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combinatorial biosynthesis

Ying Zhao, Bi-Han Wu, Zhen-Ning Liu, Jianjun Qiao, Guang-Rong Zhao
Resveratrol, a plant-derived polyphenolic compound with various health activities, is widely used in nutraceutical and food additives. Herein, combinatorial optimization of resveratrol biosynthetic pathway and intracellular environment of E. coli was carried out. Screening pathway genes from various species and exploring their expression pattern, we constructed initial resveratrol-producing strain. Further targeting at availability of malonyl-CoA through expressing ACC of Corynebacterium glutamicum and antisense inhibiting native fabD significantly increased resveratrol biosynthesis...
November 29, 2018: Journal of Agricultural and Food Chemistry
Yujie Yuan, Martin Litzenburger, Shu Cheng, Guangkai Bian, Ben Hu, Pan Yan, Yousheng Cai, Zixin Deng, Rita Bernhardt, Tiangang Liu
Sesquiterpenes represent a class of important terpenoids with high structural diversity and a wide range of applications. The cyclized core-skeletons are generated by sesquiterpene cyclases, and the structural diversity is further increased by a series of modification steps. Cytochromes P450 (P450s) are a class of monooxygenases and one of the main contributors for the structure diversity of natural products. Some of these P450s show a broad substrate range and might be promising candidates for the implementation of cascade reactions...
November 28, 2018: Chembiochem: a European Journal of Chemical Biology
Nicholas Gold, Elena Fossati, Cecilie Cetti Hansen, Marcos Di Falco, Veronique Douchin, Vincent J J Martin
Biosynthesis of steviol glycosides in planta proceeds via two cytochrome P450 enzymes (CYPs): kaurene oxidase (KO) and kaurenoic acid hydroxylase (KAH). KO and KAH function in succession with the support of a NADPH-dependent cytochrome P450 reductase (CPR) to convert kaurene to steviol. This work describes a platform for recombinant production of steviol glucosides (SGs) in Saccharomyces cerevisiae, demonstrating the full reconstituted pathway from the simple sugar glucose to the SG precursor steviol. With a focus on optimization of the KO-KAH activities, combinations of functional homologs were tested in batch growth...
November 26, 2018: ACS Synthetic Biology
Rishab Ramapriyan, Mauricio da Silva Caetano, Hampartsoum B Barsoumian, Ana Carolina P Mafra, Erika Pereira Zambalde, Hari Menon, Efrosini Tsouko, James W Welsh, Maria Angelica Cortez
Many metabolic alterations, including the Warburg effect, occur in cancer cells that influence the tumor microenvironment, including switching to glycolysis from oxidative phosphorylation, using opportunistic modes of nutrient acquisition, and increasing lipid biosynthesis. The altered metabolic landscape of the tumor microenvironment can suppress the infiltration of immune cells and other functions of antitumor immunity through the production of immune-suppressive metabolites. Metabolic dysregulation in cancer cells further affects the expression of cell surface markers, which interferes with immune surveillance...
November 12, 2018: Pharmacology & Therapeutics
Hiroya Itoh, Makoto Matsui, Yuki Miyamura, Itaru Takeda, Jun Ishii, Toshitaka Kumagai, Masayuki Machida, Takashi Shibata, Masanori Arita
For many secondary metabolites, heterologous synthesis is the definitive step to determine their required biosynthetic genes. Using a multivector expression system in Saccharomyces cerevisiae, we reconstituted not only two natural statins from two fungal species, i.e., lovastatin from Aspergillus terreus and FR901512 from Xylaria grammica, but also new statin structures by mixing their genes. Combinatorial gene exchange experiments revealed the functional promiscuity of two polyketide synthases in A. terreus, lovB, and lovF; they could synthesize FR901512 with Xylaria genes...
November 13, 2018: ACS Synthetic Biology
Yuki Tobimatsu, Mathias Schuetz
The final step of lignin biosynthesis is the polymerization of monolignols in apoplastic cell wall domains. In this process, monolignols secreted by lignifying cells, or occasionally neighboring non-lignifying and/or other lignifying cells, are activated by cell-wall-localized oxidation systems, such as laccase/O2 and/or peroxidase/H2 O2 , for combinatorial radical coupling to make the final lignin polymers. Plants can precisely control when, where, and which types of lignin polymers are assembled at tissue and cellular levels, but do not control the polymers' exact chemical structures per se...
October 22, 2018: Current Opinion in Biotechnology
Philip A Storm, Paramita Pal, Callie R Huitt-Roehl, Craig A Townsend
Polyketide C-methylation occurs during a programmed sequence of dozens of reactions carried out by multidomain polyketide synthases (PKSs). Fungal PKSs perform these reactions iteratively, where a domain may be exposed to and act upon multiple enzyme-tethered intermediates during biosynthesis. We surveyed a collection of C-methyltransferase (CMeT) domains from nonreducing fungal PKSs to gain insight into how different methylation patterns are installed. Our in vitro results show that control of methylation resides primarily with the CMeT, and CMeTs can intercept and methylate intermediates from noncognate nonreducing PKS domains...
October 30, 2018: ACS Chemical Biology
Alexander G Ekström, Jue Theresa Wang, Juraj Bella, Dominic J Campopiano
Dynamic combinatorial chemistry (DCC) is a powerful tool to identify ligands for biological targets. We used 19F NMR as an in situ, non-invasive technique for measuring the composition of a dynamic combinatorial library (DCL) of N-acylhydrazones (NAHs). An NAH DCL, constructed from a fluoro-aromatic aldehyde and a small set of hydrazides, was targetted at ecFabH, an essential enzyme in bacterial fatty acid biosynthesis. Our NMR analysis identified a tert-butyl NAH as the best binder which was confirmed by enzymatic assay...
October 18, 2018: Organic & Biomolecular Chemistry
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)...
November 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 provide 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...
November 15, 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
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