Review
Biochemistry & Molecular Biology
Hiroyuki Miyachi
Summary: Recent progress in understanding the structure and pharmacology of hPPAR gamma has allowed for investigation of various ligands and their effects on biological responses. These ligands serve as valuable tools for studying hPPAR gamma function and potential drugs for hPPAR gamma-related diseases. This review summarizes the medicinal chemistry research on the design, synthesis, and evaluation of hPPAR gamma antagonists based on the induction/inhibition concept of helix 12 (H12) and presents X-ray crystallographic analyses of their unique binding modes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Iason Psilopatis, Kleio Vrettou, Florian Nima Fleckenstein, Stamatios Theocharis
Summary: Preeclampsia is a common hypertensive disorder in pregnancy, and PPARs play a significant role in its pathophysiology. Studies have shown contradictory conclusions regarding PPAR expression in preeclamptic placentae, but PPAR gamma agonists have been identified as a novel and potent anti-preeclamptic treatment option.
Review
Biochemistry & Molecular Biology
Iason Psilopatis, Kleio Vrettou, Constantinos Troungos, Stamatios Theocharis
Summary: Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor proteins which regulate gene expression. In our literature review of 27 relevant studies published between 2000 and 2023, it was found that PPAR alpha and PPAR beta/delta isoforms were upregulated in endometrial cancer cells, while PPAR gamma levels were significantly lower. Interestingly, PPAR agonists were found to be potent anti-cancer therapeutic alternatives. Overall, PPARs seem to play a significant role in endometrial cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Shan Zhang, Yanru You, Yachong Li, Hairui Yuan, Jie Zhou, Lijie Tian, Ying Liu, Baoli Wang, Endong Zhu
Summary: Foxk1 promotes adipocyte differentiation by facilitating nuclear translocation and upregulating the transcriptional activity of the Ppar gamma 2 promoter.
Review
Biochemistry & Molecular Biology
Hiroyuki Miyachi
Summary: The review highlights the development of new subtype-selective PPAR ligands for investigating PPAR functions and treating PPAR-mediated diseases, based on two working hypotheses. After over 20 years of medicinal chemistry research, X-ray crystallographic analyses confirm the validity of the author's hypotheses.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Hyejin Ko, Hongjun Jang, Seungchan An, In Guk Park, Sungjin Ahn, Junpyo Gong, Seok Young Hwang, Soyeon Oh, Soo Yeon Kwak, Won Jun Choi, Hyoungsu Kim, Minsoo Noh
Summary: The upregulation of adiponectin production is a potential therapeutic strategy for metabolic diseases. Galangin and its derivatives were found to promote adiponectin synthesis by binding to PPARγ and enhancing its activity while reducing the activity of ERβ. A novel galangin derivative, galangin 3-benzyl-5,7-dimethylether, showed the highest potency and selectively bound to PPARγ, suggesting its potential therapeutic use in various metabolic diseases.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Neurosciences
Riham M. Mansour, Nesrine S. El Sayed, Maha A. E. Ahmed, Ayman E. El-Sahar
Summary: This study aimed to explore the neuroprotective effect of telmisartan in 3-nitropropionic acid-induced neurotoxicity. The results showed that telmisartan improved motor and cognitive functioning, reduced neuronal inflammation and apoptosis, and promoted mitochondrial biogenesis through PPAR gamma activation.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Chemistry, Medicinal
Felix F. Lillich, Sabine Willems, Xiaomin Ni, Whitney Kilu, Carmen Borkowsky, Mirko Brodsky, Jan S. Kramer, Steffen Brunst, Victor Hernandez-Olmos, Jan Heering, Simone Schierle, Roxane- Kestner, Franziska M. Mayser, Moritz Helmstaedter, Tamara Goebel, Lilia Weizel, Dmitry Namgaladze, Astrid Kaiser, Dieter Steinhilber, Waltraud Pfeilschifter, Astrid S. Kahnt, Anna Proschak, Apirat Chaikuad, Stefan Knapp, Daniel Merk, Ewgenij Proschak
Summary: The synergistic effect of dual partial PPAR agonist/sEH inhibitor shows promise in combating metabolic syndrome, while avoiding the adverse effects of full PPAR activation. Through structure-activity relationship studies and crystal structure analysis, successful optimization of the designed drug was achieved, resulting in compounds with potential application in patients with MetS.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Weibei Sheng, Qichang Wang, Haotian Qin, Siyang Cao, Yihao Wei, Jian Weng, Fei Yu, Hui Zeng
Summary: Osteoarthritis (OA) is a common degenerative joint disease that is exacerbated by population aging, resulting in a significant economic burden. Current therapies are inadequate, but research on peroxisome proliferator-activated receptors (PPARs) shows promise in slowing OA progression. PPARs have emerged as potential targets for effective OA treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Medicine, General & Internal
Iason Psilopatis, Kleio Vrettou, Eleni Nousiopoulou, Kostas Palamaris, Stamatios Theocharis
Summary: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, causing severe menstrual irregularities, skin conditions, and insulin resistance-associated health problems. Peroxisome proliferator-activated receptors (PPARs) have been investigated for their role in PCOS, but studies have reached contradictory conclusions about PPAR expression in PCOS. However, natural agents have shown promise as alternative treatments for PCOS. Overall, PPARs appear to play a significant role in PCOS.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Biochemistry & Molecular Biology
Suvadeep Mal, Ashish Ranjan Dwivedi, Vijay Kumar, Naveen Kumar, Bhupinder Kumar, Vinod Kumar
Summary: PPAR, as a crucial transcription factor, plays a significant role in regulating various disease states, especially in cancer growth and metabolism. However, known PPAR ligands often lead to severe side effects. Therefore, the current focus is on developing novel PPAR ligands with little to no adverse effects.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Mahesha Gangadhariah, Triveni Pardhi, Jahnavi Ravilla, Subhash Chandra, Sridevi Annapurna Singh
Summary: PPAR gamma agonists are effective in treating type 2 diabetes but have severe side effects. Lemon contains eriocitrin, which may have potential as a PPAR gamma agonist.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Pathology
Shinji Kaba, Yoshitaka Kawai, Yuki Tanigami, Hiroe Ohnishi, Tomoko Kita, Masayoshi Yoshimatsu, Koichi Omori, Yo Kishimoto
Summary: This study aimed to evaluate the effects of pioglitazone on macrophage phenotype and fibrosis following vocal fold injury. The results showed that pioglitazone reduced the expression of Ccl2, inhibited the accumulation of inflammatory macrophages, and improved tissue repair in a PPARy-dependent manner, resulting in decreased fibrosis.
AMERICAN JOURNAL OF PATHOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Chaitra Rai, C. D. Nandini, Poornima Priyadarshini
Summary: The study demonstrated the anti-adipogenic activity of bovine milk Glycosaminoglycans (bmGAGs) by modulating adipogenesis-related marker proteins, suggesting a potential therapeutic use of bmGAGs in the management of obesity.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Review
Cell Biology
Yaqin Zhao, Huabing Tan, Xiaoyu Zhang, Jing Zhu
Summary: This article summarizes the role of PPARs in the occurrence and development of HCC, as well as their value in the diagnosis, treatment, and prognosis of HCC.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2023)
Article
Chemistry, Medicinal
Miyuki Kumazawa, Manabu Tejima, Miwa Fukuda, Shota Takeda, Kenji Suzuki, Yukiko Mizumoto, Kakeru Sato, Minoru Waki, Hiroyuki Miyachi, Akira Asai, Osamu Takikawa, Tomoko Hashimoto, Osamu Ohno, Kenji Matsuno
Summary: The study unexpectedly discovered that carbonothioates 4a and 4b are novel scaffolds for IDO1 inhibitors, with derivatives showing enhanced inhibitory activity. Further exploration led to the discovery of related scaffolds as potential leads for future development.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Multidisciplinary
Mengting Liu, Masao Ohashi, Yiu-Sun Hung, Kirstin Scherlach, Kenji Watanabe, Christian Hertweck, Yi Tang
Summary: Enzymes capable of halogenation of aliphatic carbons are important to synthetic and biocatalysis fields. AoiQ, a flavin-dependent halogenase, catalyzes gem-dichlorination of 1,3-diketone substrates in the biosynthesis of dichlorodiaporthin, representing the first biochemically reconstituted FDH that can halogenate an enolizable sp(3)-hybridized carbon atom.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Multidisciplinary
Masao Ohashi, Thomas B. Kakule, Man-Cheng Tang, Cooper S. Jamieson, Mengting Liu, Yi-Lei Zhao, Kendall N. Houk, Yi Tang
Summary: Hirsutellones are fungal natural products with a macrocyclic structure, and the biosynthetic pathway involves the cooperative action of several proteins, such as oxidoreductase and lipocalin-like protein, in oxidative cyclization and exo-specific cycloaddition processes.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Lee Joon Kim, Masao Ohashi, Zhuan Zhang, Dan Tan, Matthew Asay, Duilio Cascio, Jose A. Rodriguez, Yi Tang, Hosea M. Nelson
Summary: The combined use of microcrystal electron diffraction and genome mining has enabled rapid structural elucidation of natural products, including the discovery of a new 2-pyridone compound and the revision of fischerin structure. This study demonstrates the synergy of MicroED and synthetic biology in natural product discovery, which will ultimately accelerate the rate at which new drugs are discovered.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Wei Cheng, Mengbin Chen, Masao Ohashi, Yi Tang
Summary: The fungal natural product CJ-12662, a terpene-amino acid hybrid, is a potent anthelmintic compound. The biosynthetic pathway of CJ-12662 involves successive P450-catalyzed oxidations of amorpha-4,11-diene for the terpene portion, and the transformation of esterified tryptophan into a chlorinated pyrrolobenzoxazine by three flavin-dependent enzymes through a cascaded [1,2]-Meisenheimer rearrangement.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Organic
Eun Bin Go, Lee Joon Kim, Hosea M. Nelson, Masao Ohashi, Yi Tang
Summary: This study elucidated the pathway and chemical logic of (-)-sambutoxin biosynthesis, emphasizing the enzymatic origin of the tetrahydropyran moiety and the P450-catalyzed oxidation of the phenylalanine-derived side chain for installation of the p-hydroxyphenyl group.
Article
Chemistry, Medicinal
Miyako Naganuma, Nobumichi Ohoka, Genichiro Tsuji, Haruna Tsujimura, Kenji Matsuno, Takao Inoue, Mikihiko Naito, Yosuke Demizu
Summary: Targeted protein degradation using chimeric small molecules like PROTACs and SNIPERs has gained attention, but developing degraders without suitable small-molecule ligands for target proteins is challenging. A new chimeric molecule, LCL-ER(dec), selectively degrades ER alpha via a click reaction, showing promise for the development of other oligonucleotide-type degraders targeting various transcription factors.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Multidisciplinary
Cooper S. Jamieson, Masao Ohashi, K. N. Houk, Yi Tang
Summary: Here we report a computation-driven chemoenzymatic synthesis and biosynthesis of the natural product deoxyakanthomycin. Our studies also reveal a unifying biosynthetic strategy for creating diverse 2-pyridone natural products.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Masao Ohashi, Dan Tan, Jiayan Lu, Cooper S. Jamieson, Daiki Kanayama, Jiahai Zhou, K. N. Houk, Yi Tang
Summary: The synthesis of cis-decalin structures using [4 + 2] cycloaddition with high stereoselectivity is challenging. In this study, we investigated the biosynthetic pathway of the fungal natural product fischerin (1) and identified a novel pericyclase, FinI, which catalyzes this reaction. The cocrystal structure of FinI, a predicted O-methyltransferase, with the product and SAM provides valuable insights into the natural formation of cis-decalin.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Review
Biochemistry & Molecular Biology
Chen-Yu Chiang, Masao Ohashi, Yi Tang
Summary: This review highlights key examples in the integration of heterologous expression into genome mining and biosynthetic investigations in the last decade. By choosing appropriate heterologous hosts, prioritizing BGCs for structural novelty, and using shunt products from heterologous expression, important insights into the chemical logic of biosynthesis can be revealed. This study demonstrates the usefulness and limitations of heterologous biosynthesis in fungal natural product discovery.
NATURAL PRODUCT REPORTS
(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, Multidisciplinary
Mengting Liu, Masao Ohashi, Qingyang Zhou, Jacob N. Sanders, Erin P. Mccauley, Phillip Crews, K. N. Houk, Yi Tang
Summary: We have discovered and reconstructed a concise biosynthetic pathway of the strained dipeptide (+)-azonazine A using Aspergillus insulicola from marine sources. A P450 enzyme catalyzes the formation of the hexacyclic benzofuranoindoline ring system from cyclo-(L-Trp-N-methyl-L-Tyr) through oxidative cyclization. Supplementing the producing strain with different indole-substituted tryptophan derivatives resulted in the production of a series of azonazine A analogs.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Bruno Perlatti, Gerald F. Bills, Masao Ohashi, Yi Tang, Yalong Zhang, Eun Bin Go
Summary: The biosynthesis of the antifungals AS2077715 and funiculosin involves a five-enzyme cascade that allows the conversion of a hydroxyphenyl-containing precursor into an unusual all-cis cyclopentanetetraol moiety. The cascade includes a multifunctional flavin-dependent monooxygenase and a repurposed O-methyltransferase.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Mengting Liu, Masao Ohashi, Qingyang Zhou, Jacob N. Sanders, Erin P. McCauley, Phillip Crews, K. N. Houk, Yi Tang
Summary: We uncovered the biosynthetic pathway of (+)-azonazine A and generated a series of analogs through supplementation of indole-substituted tryptophan derivatives.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Osamu Ohno, Keigo Sato, Ryo Honma, Ruri Chiba, Kenji Matsuno
Summary: In this study, potential inhibitors of cell death in human cervical carcinoma HeLa cells induced by thapsigargin were screened among marine organisms metabolites. Methyl (3R,4E,6Z,15E)-3-hydroxyoctadecatrienoate (MHO) isolated from the cyanobacterium Rivularia sp. was identified as the active compound that inhibits apoptotic stimuli-induced cell death in HeLa cells.
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
(2021)