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polyketide synthase

Christopher R Vickery, Javier Cardenas, Marianne Bowman, Michael D Burkart, Nancy A Da Silva, Joseph P Noel
Polyketides are attractive compounds for uses ranging from biorenewable chemical precursors to high-value therapeutics. In many cases, synthesis in a heterologous host is required to produce these compounds in industrially relevant quantities. The type III polyketide synthase 2-pyrone synthase (2-PS) from Gerbera hybrida was used for the production of triacetic acid lactone (TAL) in Saccharomyces cerevisiae. Initial in vitro characterization of 2-PS led to the identification of active site variants with improved kinetic properties relative to wildtype...
February 19, 2018: Biotechnology and Bioengineering
Xiaomei Zheng, Ping Zheng, Jibin Sun, Zhang Kun, Yanhe Ma
Background: U6 promoters have been used for single guide RNA (sgRNA) transcription in the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas9) genome editing system. However, no available U6 promoters have been identified in Aspergillus niger, which is an important industrial platform for organic acid and protein production. Two CRISPR/Cas9 systems established in A. niger have recourse to the RNA polymerase II promoter or in vitro transcription for sgRNA synthesis, but these approaches generally increase cloning efforts and genetic manipulation...
2018: Fungal Biology and Biotechnology
Catarina Loureiro, Marnix H Medema, John van der Oost, Detmer Sipkema
Microorganisms are Nature's little engineers of a remarkable array of bioactive small molecules that represent most of our new drugs. The wealth of genomic and metagenomic sequence data generated in the last decade has shown that the majority of novel biosynthetic gene clusters (BGCs) is identified from cultivation-independent studies, which has led to a strong expansion of the number of microbial taxa known to harbour BGCs. The large size and repeat sequences of BGCs remain a bioinformatic challenge, but newly developed software tools have been created to overcome these issues and are paramount to identify and select the most promising BGCs for further research and exploitation...
February 14, 2018: Current Opinion in Biotechnology
Fehmida Bibi, Gary A Strobel, Muhammad I Naseer, Muhammad Yasir, Ahmed A Khalaf Al-Ghamdi, Esam I Azhar
Halophytes are associated with the intertidal forest ecosystem of Saudi Arabia and seemingly have an immense potential for yielding useful and important natural products. In this study we have aimed to isolate and characterize the endophytic and rhizospheric bacterial communities from the halophyte, Salsola imbricata , In addition these bacterial strains were identified and selected strains were further studied for bioactive secondary metabolites. At least 168 rhizspheric and endophytic bacteria were isolated and of these 22 were active antagonists against the oomycetous fungal plant pathogens, Phytophthora capsici and Pythium ultimum ...
2018: Frontiers in Microbiology
Tobias Engl, Johannes Kroiss, Marco Kai, Taras Y Nechitaylo, Aleš Svatoš, Martin Kaltenpoth
The increasing resistance of human pathogens severely limits the efficacy of antibiotics in medicine, yet many animals, including solitary beewolf wasps, successfully engage in defensive alliances with antibiotic-producing bacteria for millions of years. Here, we report on the in situ production of 49 derivatives belonging to three antibiotic compound classes (45 piericidin derivatives, 3 streptochlorin derivatives, and nigericin) by the symbionts of 25 beewolf host species and subspecies, spanning 68 million years of evolution...
February 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Luyun Zhang, Junjie Ji, Meijuan Yuan, Yuanyuan Feng, Lei Wang, Zixin Deng, Linquan Bai, Jianting Zheng
An enoylreductase (ER) domain of a polyketide synthase module recruiting a methylmalonate extender unit sets the C2 methyl branch to either S or R configuration during processing of a polyketide intermediate carried by an acyl carrier protein (ACP) domain. In the present study, pantetheine- and ACP-bound trans-2-methylcrotonyl substrate surrogates were used to scrutinize the stereospecificity of the ER domains. The pantetheine-bound thioester was reduced to mixtures of both 2R and 2S products, whereas the expected 2S epimer was almost exclusively generated when the cognate ACP-bound substrate surrogate was utilized...
February 13, 2018: ACS Chemical Biology
Hai-Na Yu, Xin-Yan Liu, Shuai Gao, Bin Sun, Hong-Bo Zheng, Mei Ji, Ai-Xia Cheng, Hong-Xiang Lou
Chalcone synthases (CHSs) of the type III polyketide synthases (PKSs), catalyze the formation of a tetraketide intermediate from a CoA-tethered starter and malonyl-CoA but use different cyclization mechanisms to produce distinct chemical scaffolds. Herein, we characterized CHS and CHS-like enzymes (designated MpCHS and MpCHSL1, 2 and 3) from Marchantia paleacea and determined the crystal structure of MpCHSL1. MpCHS catalyzed a Claisen condensation to form chalcone, while MpCHSLs catalyzed the formation of lactonized α-pyrones in vitro...
January 31, 2018: Plant Physiology and Biochemistry: PPB
Xiwei Chen, Meng Xu, Cheng Feng, Changhua Hu
Fungal polyketides display complex structures and variously biological activities. Their biosynthetic pathways generally contain novel enzyme-catalyzed reactions. This review provides a summary of recent research advances in molecular mechanism of the biosynthesis of fungal polyketides including highly-reducing polyketide synthases (HR-PKSs), non-reducing polyketide synthases (NR-PKSs), as well as polyketide-nonribosomal peptide synthase (PKS-NRPSs) and reducingnon- reducing polyketide synthase (HR-NR PKSs) hybrids...
February 25, 2018: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Satoshi Yuzawa, Tyler W H Backman, Jay D Keasling, Leonard Katz
Complex reduced polyketides represent the largest class of natural products that have applications in medicine, agriculture, and animal health. This structurally diverse class of compounds shares a common methodology of biosynthesis employing modular enzyme systems called polyketide synthases (PKSs). The modules are composed of enzymatic domains that share sequence and functional similarity across all known PKSs. We have used the nomenclature of synthetic biology to classify the enzymatic domains and modules as parts and devices, respectively, and have generated detailed lists of both...
February 9, 2018: Journal of Industrial Microbiology & Biotechnology
Ting Zou, Mingxing Liu, Qiao Xiao, Tao Wang, Dan Chen, Tao Luo, Guoqiang Yuan, Qiao Li, Jun Zhu, Yueyang Liang, Qiming Deng, Shiquan Wang, Aiping Zheng, Lingxia Wang, Ping Li, Shuangcheng Li
OsPKS2, the rice orthologous gene of Arabidopsis PKSB/LAP5, encodes a polyketide synthase that is involved in pollen wall formation in rice. In flowering plants, the pollen wall protects male gametes from various environmental stresses and pathogen attacks, as well as promotes pollen germination. The biosynthesis of sporopollenin in tapetal cell is critical for pollen wall formation. Recently, progress has been made in understanding sporopollenin metabolism during pollen wall development in Arabidopsis. However, little is known about the molecular mechanism that underlies the sporopollenin synthesis in pollen wall formation in rice (Oryza sativa)...
February 6, 2018: Plant Cell Reports
Chuixing Kong, Hezhou Huang, Ying Xue, Yiqi Liu, Qiangqiang Peng, Qi Liu, Qin Xu, Qiaoyun Zhu, Ying Yin, Xiangshan Zhou, Yuanxing Zhang, Menghao Cai
Terreic acid is a potential anticancer drug as it inhibits Bruton's tyrosine kinase; however, its biosynthetic molecular steps remain unclear. In this work, the individual reactions of terreic acid biosynthesis were determined by stepwise pathway assembly in a heterologous host, Pichia pastoris, on the basis of previous knockout studies in a native host, Aspergillus terreus. Polyketide synthase AtX was found to catalyze the formation of partially reduced polyketide 6-methylsalicylic acid, followed by 3-methylcatechol synthesis by salicylate 1-monooxygenase AtA-mediated decarboxylative hydroxylation of 6-methylsalicylic acid...
February 1, 2018: Scientific Reports
Stephanie W Chun, Meagan E Hinze, Meredith A Skiba, Alison R Narayan
Like many complex natural products, the intricate architecture of saxitoxin (STX) has hindered full exploration of this scaffold's utility as a tool for studying voltage-gated sodium ion channels and as a pharmaceutical agent. Established chemical strategies can provide access to the natural product; however, a chemoenzymatic route to saxitoxin that could provide expedited access to related compounds has not been devised. The first step toward realizing a chemoenzymatic approach toward this class of molecules is the elucidation of the saxitoxin biosynthetic pathway...
February 1, 2018: Journal of the American Chemical Society
Si-Jia Xue, Zhe Chi, Yu Zhang, Yan-Feng Li, Guang-Lei Liu, Hong Jiang, Zhong Hu, Zhen-Ming Chi
PURPOSE: Oleaginous yeasts, fatty acids biosynthesis and regulation in the oleaginous yeasts and the fatty acids from the oleaginous yeasts and their applications are reviewed in this article. RESULTS: Oleaginous yeasts such as Rhodosporidium toruloides, Yarrowia lipolytica, Rhodotorula mucilaginosa, and Aureobasidium melanogenum, which can accumulate over 50% lipid of their cell dry weight, have many advantages over other oleaginous microorganisms. The fatty acids from the oleaginous yeasts have many potential applications...
February 1, 2018: Critical Reviews in Biotechnology
Zhen Jie Low, Li Mei Pang, Yichen Ding, Qing Wei Cheang, Kim Le Mai Hoang, Hoa Thi Tran, Jinming Li, Xue-Wei Liu, Yoganathan Kanagasundaram, Liang Yang, Zhao-Xun Liang
Streptomyces are a genus of Actinobacteria capable of producing structurally diverse natural products. Here we report the isolation and characterization of a biosynthetically talented Streptomyces (Streptomyces sp. SD85) from tropical mangrove sediments. Whole-genome sequencing revealed that Streptomyces sp. SD85 harbors at least 52 biosynthetic gene clusters (BGCs), which constitute 21.2% of the 8.6-Mb genome. When cultivated under lab conditions, Streptomyces sp. SD85 produces sceliphrolactam, a 26-membered polyene macrolactam with unknown biosynthetic origin...
January 25, 2018: Scientific Reports
Yudi Rusman, Benjamin W Held, Robert A Blanchette, Yanan He, Christine E Salomon
Recent investigations of filamentous fungi isolated from coastal areas and historic wooden structures in the Ross Sea and Peninsula regions of Antarctica have identified the genus Cadophora as one of the most abundant fungal groups, comprising more than 30% of culturable fungi at some locations. A methanol extract of Cadophora luteo-olivacea grown on rice media yielded the known polyketides spiciferone A, spiciferol A, dihydrospiciferone A and dihydrospiciferol A. Additionally, nine related hexaketides were identified, including spiciferone F, two isomers of the known fungal bicyclic ketal colomitide B, cadopherones A-D, similin C, and spicifernin B...
January 19, 2018: Phytochemistry
Hadi H Mohammad, Jack A Connolly, Zhongshu Song, Joanne Hothersall, Paul R Race, Christine L Willis, Thomas J Simpson, Christopher Morton Thomas
Hydroxylation modulates the activity of many pharmacological biomolecules. It can be integral to the basic biosynthetic factory or result from tailoring steps. For anti-MRSA antibiotic mupirocin, removal of C8-hydroxyl late in biosynthesis gives the active pseudomonic acid A. An extra hydroxylation, at C4, occurs in the related antibiotic thiomarinol A. We report here that putative non-heme-iron(II)/α-ketoglutarate-dependent dioxygenase TmuB, from the thiomarinol cluster, 4-hydroxylates various pseudomonic acids while C8-OH, and other substituents around the pyran ring, block enzyme action but not substrate binding...
January 24, 2018: Chembiochem: a European Journal of Chemical Biology
Douglas R Cohen, Craig A Townsend
Dynemicin A is a member of a subfamily of enediyne antitumour antibiotics characterized by a 10-membered carbocycle fused to an anthraquinone, both of polyketide origin. Sequencing of the dynemicin biosynthetic gene cluster in Micromonospora chersina previously identified an enediyne polyketide synthase (PKS), but no anthraquinone PKS, suggesting gene(s) for biosynthesis of the latter were distant from the core dynemicin cluster. To identify these gene(s), we sequenced and analysed the genome of M. chersina...
February 2018: Nature Chemistry
Wei Zhang, Shichun Lun, Shu-Huan Wang, Xingwu Jiang, Fan Yang, Jie Tang, Abigail L Manson, Ashlee M Earl, Hendra Gunosewoyo, William R Bishai, Li-Fang Yu
Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound, whose X-ray co-crystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally-related benzofurans with the aim to improve their potency and bioavailability...
January 12, 2018: Journal of Medicinal Chemistry
Alexander Rittner, Karthik S Paithankar, Khanh Vu Huu, Martin Grininger
Fatty acid synthases (FASs) and polyketide synthases (PKSs) condense acyl compounds to fatty acids and polyketides, respectively. Both, FASs and PKSs, harbor acyltransferases (ATs), which select substrates for condensation by β-ketoacyl synthases (KSs). Here, we present the structural and functional characterization of the polyspecific malonyl/acetyltransferase (MAT) of murine FAS. We assign kinetic constants for the transacylation of the native substrates, acetyl- and malonyl-CoA, and demonstrate the promiscuity of FAS to accept structurally and chemically diverse CoA-esters...
January 12, 2018: ACS Chemical Biology
Jessica Gil-Serna, Marta García-Díaz, María Teresa González-Jaén, Covadonga Vázquez, Belén Patiño
Ochratoxin A (OTA) is one of the most important mycotoxins due to its toxic properties and worldwide distribution which is produced by several Aspergillus and Penicillium species. The knowledge of OTA biosynthetic genes and understanding of the mechanisms involved in their regulation are essential. In this work, we obtained a clear picture of biosynthetic genes organization in the main OTA-producing Aspergillus and Penicillium species (A. steynii, A. westerdijkiae, A. niger, A. carbonarius and P. nordicum) using complete genome sequences obtained in this work or previously available on databases...
January 3, 2018: International Journal of Food Microbiology
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