Article
Biochemistry & Molecular Biology
Leena Hussein Bajrai, Aiah M. Khateb, Maha M. Alawi, Hashim R. Felemban, Anees A. Sindi, Vivek Dhar Dwivedi, Esam Ibraheem Azhar
Summary: This study demonstrates the potential of a diverse set of glycosylated flavonoids as inhibitors of Mtb CYP121. The findings provide a basis for further experimental validation and development of therapies for drug-resistant Mtb strains.
Article
Chemistry, Medicinal
Martyn Frederickson, Irwin R. Selvam, Dimitrios Evangelopoulos, Kirsty J. McLean, Mona M. Katariya, Richard B. Tunnicliffe, Bethany Campbell, Madeline E. Kavanagh, Sitthivut Charoensutthivarakul, Richard T. Blankley, Colin W. Levy, Luiz Pedro S. de Carvalho, David Leys, Andrew W. Munro, Anthony G. Coyne, Chris Abell
Summary: A novel strategy combining X-ray crystallographic screening with phenotypic screening is described for hit generation against promising tuberculosis (TB) targets. This method provides validation of target engagement and determination of in vitro activity. The utility of this approach is demonstrated through the screening against CYP121A1, a validated drug discovery target for TB. Several compounds showed promising activity against Mycobacterium tuberculosis strain H37Rv, and structure-based design resulted in analogues with pan-assay activity. This study highlights the importance of developing new drugs for combating drug resistance in TB.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Songya Zhang, Lin Zhang, Anja Greule, Julien Tailhades, Edward Marschall, Panward Prasongpholchai, Daniel J. Leng, Jingfan Zhang, Jing Zhu, Joe A. Kaczmarski, Ralf B. Schittenhelm, Oliver Einsle, Colin J. Jackson, Fabrizio Alberti, Andreas Bechthold, Youming Zhang, Manuela Tosin, Tong Si, Max J. Cryle
Summary: WS9326A is a peptide antibiotic synthesized by a non-ribosomal peptide synthetase (NRPS). The cytochrome P450 encoded by sas16 (P450Sas) is critical for the formation of an unusual amino acid residue in WS9326A. In this study, the researchers identified the substrate of P450Sas and elucidated its role in the biosynthetic pathway of WS9326A. The results suggest that P450Sas catalyzes the direct dehydrogenation of a dipeptide intermediate, expanding the range of P450 enzymes that can be used for the production of biologically active peptides.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Chemistry, Multidisciplinary
Mona M. Katariya, Matthew Snee, Richard B. Tunnicliffe, Madeline E. Kavanagh, Helena I. M. Boshoff, Cecilia N. Amadi, Colin W. Levy, Andrew W. Munro, Chris Abell, David Leys, Anthony G. Coyne, Kirsty J. McLean
Summary: Mycobacterium tuberculosis (Mtb) caused approximately 1.6 million deaths in 2021. Due to the emergence of drug resistance, there is an urgent need for new therapeutic agents and ongoing drug discovery efforts. Host-derived lipids like cholesterol not only support Mtb growth but also play a role in immunomodulation and immune evasion. Mtb cytochrome P450 (CYP) enzymes, particularly CYP125 and CYP142, are potential targets for inhibition in lipid catabolism. Compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore showed strong binding to both CYP125 and CYP142, with in-cell activity against drug-resistant isolates. These findings are important for developing additional treatment options and exploring the role of CYP125 and CYP142 in Mtb pathogenesis.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Physical
Shinya Ariyasu, Kai Yonemura, Chie Kasai, Yuichiro Aiba, Hiroki Onoda, Yuma Shisaka, Hiroshi Sugimoto, Takehiko Tosha, Minoru Kubo, Takashi Kamachi, Kazunari Yoshizawa, Osami Shoji
Summary: This study reports the catalytic oxidation of methane to methanol by wild-type P450BM3 without mutagenesis. The findings have significant implications for the development of biological methane oxidation technology.
Article
Biochemistry & Molecular Biology
Amna Ghith, John B. Bruning, Stephen G. Bell
Summary: The CYP124 family of cytochrome P450 enzymes plays a role in the metabolism of methyl branched lipids and cholesterol derivatives. By comparing the equivalent enzymes from Mycobacterium marinum and Mycobacterium tuberculosis, differences in substrate binding and catalytic oxidation were observed. The CYP124 enzyme from M. tuberculosis showed a larger shift to the ferric high-spin state and displayed distinct UV-vis spectra compared to the enzyme from M. marinum when binding cholesterol derivatives. However, both enzymes maintained selectivity for oxidation at the omega-carbon of a branched chain.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Jan Snasel, Iva Machova, Veronika Solinova, Vaclav Kasicka, Marcela Krecmerova, Iva Pichova
Summary: Tuberculosis caused by Mycobacterium tuberculosis is a major global health concern. The two Pfk isoenzymes encoded by Mtb, Pfk A and Pfk B, exhibit different kinetic properties in regulating glycolysis, with Pfk A being more susceptible to inhibition by various factors compared to Pfk B. Pfk B, in addition to supporting glycolysis, can also catalyze the reverse gluconeogenic reaction under certain conditions, providing a mechanism for Mtb survival.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Christopher S. Campomizzi, George E. Ghanatios, D. Fernando Estrada
Summary: Cytochromes P450 are versatile enzymes involved in endogenous and exogenous metabolism, undergoing structural changes related to function. This study demonstrates the utility of fluorine (19F)-NMR spectroscopy in monitoring structural changes in CYP121A1, revealing insights into its role in substrate recognition and mechanistic details of this essential enzyme from Mycobacterium tuberculosis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Chemistry, Physical
Donya Valikhani, Juan M. Bolivar, Joelle N. Pelletier
Summary: Cytochrome P450s are a large superfamily of heme proteins with important applications in drug metabolism studies and biocatalytic transformations. Immobilization of P450 enzymes on biosensing platforms and in biocatalytic reactions plays a key role in improving operational stability. Various methods and materials have been developed to address the challenges associated with the unique characteristics of P450s in different applications.
Article
Biochemistry & Molecular Biology
Peter D. Giang, Luke R. Churchman, Jeanette E. Stok, Rochelle M. Soo, James J. De Voss
Summary: A study found that Rhodococcus globerulus (R. globerulus) isolated from soil beneath Eucalyptus sp. can thrive on mono-terpenes such as 1,8-cineole, p-cymene and (R)- and (S)-limonene as its sole sources of carbon and energy. The research revealed a novel cytochrome P450 (CYP108N12) in R. globerulus which may be responsible for initiating the biodegradation of structurally similar monoterpene compounds. This finding suggests that CYP108N12 has potential as a biocatalyst with specific hydroxylation capabilities.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2022)
Review
Biotechnology & Applied Microbiology
Dani Permana, Takuya Kitaoka, Hirofumi Ichinose
Summary: Cytochrome P450s are heme-containing monooxygenases found in all biological kingdoms. Fungi, in particular, are an important source of diverse P450s that play key roles in sterol synthesis. This review discusses fungal P450s and their applications in bioconversion and biosynthesis, highlighting their history, availability, and versatility. The ability of P450s to catalyze various reactions makes them promising enzymes for numerous applications, and future research in this field is encouraged.
BIOTECHNOLOGY AND BIOENGINEERING
(2023)
Article
Chemistry, Multidisciplinary
Thien-Kim Le, Jinhyun Kim, Ngoc Anh Nguyen, Thi Huong Ha Nguyen, Eun-Gene Sun, Su-Min Yee, Hyung-Sik Kang, Soo-Jin Yeom, Chan Beum Park, Chul-Ho Yun
Summary: Photobiocatalysis is a green platform for driving redox enzymatic reactions using solar energy without high-cost cofactors. Natural flavins were used as photosensitizers to develop a visible light-driven whole-cell platform for human cytochrome P450 (CYP) photobiocatalysis. The research showed that flavins can mediate light-driven biocatalysis by human CYPs in whole-cell systems, demonstrating the general applicability of solar-powered P450 photobiocatalytic system.
Review
Chemistry, Inorganic & Nuclear
Lei Feng, Jing Ning, Xiangge Tian, Chao Wang, Zhenlong Yu, Xiaokui Huo, Tian Xie, Baojing Zhang, Tony D. James, Xiaochi Ma
Summary: Cytochrome P450 (CYP) enzymes are haem-containing proteins mainly involved in the oxidative metabolism of various chemicals. Fluorescent probes are useful molecular tools for selectively detecting CYP activity, facilitating important insights into the activity expression of CYP enzymes.
COORDINATION CHEMISTRY REVIEWS
(2021)
Article
Chemistry, Organic
Chenghai Sun, Haidong Peng, Wenlu Zhang, Mei Zheng, Wenya Tian, Yanan Zhang, Huanhuan Liu, Zhi Lin, Zixin Deng, Xudong Qu
Summary: By validating the functions of two pairs of redox partners sourced from Mycobacterium smegmatis and comparing the efficiency of different biocatalytic systems, it was demonstrated that M. smegmatis is more efficient, robust, and cleaner in metabolites background when converting HTDKPs. Via this system, 12 novel HTDPKs were obtained, with five of them showing neuroprotective properties.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Hebatalla Mohamed, Stella A. Child, John B. Bruning, Stephen G. Bell
Summary: Members of the CYP51 family of cytochrome P450 enzymes, including CYP51 from Mycobacterium marinum and Mycobacterium tuberculosis, were studied to determine their functional conservation. The enzymes displayed differences in heme spin state and ligand binding, indicating structural differences. Both enzymes were able to oxidatively demethylate lanosterol, but had different binding properties compared to other bacterial and eukaryotic species.
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2022)
Article
Chemistry, Medicinal
Yu Yang, Timothy Borel, Francisco de Azambuja, David Johnson, Jacob P. Sorrentino, Chinedum Udokwu, Ian Davis, Aimin Liu, Ryan A. Altman
Summary: This study reveals that inhibiting ACMSD can increase NAD(+) levels, and an FDA-approved drug, diflunisal, competitively inhibits ACMSD, thereby affecting NAD(+) levels. Additionally, synthesized diflunisal derivatives show promise in modulating NAD(+) levels.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Yifan Wang, Ian Davis, Inchul Shin, Hui Xu, Aimin Liu
Summary: This study characterized a new heme-dependent L-tyrosine hydroxylase (TyrH) from the thermophilic bacterium Streptomyces sclerotialus, providing insights into its catalytic mechanism and the primary factor governing product distribution in substrate reactions.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Yifan Wang (Amber), Inchul Shin, Jiasong Li, Aimin Liu
Summary: The crystal structure of human ADO was reported for the first time, revealing a metal center near an entry site in the tunnel, showcasing the enzyme's flexibility in handling substrates of different sizes and utilizing proline pairs to maintain core protein structure and catalytic residues. These features differentiate ADO from other thiol dioxygenases in terms of substrate specificity and oxygen sensing mechanisms.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Ronald A. Besandre, Zhang Chen, Ian Davis, Jiawei Zhang, Mark Walter Ruszczycky, Aimin Liu, Hung-wen Liu
Summary: HygY is a SPASM/twitch radical SAM enzyme catalyzing the C2'-epimerization of galacamine during hygromycin B biosynthesis. The biochemical and structural analysis of reaction products confirmed this activity, and also revealed a latent dehydrogenase activity in this enzyme. This discovery offers insights into the mechanistic features distinguishing oxidative versus redox-neutral SPASM/twitch enzymes and the evolution of new enzyme activities.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Multidisciplinary
Li Ma, Yi Xie, Rebecca Shu Hui Khoo, Hadi Arman, Bin Wang, Wei Zhou, Jian Zhang, Rui-Biao Lin, Banglin Chen
Summary: In this study, an adaptive hydrogen-bonded organic framework was reported, which can selectively recognize and separate p-xylene. The single crystal structure and NMR studies demonstrated the efficient separation of xylene isomers by the organic framework.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Multidisciplinary
Li Ma, Hadi Arman, Yi Xie, Wei Zhou, Banglin Chen
Summary: Three hydrogen-bonded organic frameworks (HOF-26, HOF-27, HOF-28) have been synthesized and their crystal structures were analyzed. The PTTBN units in these frameworks form a two-dimensional network with varied bonding connectivities, packing patterns, and host-guest interactions. The pore system in these frameworks can be systematically modulated by guest molecules, and the solvent-dependent self-assembly process was investigated using energy decomposition analysis.
CRYSTAL GROWTH & DESIGN
(2022)
Article
Chemistry, Physical
Ephrahime S. Traore, Aimin Liu
Summary: This study analyzes the choice of the first coordination shell of the metal center in nonheme iron oxygenases from the perspective of charge maintenance. The importance of charge maintenance after substrate binding is highlighted, and the charge analysis is extended to different types of nonheme iron oxygenases. The concept of charge maintenance is significant in promoting the reaction of the iron center and may be applicable to other oxygen-activating metalloenzymes systems.
Article
Biochemistry & Molecular Biology
Ashley Newton, Luree McCann, Lu Huo, Aimin Liu
Summary: The kynurenine pathway (KP) is an important process in the human body, but its regulatory mechanisms are not well understood. This article proposes a potential regulatory mechanism in the KP, which involves the formation of transient enzyme complexes to modulate the distribution of metabolites and influence the autocyclization of products. Further research is needed to establish this hypothesis, but our docking model studies provide support for this new mechanism.
Review
Biochemistry & Molecular Biology
Romie C. Nguyen, Cassadee Stagliano, Aimin Liu
Summary: Half-of-sites reactivity in metalloenzymes has been known for a long time, but its benefits are still unclear. Recent research on ribonucleotide reductase suggests that asymmetric association of subunits may play a role in its less optimized reactivity. Many other enzymes also exhibit nonequivalence of active sites, potentially for regulation purposes. Overall, this phenomenon is likely a natural method to accommodate catalytic or regulatory needs.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2023)
Article
Microbiology
Ian Davis, Jackie M. Payne, Victoria L. Olguin, Madison P. Sanders, Tamara Clements, Christopher P. Stefan, Janice A. Williams, Jay W. Hooper, John W. Huggins, Eric M. Mucker, Keersten M. Ricks
Summary: This study reports the development of an mpox-specific antigen detection immunoassay, which can detect viral antigens in serum and exhibit a correlation with quantitative PCR results. This assay is essential for identifying cases and ensuring proper treatment.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Romie C. Nguyen, Ian Davis, Medhanjali Dasgupta, Yifan Wang, Philipp S. Simon, Agata Butryn, Hiroki Makita, Isabel Bogacz, Kednerlin Dornevil, Pierre Aller, Asmit Bhowmick, Ruchira Chatterjee, In-Sik Kim, Tiankun Zhou, Derek Mendez, Daniel W. Paley, Franklin Fuller, Roberto Alonso Mori, Alexander Batyuk, Nicholas K. Sauter, Aaron S. Brewster, Allen M. Orville, Vittal K. Yachandra, Junko Yano, Jan F. Kern, Aimin Liu
Summary: This study reports the structural observation of an intermediate during a catalytic reaction using a new on-demand-rapid-mixing method. The unique binding mode of the intermediate suggests its potential role as an active oxidant for direct substrate oxidation in the reaction.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Multidisciplinary Sciences
Inchul Shin, Yifan Wang, Aimin Liu
Summary: Recent findings of TyrH and SfmD proteins resembling enzymes from the TDO superfamily have prompted a reexamination of the structure and function of this superfamily. These enzymes share a similar core architecture and histidine-ligated heme, primarily functioning to promote O-atom transfer to aromatic metabolites. The expanding boundaries of the superfamily include new members like PrnB, SfmD, TyrH, and MarE, which mediate monooxygenation on a broader set of aromatic substrates.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Multidisciplinary
Inchul Shin, Ian Davis, Karinel Nieves-Merced, Yifan Wang, Stanton McHardy, Aimin Liu
Summary: The study unveiled SfmD as a heme-dependent enzyme with a unique heme cofactor structure and catalytic activity for single-oxygen insertion into 3-methyl-l-tyrosine. Experimental results demonstrated the importance of thioether linkage and axial protein ligands for the catalytic activity of SfmD.