Article
Agriculture, Multidisciplinary
Zongqin Gou, Xin Song, Guangqiang Wang, Yongjun Xia, Lianzhong Ai, Zhiqiang Xiong
Summary: This study demonstrates that Escherichia coli can express the C-30 carotenoid genes from Lactiplantibacillus plantarum and significantly increase carotenoid production through fermentation optimization. The C-30 carotenoids synthesized in E. coli show high antioxidant activity.
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
(2023)
Article
Biochemistry & Molecular Biology
Hanyu Liang, Hongjuan Chen, Xinya Liu, Zihan Wang, Pengfu Li, Shan Lu
Summary: This study aims to investigate the synthesis mechanism of astaxanthin and suggests that the hydroxylation step may be the bottleneck for heterologous production of astaxanthin in Synechocystis.
Review
Biochemical Research Methods
Lei Li, Logan W. Maclntyre, Sean F. Brady
Summary: This review summarizes recent advances in heterologous production of bacterial and fungal NPs, with a focus on next-generation transcriptional regulatory modules, novel BGC refactoring techniques, and optimized heterologous hosts.
CURRENT OPINION IN BIOTECHNOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Zerlina G. Wuisan, I. Dewa M. Kresna, Nils Boehringer, Kim Lewis, Till F. Schaeberle
Summary: Darobactin A (DAR) is a promising antibiotic targeting Gram-negative bacteria, initially identified in bacteria from several genera. It targets the outer membrane protein BamA and has shown convincing in vivo activities in mouse infection models. By establishing a heterologous production and engineering platform, DAR production yield can be improved and structure modification approaches can be facilitated. Only two genes are necessary for the heterologous production of this RiPP antibiotic.
METABOLIC ENGINEERING
(2021)
Article
Biotechnology & Applied Microbiology
Daniel Oves-Costales, Tetiana Gren, Eva Baggesgaard Sterndorff, Jesus Martin, Francisco Javier Ortiz-Lopez, Tue S. Jorgensen, Xinglin Jiang, Fernando Roman-Hurtado, Fernando Reyes, Olga Genilloud, Tilmann Weber
Summary: This study successfully identified the biosynthetic gene cluster of Globomycin using genome mining, and demonstrated the close correlation between the gene cluster and Globomycin production. This discovery paves the way for the synthesis of novel Globomycin derivatives with improved pharmacological properties.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2023)
Article
Multidisciplinary Sciences
Jasmin Hafner, James Payne, Homa MohammadiPeyhani, Vassily Hatzimanikatis, Christina Smolke
Summary: This study introduces a computational workflow to systematically screen the biochemical vicinity of plant natural product (PNP) biosynthetic pathways for pharmaceutical compounds. Applying the workflow to noscapine biosynthesis pathway, pathways and enzyme candidates for the production of (S)-tetrahydropalmatine were identified, showcasing the value of cheminformatic tools in predicting reactions, pathways, and enzymes in synthetic biology.
NATURE COMMUNICATIONS
(2021)
Article
Biotechnology & Applied Microbiology
Chanjuan Jiang, Haibo Zhou, Hongluan Sun, Ruoting He, Chaoyi Song, Tianqi Cui, Ji Luan, Jun Fu, Youming Zhang, Nianzhi Jiao, Hailong Wang
Summary: This study engineered an artificial 106-kb salinomycin gene cluster and achieved efficient heterologous expression in three hosts, leading to improved production compared to the native producer. The established system will facilitate structural diversification of salinomycin for drug development and structure-activity studies.
BIOTECHNOLOGY AND BIOENGINEERING
(2021)
Article
Biochemistry & Molecular Biology
Nils Bohringer, Maria A. Patras, Till F. Schaeberle
Summary: Pseudouridimycin (PUM) is a novel bacterial nucleoside analog that inhibits bacterial growth by blocking transcription of bacterial RNAP. Heterologous expression studies identified the minimal set of genes necessary for PUM production.
Article
Chemistry, Multidisciplinary
Shu-Yi Lin, C. Elizabeth Oakley, Cory B. Jenkinson, Yi-Ming Chiang, Ching-Kuo Lee, Christopher G. Jones, Paul M. Seidler, Hosea M. Nelson, Richard B. Todd, Clay C. C. Wang, Berl R. Oakley
Summary: In this study, a heterologous expression platform was developed in Aspergillus nidulans to express a previously unknown biosynthetic gene cluster (BGC) from A. fumigatus and determine its products. The BGC produced sartorypyrones, and a biosynthetic pathway for these compounds was proposed. Additionally, a polyketide synthase (PKS) gene from the BGC was identified to produce a potentially important biorenewable platform chemical called triacetic acid lactone (TAL). This study highlights the potential of using the A. nidulans heterologous expression platform to uncover cryptic BGCs from A. fumigatus and other species.
Article
Biotechnology & Applied Microbiology
Heung-Soon Park, Ji-Hee Park, Hye-Jin Kim, Seung-Hoon Kang, Si-Sun Choi, Eung-Soo Kim
Summary: This study isolated a Streptomyces strain with strong antifungal activity and identified a large biosynthetic gene cluster (BGC) for a polyene compound. Overexpression of the BGC in the strain and heterologous expression in another strain led to increased production of the compound. The researchers also created strains lacking the sugar moiety of the compound and found that the sugar played a critical role in its biological activity. BAC cloning of large natural product BGCs in Streptomyces is a valuable approach for improving production and screening for biological activity.
FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
(2022)
Review
Chemistry, Medicinal
Yushan Xu, Xinhua Du, Xionghui Yu, Qian Jiang, Kaiwen Zheng, Jinzhong Xu, Pinmei Wang
Summary: Marine natural products are an important source of biologically active compounds, but the majority of biosynthetic gene clusters in marine microorganisms are not expressed under traditional laboratory conditions. Efficient heterologous expression systems can activate silent gene clusters and increase compound yield, providing a reference for exploring unknown marine natural products.
Review
Biochemistry & Molecular Biology
Jiawang Liu, Anan Liu, Youcai Hu
Summary: This review highlights the significant role played by dimeric natural products generated by microorganisms and plants in drug discovery up to August 2020. It focuses on key enzymes involved in the biosynthetic pathways of these products.
NATURAL PRODUCT REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Natali Ozber, Lisa Yu, Jillian M. Hagel, Peter J. Facchini
Summary: Systematic screening of morphine pathway intermediates in engineered yeast identified key biosynthetic enzymes that exhibit potent feedback inhibition. Specifically, 4'-O-methyltransferase (4' OMT) produces (S)-reticuline and salutaridinol-7-O-acetyltransferase (SalAT) and thebaine synthase (THS2) form the enzyme system responsible for the synthesis of thebaine. Addition of deuterated reticuline-d1 to a yeast strain capable of converting (S)-norcoclaurine to (S)-reticuline resulted in reduced product accumulation. Similar effects were observed with deuterated thebaine-d3 and a yeast strain able to convert salutaridine to thebaine. In vitro analysis showed that reticuline inhibits 4' OMT in a noncompetitive manner, while thebaine exerts mixed inhibition on SalAT/THS2. Furthermore, the addition of reticuline and thebaine led to the accumulation of pathway intermediates in a yeast strain engineered for de novo morphine biosynthesis, suggesting that blocking the interaction of these compounds with their respective enzymes could significantly increase opiate alkaloid production in engineered yeast.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Sebastian Gross, Fabian Panter, Domen Pogorevc, Carsten E. Seyfert, Selina Deckarm, Chantal D. Bader, Jennifer Herrmann, Rolf Mueller
Summary: The development of new antibiotics is crucial in combating infections caused by multidrug-resistant bacteria, with Gram-negative pathogens posing particular challenges. Through synthetic engineering of darobactin biosynthetic gene cluster in Escherichia coli, high yields of darobactin A and its active derivatives have been successfully produced, showing improved efficacy against various bacteria. This study also sheds light on the potential self-resistance mechanism in native darobactin producers.
Article
Biochemistry & Molecular Biology
Shumao Chai, Mingming Cao, Zhiyang Feng
Summary: Nitrogen heterocycle small molecules exhibit various pharmaceutically important bioactivities and have great potential in drug development and application. Microbes serve as an important source for discovering nitrogen heterocycle natural products, and this study uncovered a new biosynthetic machinery in Streptomyces for producing nitrogen heterocycle natural products.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Review
Chemistry, Multidisciplinary
Hiroki Oguri
Summary: Artemisinin and its semi-synthetic derivatives have been crucial in malaria chemotherapy due to their life-saving effects and unique peroxide bridge structure. This review outlines state-of-the-art approaches for artificial production, including engineered biosynthesis, chemo-enzymatic synthesis, total synthesis, and derivatization via siteselective C-H functionalization. Additionally, two synthetic campaigns producing skeletally diverse tetracyclic peroxides and 6-aza-artemisinins are summarized for rapid and flexible access to artemisinin-related chemical space.
Article
Chemistry, Multidisciplinary
Yuta Tsunematsu, Naoya Maeda, Michio Sato, Kodai Hara, Hiroshi Hashimoto, Kenji Watanabe, Christian Hertweck
Summary: Epidithiodiketopiperazines (ETPs) are a class of ecologically and medicinally important cyclodipeptides with a reactive transannular disulfide bridge. A novel oxidoreductase (AcIR) has been discovered to catalyze both carbon-sulfur bond migration and spiro-ring formation, with a pathway involving cryptic acetylation. The discovery highlights the specialized role of the thioredoxin oxidoreductase family enzyme in the ETP pathway and expands the chemical diversity of small molecules bearing an aberrant disulfide pharmacophore.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Multidisciplinary
Zhuan Zhang, Yui Tamura, Mancheng Tang, Tianzhang Qiao, Michio Sato, Yoshihiro Otsu, Satoshi Sasamura, Masatoshi Taniguchi, Kenji Watanabe, Yi Tang
Summary: The study characterized the biosynthetic pathway of the immunosuppressant (-)-FR901483 (1) through heterologous expression and enzymatic assays, proposing a possible target of 1 based on the biosynthetic studies. The biosynthetic logic involves aza-spiro annulation of dityrosyl-piperazine to form a ketoaldehyde intermediate, followed by regioselective aldol condensation, stereoselective ketoreduction, and phosphorylation.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Organic
Yuta Arai, Hiroki Oguri
Summary: This method enables the metal-free divergent synthesis of 1,6-dihydropyridines and 3,5-disubstituted pyrroles in one-pot, demonstrating an atom-economical process. The approach allows for the synthesis of densely functionalized products at ambient temperature.
TETRAHEDRON LETTERS
(2021)
Article
Oncology
Motoki Iwasaki, Rieko Kanehara, Taiki Yamaji, Ryoko Katagiri, Michihiro Mutoh, Yuta Tsunematsu, Michio Sato, Kenji Watanabe, Koji Hosomi, Yasuo Kakugawa, Hiroaki Ikematsu, Kinichi Hotta, Jun Kunisawa, Keiji Wakabayashi, Takahisa Matsuda
Summary: This study investigated the association between the presence of polyketide synthase in Escherichia coli and the prevalence of colorectal neoplasia, finding no significant association overall. However, positive associations were suggested under certain intake levels of cereals or vegetables.
Article
Biochemistry & Molecular Biology
Shinya Matsuda, Yuta Tsunematsu, Takuma Matsushita, Yuji Ogata, Shihomi Hachiya, Shinji Kishimoto, Noriyuki Miyoshi, Kenji Watanabe
Summary: The study demonstrates that HeLa cells harboring fma-P450 can biosynthesize 5-hydroxyl-beta-trans-bergamoten and cytotoxic 5-epi-demethoxyfumagillol when supplemented with the nontoxic precursor beta-trans-bergamotene. While the production level was insufficient to effect cell death, it shows that programming human cells to autogenerate antibiotics by introducing a heterologous biosynthetic gene is feasible.
Article
Chemistry, Organic
Toshiaki Wayama, Yuta Arai, Hiroki Oguri
Summary: This paper reports a method for the regioselective dimerization reaction to prepare bis-nitrogen bicyclic scaffolds under metal-free conditions. The regioselectivity of the reaction can be controlled by introducing electron-withdrawing substituents. This method not only provides a synthetic route to important compounds from a biosynthetic perspective, but also offers insights into the reaction mechanism.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Shinji Kishimoto, Yuya Matsubara, Kenji Watanabe
Summary: Ergopeptines are representative ergoline alkaloids with a tripeptide extension on the lysergic acid core. In this study, we characterized newly isolated ergopeptine-like compounds called lentopeptins from Aspergillus lentulus, which differ from traditional ergopeptines in structure and biosynthetic pathway. Targeted deletion of len cluster biosynthetic genes predicted from the genome sequence revealed the atypical biosynthetic pathway of lentopeptins.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Yuichiro Hirayama, Michio Sato, Kenji Watanabe
Summary: Recent studies have identified a gene cluster in Escherichia coli that produces a genotoxic secondary metabolite known as colibactin, which is suspected to be a risk factor for colorectal cancer. There is a need to develop simple detection methods for colibactin-producing strains and understand the mechanism of colibactin-induced oncogenesis to improve early screening and prevention of colorectal cancer. This review discusses recent efforts in identifying the structure of colibactin and developing detection methods using polymerase chain reaction and isothermal amplification techniques.
Article
Chemistry, Medicinal
Takuma Kobayashi, Shinji Kishimoto, Shogo Watanabe, Yasukiyo Yoshioka, Takeshi Toyoda, Kumiko Ogawa, Kenji Watanabe, Yukari Totsuka, Keiji Wakabayashi, Noriyuki Miyoshi
Summary: This study identifies the formation of several p-semidine-type dimers, including MMBD and MxMxBD, during the metabolic conversion of o-Tol and o-Ans. The dimers containing the o-Ans moiety showed faster dimerization rates but decreased levels with prolonged incubation. These findings suggest the potential significance of the homo-and hetero-dimers of monocyclic aromatic amines in bladder carcinogenesis and the combined exposure risk.
CHEMICAL RESEARCH IN TOXICOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Shinji Kishimoto, Ayumi Minami, Yoshimitsu Aoki, Yuya Matsubara, Shogo Watanabe, Kenji Watanabe
Summary: Pathogenic fungi of Aspergillus section Fumigati are capable of producing various secondary metabolites. This study reports the isolation of fumimycin and a new compound named lentofuranine from A. lentulus. These compounds were found to be assembled through a nonenzymatic condensation involving a polyketide intermediate from the terrein biosynthetic pathway and a highly reactive azlactone intermediate. The formation of an unusual carbon skeleton is attributed to the reactivity of azlactone.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Gavin Tay, Toshiaki Wayama, Hiroki Takezawa, Satoshi Yoshida, Sota Sato, Makoto Fujita, Hiroki Oguri
Summary: In this study, the first X-ray structural determination of a dehydrosecodine-type compound was achieved by stabilizing the fragile molecule by encapsulation into a supramolecular host. This integrated approach not only provides insights into the biosynthetic conversions but also allows stabilization and storage of the reactive and otherwise short-lived intermediate.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Kanji Niwa, Masao Ohashi, Kaili Xie, Chen-Yu Chiang, Cooper S. Jamieson, Michio Sato, Kenji Watanabe, Fang Liu, K. N. Houk, Yi Tang
Summary: We have discovered biosynthetic pathways that can produce and transform conjugated octaenes and nonaenes into complex natural products. The biosynthesis of (-)-PF1018 involves an enzyme called PfB, which controls the regio-, stereo-, and periselectivity of multiple reactions starting from a conjugated octaene. By using PfB as a starting point, we found a homologous enzyme, BruB, that facilitates diene isomerization, tandem 8π-6π-electrocyclization, and a 1,2-divinylcyclobutane Cope rearrangement to generate a novel compound not previously found in nature.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Organic
Toshiaki Wayama, Hiroki Oguri
Summary: Previous attempts to perform biomimetic transannular reactions utilizing DHP rings within macrocycles similar to manzamine alkaloids had been unsuccessful. In this study, an efficient regiocontrolled transannular cyclization of a C2-symmetric macrocyclic precursor was achieved through rational modifications of the 3 and 6 positions of the DHP rings, resulting in the synthesis of a halicyclamine-type scaffold. The presence of cis-double bonds in the macrocyclic alkyl loops played a critical role in the success of the biomimetic transannular cyclization.
Article
Genetics & Heredity
Tao Zhou, Takayuki Ando, Akihiro Kudo, Michio Sato, Noriyuki Miyoshi, Michihiro Mutoh, Hideki Ishikawa, Keiji Wakabayashi, Kenji Watanabe
Summary: The study established an efficient screening system for identifying ClbP-specific inhibitors. Two different assays were used to screen a large number of compounds, resulting in the identification of one compound with moderate inhibitory activity against ClbP. This screening method is believed to be reliable and useful in developing potential prophylactic agents for colorectal cancer.
GENES AND ENVIRONMENT
(2023)
