus and Bacillus subtilis were observed with the fermentation broth of ΔadpA but not with that of the wild-type strain. Transcriptional analysis showed that a cryptic gene cluster (pks7), which shows high identity with an oviedomycin biosynthetic gene cluster (ovm), was activated in ΔadpA...
September 25, 2017: Journal of Biological Chemistry
Haruki Hasegawa, Mei Geng, Randal R Ketchem, Ling Liu, Kevin Graham, Frederick Jacobsen
Full-length immunoglobulins (Igs) are widely considered difficult to crystallize because of their large size, N-linked glycosylation, and flexible hinge region. However, numerous cases of intracellular Ig crystallization are reported in plasma cell dyscrasias. What makes some Ig clones more prone to crystallize during biosynthesis as well as the biochemical and cell biological requirements for this cryptic event are poorly understood. To investigate the underlying process of intracellular Ig crystallization we searched for model IgGs that can induce crystalline inclusions during recombinant overexpression...
2017: Cellular Logistics
Shanren Li, Xiuli Wu, Limei Zhang, Yuemao Shen, Liangcheng Du
Lysobacter are considered "peptide specialists". However, many of the nonribosomal peptide synthetase genes are silent. Three new compounds were identified from L. enzymogenes upon activating the six-module-containing led cluster by the strong promoter PHSAF. Although ledD was the first gene under PHSAF control, the second gene ledE was expressed the highest. Targeted gene inactivation showed that the two-module LedE and the one-module LedF were selectively used in pyrrolopyrazine biosynthesis, revealing a module/domain portable mechanism...
October 6, 2017: Organic Letters
Wei Ding, Wenjuan Ji, Yujie Wu, Runze Wu, Wan-Qiu Liu, Tianlu Mo, Junfeng Zhao, Xiaoyan Ma, Wei Zhang, Ping Xu, Zixin Deng, Boping Tang, Yi Yu, Qi Zhang
Nosiheptide is a prototypal thiopeptide antibiotic, containing an indole side ring in addition to its thiopeptide-characteristic macrocylic scaffold. This indole ring is derived from 3-methyl-2-indolic acid (MIA), a product of the radical S-adenosylmethionine enzyme NosL, but how MIA is incorporated into nosiheptide biosynthesis remains to be investigated. Here we report functional dissection of a series of enzymes involved in nosiheptide biosynthesis. We show NosI activates MIA and transfers it to the phosphopantetheinyl arm of a carrier protein NosJ...
September 5, 2017: Nature Communications
Yousra Ahmed, Yuriy Rebets, Bogdan Tokovenko, Elke Brötz, Andriy Luzhetskyy
A large majority of genome-encrypted chemical diversity in actinobacteria remains to be discovered, which is related to the low level of secondary metabolism genes expression. Here, we report the application of a reporter-guided screening strategy to activate cryptic polycyclic tetramate macrolactam gene clusters in Streptomyces albus J1074. The analysis of the S. albus transcriptome revealed an overall low level of secondary metabolism genes transcription. Combined with transposon mutagenesis, reporter-guided screening resulted in the selection of two S...
August 29, 2017: Scientific Reports
I Kutay Ozturk, Pranav Chettri, Pierre-Yves Dupont, Irene Barnes, Rebecca L McDougal, Geromy G Moore, Andre Sim, Rosie E Bradshaw
Fungal secondary metabolites have many important biological roles and some, like the toxic polyketide aflatoxin, have been intensively studied at the genetic level. Complete sets of polyketide synthase (PKS) genes can now be identified in fungal pathogens by whole genome sequencing and studied in order to predict the biosynthetic potential of those fungi. The pine needle pathogen Dothistroma septosporum is predicted to have only three functional PKS genes, a small number for a hemibiotrophic fungus. One of these genes is required for production of dothistromin, a polyketide virulence factor related to aflatoxin, whose biosynthetic genes are dispersed across one chromosome rather than being clustered...
July 6, 2017: Fungal Genetics and Biology: FG & B
Susann Kugel, Martin Baunach, Philipp Baer, Mie Ishida-Ito, Srividhya Sundaram, Zhongli Xu, Michael Groll, Christian Hertweck
Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis...
June 15, 2017: Nature Communications
Li-Qiang Song, Ying-Ying Zhang, Jin-Yue Pu, Man-Cheng Tang, Chao Peng, Gong-Li Tang
The biosynthesis of antibiotics in bacteria is usually believed to be an intracellular process, at the end of which the matured compounds are exported outside the cells. The biosynthesis of saframycin A (SFM-A), an antitumor antibiotic, requires a cryptic fatty acyl chain to guide the construction of a pentacyclic tetrahydroisoquinoline scaffold; however, the follow-up deacylation and deamination steps remain unknown. Herein we demonstrate that SfmE, a membrane-bound peptidase, hydrolyzes the fatty acyl chain to release the amino group; and SfmCy2, a secreted oxidoreductase covalently associated with FAD, subsequently performs an oxidative deamination extracellularly...
May 31, 2017: Angewandte Chemie
Yuhong Uhong Lü, Xiaoli Liu, Miao Wang, Yuanyuan Li, Ning Liu, Yuxin Bao, Minghao Liu, Xiaoqian Li, Yinyin Wang, Shenyan Qian, Changwu Yue, Ying Huang
In order to obtain the natural products synthesized by the three putative xiamycin biosynthesis gene clusters which were predicted via antiSMASH during the genome mining of marine Streptomyces sp. FXJ 7.388, Streptomyces sp. FXJ 8.012, and Streptomyces olivaceus FXJ 7.023. Sixteen genes involved in xiamycin assembly, modification, and regulation with higher identity than the newest reported xiamycin biosynthetic gene cluster from marine Streptomyces sp. SCSIO 02999, Streptomyces sp. HKI0576, and Streptomyces sp...
September 2016: Pakistan Journal of Pharmaceutical Sciences
Ju-Ling Liu, Callista Yee, Ying Wang, Siegfried Hekimi
The Caenorhabditis elegans clk-1 gene and the orthologous mouse gene Mclk1 encode a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (UQ). Mutations in these genes produce broadly pleiotropic phenotypes in both species, including a lengthening of animal lifespan. A number of features of the C. elegans clk-1 mutants, including a maternal effect, particularly extensive pleiotropy, as well as unexplained differences between alleles have suggested that CLK-1/MCLK1 might have additional functions besides that in UQ biosynthesis...
April 12, 2017: Scientific Reports
Biju Joseph Ampattu, Laura Hagmann, Chunguang Liang, Marcus Dittrich, Andreas Schlüter, Jochen Blom, Elizaveta Krol, Alexander Goesmann, Anke Becker, Thomas Dandekar, Tobias Müller, Christoph Schoen
BACKGROUND: Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence...
April 7, 2017: BMC Genomics
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