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combinatorial biosynthesis

Bei-Bei He, Xu-Liang Bu, Ting Zhou, Shu-Ming Li, Minjuan Xu, Jun Xu
Prenylated aromatic compounds are important intermediates in the biosynthesis of bioactive molecules such as secondary metabolites from plants, ubiquinone 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 analogs was feasible in a metabolically engineered E...
August 13, 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...
July 9, 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...
June 15, 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 susceptibility to cell wall targeting agents. M. smegmatis encodes 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 varying degrees but MSMEG_4643 was significantly greater during exponential growth...
June 18, 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
Thomas Vanhercke, Srinivas Belide, Matthew C Taylor, Anna El Tahchy, Shoko Okada, Vivien Rolland, Qing Liu, Madeline Mitchell, Pushkar Shrestha, Ingrid Venables, Lina Ma, Cheryl Blundell, Anu Mathew, Lisa Ziolkowski, Nathalie Niesner, Dawar Hussain, Bei Dong, Guoquan Liu, Ian D Godwin, Jiwon Lee, Melanie Rug, Xue-Rong Zhou, Surinder P Singh, James R Petrie
Synthesis and accumulation of the storage lipid triacylglycerol in vegetative plant tissues has emerged as a promising strategy to meet the world's future need for vegetable oil. Sorghum (Sorghum bicolor) is a particularly attractive target crop given its high biomass, drought resistance and C4 photosynthesis. While oilseed-like triacylglycerol levels have been engineered in the C3 model plant tobacco, progress in C4 monocot crops has been lagging behind. In this study, we report the accumulation of triacylglycerol in sorghum leaf tissues to levels between 3 and 8...
June 6, 2018: Plant Biotechnology Journal
Fabian Schweizer, Maite Colinas, Jacob Pollier, Alex Van Moerkercke, Robin Vanden Bossche, Rebecca de Clercq, Alain Goossens
To fend off microbial pathogens and herbivores, plants have evolved a wide range of defense strategies such as physical barriers, or the production of anti-digestive proteins or bioactive specialized metabolites. Accumulation of the latter compounds is often regulated by transcriptional activation of the biosynthesis pathway genes by the phytohormone jasmonate-isoleucine. Here, we used our recently developed flower petal transformation method in the medicinal plant Catharanthus roseus to shed light on the complex regulatory mechanisms steering the jasmonate-modulated biosynthesis of monoterpenoid indole alkaloids (MIAs), to which the anti-cancer compounds vinblastine and vincristine belong...
July 2018: Metabolic Engineering
Ozkan Fidan, Riming Yan, Gabrielle Gladstone, Tong Zhou, Du Zhu, Jixun Zhan
Sch47554 and Sch47555 are antifungal compounds from Streptomyces sp. SCC-2136. The availability of the biosynthetic gene cluster made it possible to track genes that encode biosynthetic enzymes responsible for the structural features of these two angucyclines. Sugar moieties play important roles in the biological activities of many natural products. An investigation into glycosyltransferases (GTs) might potentially help to diversify pharmaceutically significant drugs through combinatorial biosynthesis. Sequence analysis indicates that SchS7 is a putative C-GT, whereas SchS9 and SchS10 are proposed to be O-GTs...
July 4, 2018: Chembiochem: a European Journal of Chemical Biology
Oliver Kayser
Secondary natural products from plants are important drug leads for the development of new drug candidates for rational clinical therapy and exhibit a variety of biological activities in experimental pharmacology and serve as structural template in medicinal chemistry. The exploration of plants and discovery of natural compounds based on ethnopharmacology in combination with high sophisticated analytics is still today an important drug discovery to characterize and validate potential leads. Due to structural complexity, low abundance in biological material, and high costs in chemical synthesis, alternative ways in production like plant cell cultures, heterologous biosynthesis, and synthetic biotechnology are applied...
May 24, 2018: Planta Medica
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...
June 15, 2018: Organic Letters
B A Blount, G-O F Gowers, J C H Ho, R Ledesma-Amaro, D Jovicevic, R M McKiernan, Z X Xie, B Z Li, Y J Yuan, T Ellis
Synthetic biology tools, such as modular parts and combinatorial DNA assembly, are routinely used to optimise the productivity of heterologous metabolic pathways for biosynthesis or substrate utilisation, yet it is well established that host strain background is just as important for determining productivity. Here we report that in vivo combinatorial genomic rearrangement of Saccharomyces cerevisiae yeast with a synthetic chromosome V can rapidly generate new, improved host strains with genetic backgrounds favourable to diverse heterologous pathways, including those for violacein and penicillin biosynthesis and for xylose utilisation...
May 22, 2018: Nature Communications
Christoph Müller, Thomas Neugebauer, Patrizia Zill, Cornelia Lass-Flörl, Franz Bracher, Ulrike Binder
Mucorales are fungi with increasing importance in the clinics. Infections take a rapidly progressive course resulting in high mortality rates. The ergosterol biosynthesis pathway and sterol composition are of interest, since they are targeted by currently applied antifungal drugs. Nevertheless, Mucorales often exhibit resistance to these drugs, resulting in therapeutic failure. Here, sterol patterns of six clinically relevant Mucorales ( Lichtheimia corymbifera , Lichtheimia ramosa , Mucor circinelloides , Rhizomucor pusillus , Rhizopus arrhizus , and Rhizopus microsporus ) were analysed in a targeted metabolomics fashion after derivatization by gas chromatography-mass spectrometry...
May 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Wenjia Gu, Shi-Hui Dong, Snigdha Sarkar, Satish K Nair, Eric W Schmidt
Cyanobactin biosynthetic enzymes have exceptional versatility in the synthesis of natural and unnatural products. Cyanobactins are ribosomally synthesized and posttranslationally modified peptides synthesized by multistep pathways involving a broad suite of enzymes, including heterocyclases/cyclodehydratases, macrocyclases, proteases, prenyltransferases, methyltransferases, and others. Here, we describe the enzymology and structural biology of cyanobactin biosynthetic enzymes, aiming at the twin goals of understanding biochemical mechanisms and biosynthetic plasticity...
2018: Methods in Enzymology
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