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combinatorial biosynthesis

Fu Yan, Christian Burgard, Alexander Popoff, Nestor Zaburannyi, Gregor Zipf, Josef Maier, Hubert S Bernauer, Silke C Wenzel, Rolf Müller
Synthetic biology techniques coupled with heterologous secondary metabolite production offer opportunities for the discovery and optimisation of natural products. Here we developed a new assembly strategy based on type IIS endonucleases and elaborate synthetic DNA platforms, which could be used to seamlessly assemble and engineer biosynthetic gene clusters (BGCs). By applying this versatile tool, we designed and assembled more than thirty different artificial myxochromide BGCs, each around 30 kb in size, and established heterologous expression platforms using a derivative of Myxococcus xanthus DK1622 as a host...
October 14, 2018: Chemical Science
Elizabeth Skellam
Fungi are a prolific source of bioactive compounds, some of which have been developed as essential medicines and life-enhancing drugs. Genome sequencing has revealed that fungi have the potential to produce considerably more natural products (NPs) than are typically observed in the laboratory. Recently, there have been significant advances in the identification, understanding, and engineering of fungal biosynthetic gene clusters (BGCs). This review briefly describes examples of the engineering of fungal NP biosynthesis at the global, pathway, and enzyme level using in vivo and in vitro approaches and refers to the range and scale of heterologous expression systems available, developments in combinatorial biosynthesis, progress in understanding how fungal BGCs are regulated, and the applications of these novel biosynthetic enzymes as biocatalysts...
October 10, 2018: Trends in Biotechnology
Haibo Yuan, Yanfeng Liu, Xueqin Lv, Jianghua Li, Guocheng Du, Zhongping Shi, Long Liu
The compound 2,5-furandicarboxylic acid (FDCA), an important bio-based monomer for the production of various polymers, can be obtained from 5-hydroxymethylfurfural (HMF). However, efficient production of FDCA from HMF via biocatalysis has not been well studied. In this study, we report the identification of key genes that are involved in FDCA synthesis and then the engineering of Raoultella ornithinolytica BF60 for biocatalytic oxidation of HMF to FDCA using its resting cells. Specifically, previously unknown candidate genes, adhP3 and alkR , which were responsible for the reduction of HMF to the undesired product 2,5-bis(hydroxymethyl) furan (HMF alcohol), were identified by transcriptomic analysis...
October 10, 2018: Journal of Microbiology and Biotechnology
A C Ward, Nee Allenby
The need for new antimicrobials is indisputable. The flight from natural products in drug discovery was unfortunate. However, the revolution that is genome mining, enabled by the explosion in sequencing technology, is a cause for hope. Nevertheless, renewed search and discovery is still a challenge. We explore novel metabolite diversity and the challenges in Streptomyces. Estimating novel bioactive metabolites remaining to be discovered is an important driver for future investment. Frequent re-discovery of known natural products was a major factor in big pharma exiting search and discovery and remains a reality...
September 27, 2018: FEMS Microbiology Letters
Young Jin Ko, Young-Chul Joo, Jeong Eun Hyeon, Eunhye Lee, Myeong-Eun Lee, Jiho Seok, Seung Wook Kim, Chulhwan Park, Sung Ok Han
Zn-porphyrin is a promising organic photosensitizer in various fields including solar cells, interface and biomedical research, but the biosynthesis study has been limited, probably due to the difficulty of understanding complex biosynthesis pathways. In this study, we developed a Corynebacterium glutamicum platform strain for the biosynthesis of Zn-coproporphyrin III (Zn-CP III), in which the heme biosynthesis pathway was efficiently upregulated. The pathway was activated and reinforced by strong promoter-induced expression of hemAM (encoding mutated glutamyl-tRNA reductase) and hemL (encoding glutamate-1-semialdehyde aminotransferase) genes...
September 27, 2018: Scientific Reports
Tianmin Wang, Jiahui Guo, Yangyang Liu, Zhenglian Xue, Chong Zhang, Xin-Hui Xing
Terpenoids are a large family of natural compounds that are important for both biotechnological applications and basic microorganism physiology. Inspired by the current literature, we hypothesized that recently deciphered phosphatase promiscuity may be an unexplored factor that negatively affects terpenoid biosynthesis by redirecting carbon flux away from the pathway via unrecognized catalytic activities on the phosphorylated intermediates. We used lycopene as a proof-of-concept to test this hypothesis. Based on an extensive bioinformatics analysis, we selected 56 phosphatase-encoding genes in Escherichia coli and constructed a knockdown library for these genes in a lycopene overproducer via CRISPR interference (CRISPRi)...
September 18, 2018: Applied Microbiology and Biotechnology
Gudan Xu, Liyuan Kong, Rong Gong, Liudong Xu, Yaojie Gao, Ming Jiang, You-Sheng Cai, Kui Hong, Youcai Hu, Peng Liu, Zixin Deng, Neil P J Price, Wenqing Chen
Purine nucleoside antibiotic pairs, concomitantly produced by a single strain, are an important group of microbial natural products. Here, we report a target-directed genome mining approach to elucidate the biosynthesis of the purine nucleoside antibiotic pair aristeromycin (ARM) and coformycin (COF) in Micromonospora haikouensis DSM 45626 (a new producer for ARM and COF) and Streptomyces citricolor NBRC 13005 (a new COF producer). We also provided biochemical data that MacI and MacT function as unusual phosphorylases, catalyzing an irreversible reaction for the tailoring assembly of neplanocin A (NEP-A) and ARM...
September 14, 2018: Applied and Environmental Microbiology
Tingting Huang, Yingyi Duan, Yi Zou, Zixin Deng, Shuangjun Lin
Maremycins are a group of structurally diverse 2,5-diketopiperazine natural products featuring a rare amino acid building block, S-methyl-l-cysteine (Me-Cys). Three freestanding nonribosomal peptide synthetase (NRPS) proteins from the maremycins biosynthetic pathway were proposed for the formation of the 2,5-diketopiperazine scaffold: MarQ, MarM, and MarJ. MarQ displays flexible adenylation activity toward Cys, Me-Cys, Ser, and ( S)-2,3-diaminopropanoic acid (DAP) and transfers these substrates to MarJ, which is the discrete peptidyl carrier protein (PCP)...
September 21, 2018: ACS Chemical Biology
Bei-Bei He, Xu-Liang Bu, Ting Zhou, Shu-Ming Li, Min-Juan Xu, Jun Xu
Prenylated aromatic compounds are important intermediates in the biosynthesis of bioactive molecules such as 3-chromanols from plants, ubiquinones from prokaryotes and meroterpenoids from sponges. Biosynthesis of prenylated aromatic compounds using prokaryotic microorganisms has attracted increasing attention in the field of synthetic biology. In this study, we demonstrated that the production of 3-geranyl-4-hydroxybenzoic acid (GBA) and a variety of GBA analogues was feasible in a metabolically engineered E...
August 30, 2018: ACS Synthetic Biology
David Bergenholm, Guodong Liu, Petter Holland, Jens Nielsen
To build transcription regulatory networks, transcription factor binding must be analyzed in cells grown under different conditions because their responses and targets differ depending on environmental conditions. We performed whole-genome analysis of the DNA binding of five Saccharomyces cerevisiae transcription factors involved in lipid metabolism, Ino2, Ino4, Hap1, Oaf1, and Pip2, in response to four different environmental conditions in chemostat cultures, which allowed us to keep the specific growth rate constant...
July 2018: MSystems
Jian Li, Renliang Sun, Xinjuan Ning, Xinran Wang, Zhuo Wang
Actinosynnema pretiosum ATCC 31280 is the producer of antitumor agent ansamitocin P-3 (AP-3). Understanding of the AP-3 biosynthetic pathway and the whole metabolic network in A. pretiosum is important for the improvement of AP-3 titer. In this study, we reconstructed the first complete Genome-Scale Metabolic Model (GSMM) Aspm1282 for A. pretiosum ATCC 31280 based on the newly sequenced genome, with 87% reactions having definite functional annotation. The model has been validated by effectively predicting growth and the key genes for AP-3 biosynthesis...
July 20, 2018: Genes
Xiao-Jing Guo, Wen-Hai Xiao, Ying Wang, Ming-Dong Yao, Bo-Xuan Zeng, Hong Liu, Guang-Rong Zhao, Ying-Jin Yuan
Background: 7-Dehydrocholesterol (7-DHC) has attracted increasing attentions due to its great medical value and the enlarging market demand of its ultraviolet-catalyzed product vitamin D3 . Microbial production of 7-DHC from simple carbon has been recognized as an attractive complement to the traditional sources. Even though our previous work realized 7-DHC biosynthesis in Saccharomyces cerevisiae , the current productivity of 7-DHC is still too low to satisfy the demand of following industrialization...
2018: Biotechnology for Biofuels
Richa Bajpai, Mala Shanmugam
PURPOSE OF REVIEW: Targeting cancer metabolism for therapy has received much attention over the last decade with various small molecule inhibitors entering clinical trials. The present review highlights the latest strategies to target glucose and glutamine metabolism for cancer therapy with a particular emphasis on novel combinatorial treatment approaches. RECENT FINDINGS: Inhibitors of glucose, lactate, and glutamine transport and the ensuing metabolism are in preclinical to clinical trial stages of investigation...
September 2018: Current Opinion in Oncology
Steven R Brown, Marta Staff, Rob Lee, John Love, David A Parker, Stephen J Aves, Thomas P Howard
Multifactorial approaches can quickly and efficiently model complex, interacting natural or engineered biological systems in a way that traditional one-factor-at-a-time experimentation can fail to do. We applied a Design of Experiments (DOE) approach to model ethanol biosynthesis in yeast, which is well-understood and genetically tractable, yet complex. Six alcohol dehydrogenase (ADH) isozymes catalyze ethanol synthesis, differing in their transcriptional and post-translational regulation, subcellular localization, and enzyme kinetics...
July 20, 2018: ACS Synthetic Biology
Darko Kero, Tanja Simic Bilandzija, Lidija Lasic Arapovic, Katarina Vukojevic, Mirna Saraga-Babic
Syndecans belong to a four-member family of cell surface heparan sulfate proteoglycans (HSPGs) abundantly present in various tissues. They are primarily recognized as extracellular matrix (ECM) receptors able to bind various ECM components and form gradients of morphogens and growth factors. Syndecans are composed of core protein with distinctive cytoplasmic, transmembrane, and extracellular domains to which several HS glycosaminoglycan (GAG) chains are covalently attached. In development of composite organs, such as teeth, expression patterns of syndecans display temporo-spatial shifts between epithelial and mesenchymal tissue compartments...
2018: Frontiers in Physiology
Jan Niklas Bröker, Boje Müller, Nicole van Deenen, Dirk Prüfer, Christian Schulze Gronover
Pentacyclic triterpenes are diverse plant secondary metabolites derived from the mevalonate (MVA) pathway. Many of these molecules are potentially valuable, particularly as pharmaceuticals, and research has focused on their production in simpler and more amenable heterologous systems such as the yeast Saccharomyces cerevisiae. We have developed a new heterologous platform for the production of pentacyclic triterpenes in S. cerevisiae based on a combinatorial engineering strategy involving the overexpression of MVA pathway genes, the knockout of negative regulators, and the suppression of a competing pathway...
August 2018: Applied Microbiology and Biotechnology
Bernadette Breiden, Konrad Sandhoff
Gangliosides are sialic acid containing glycosphingolipids, which are abundant in mammalian brain tissue. Several fatal human diseases are caused by defects in glycolipid metabolism. Defects in their degradation lead to an accumulation of metabolites upstream of the defective reactions, whereas defects in their biosynthesis lead to diverse problems in a large number of organs.Gangliosides are primarily positioned with their ceramide anchor in the neuronal plasma membrane and the glycan head group exposed on the cell surface...
2018: Methods in Molecular Biology
Leonard Katz, Yvonne Y Chen, Ramon Gonzalez, Todd C Peterson, Huimin Zhao, Richard H Baltz
Synthetic biology is a logical extension of what has been called recombinant DNA (rDNA) technology or genetic engineering since the 1970s. As rDNA technology has been the driver for the development of a thriving biotechnology industry today, starting with the commercialization of biosynthetic human insulin in the early 1980s, synthetic biology has the potential to take the industry to new heights in the coming years. Synthetic biology advances have been driven by dramatic cost reductions in DNA sequencing and DNA synthesis; by the development of sophisticated tools for genome editing, such as CRISPR/Cas9; and by advances in informatics, computational tools, and infrastructure to facilitate and scale analysis and design...
June 18, 2018: Journal of Industrial Microbiology & Biotechnology
Christopher Ealand, Binayak Rimal, James Chang, Lethabo Mashigo, Melissa Chengalroyen, Lusanda Mapela, Germar Beukes, Edith Machowski, Sung Joon Kim, Bavesh Kana
Resuscitation-promoting factors (Rpfs) have previously been shown to act as growth-stimulatory molecules via their lysozyme-like activity on peptidoglycan in the bacterial cell wall. In this study, we investigated the ability of Mycobacterium smegmatis strains lacking rpf genes to form biofilms and tested their susceptibilities to cell wall-targeting agents. M. smegmatis contains four distinct rpf homologues, namely, MSMEG_5700 ( rpfA ), MSMEG_5439 ( rpfB ), MSMEG_4640 ( rpfE2 ), and MSMEG_4643 ( rpfE ). During axenic growth of the wild-type strain, all four mRNA transcripts were expressed to various degrees, but the expression of MSMEG_4643 was significantly greater during exponential growth...
September 1, 2018: Applied and Environmental Microbiology
Aliabbas A Saleh, Gary W Jones, Frances C Tinley, Stephen F Delaney, Sahar H Alabbadi, Keith Fenlon, Sean Doyle, Rebecca A Owens
The non-ribosomal peptide gliotoxin, which autoinduces its own biosynthesis, has potent anti-fungal activity, especially in the combined absence of the gliotoxin oxidoreductase GliT and bis-thiomethyltransferase GtmA. Dithiol gliotoxin (DTG) is a substrate for both of these enzymes. Herein we demonstrate that DTG chelates Zn2+ (m/z 424.94), rapidly chelates Zn2+ from Zn(4-(2-pyridylazo)-resorcinol) (Zn(PAR)2) and also inhibits a Zn2+-dependent alkaline phosphatase (AP). Zn2+ addition rescues AP function following DTG-associated inhibition, and pre-incubation of DTG with Zn2+ completely protects AP activity...
June 20, 2018: Metallomics: Integrated Biometal Science
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