Article
Biochemistry & Molecular Biology
Natalia Ortuzar, Kersti Karu, Daniela Presa, Goreti R. Morais, Helen M. Sheldrake, Steve D. Shnyder, Francis M. Barnieh, Paul M. Loadman, Laurence H. Patterson, Klaus Pors, Mark Searcey
Summary: This study examines the potential cytochrome P450 (CYP)-mediated cancer cell killing ability of seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors. Results demonstrate up to a 10-fold increase in bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Additionally, it is shown that CYP1A2, but not CYP1B1 or CYP3A4, has a propensity for potentiating these compounds, indicating a preference for CYP1A bioactivation.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Freeborn Rwere, Sangchoul Im, Lucy Waskell
Summary: By altering the 140s FMN binding loop of CYPOR, the activity with cyt P450s can be affected, with the mutant activity primarily determined by its ability to reduce ferric cyt P450. The different behaviors of the mutants are mainly due to the altered structure and mobility of the loop.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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
Yuri D. Ivanov, Amir Taldaev, Andrey V. Lisitsa, Elena A. Ponomarenko, Alexander I. Archakov
Summary: The study predicted the three-dimensional structures of CYP102A1/WT proteins and their mutant forms using AlphaFold programs. The structures of monomers in the homodimer were found to be consistent with experimental structures, while the predicted structures of isolated monomers were different. Significant differences were observed in the structure of monomers compared to homodimers for the mutant forms. Comparative analysis showed a correlation between the electron transfer rate constants and the distances between prosthetic groups.
Article
Biotechnology & Applied Microbiology
Li Ma, Tianjian Sun, Yunjie Liu, Yue Zhao, Xiaohui Liu, Yuxuan Li, Xinwei Chen, Lin Cao, Qianqian Kang, Jiawei Guo, Lei Du, Wei Wang, Shengying Li
Summary: In this study, cytochrome P450 BM3 was engineered into peroxygenases through directed evolution. These modified enzymes were used to selectively oxidize indole derivatives to produce a variety of indigoid pigments with a reduced band gap. These indigoid photocatalysts show promise for the development of new organic electronic devices.
SYNTHETIC AND SYSTEMS BIOTECHNOLOGY
(2023)
Article
Pharmacology & Pharmacy
Ege Arzuk, Fuat Karakus, Hilmi Orhan
Summary: The study suggests that clozapine-induced cardiotoxicity may be caused by the activation of cardiac mitochondria. Mitochondria in cardiac tissue contain CYP enzymes that can catalyze the formation of reactive metabolites from clozapine. Clozapine significantly reduces mitochondrial oxygen consumption rate, providing an explanation for its adverse effects on the heart.
Article
Agriculture, Multidisciplinary
Yixi Zhang, Baojun Yang, Zhiming Yang, Lu Kai, Zewen Liu
Summary: Two P450 enzymes, CYP4C62 and CYP6BD12, in Nilaparvata lugens were found to bioactivate chlorpyrifos into its active ingredient chlorpyrifos-oxon in vivo and in vitro. Knockdown of these two genes reduced sensitivity to chlorpyrifos and the formation of chlorpyrifos-oxon in N. lugens. This study revealed a novel mechanism of insecticide resistance due to the reduction in bioactivation.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Review
Toxicology
Slobodan P. Rendic, F. Peter Guengerich
Summary: This overview discusses the metabolic activation of various compounds by cytochrome P450 enzymes, with a focus on bioactivation reactions. The study identifies a higher level of activation for general chemicals, drugs, and natural products compared to physiological compounds. Enzymes such as P450 3A4, 1A2, 2E1, and 1A1 are highlighted for their roles in catalyzing the formation of activated metabolites from different compound groups.
ARCHIVES OF TOXICOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Maria Norlin, Kjell Wikvall
Summary: Vitamin D signaling plays a crucial role in maintaining calcium balance for bone health and has various functions in different tissues. Disturbances in vitamin D signaling are associated with numerous diseases. This review focuses on the identification of bioactivating enzymes and their genes involved in the production of active vitamin D metabolites. It evaluates species- and tissue-specific expression, enzyme kinetics, substrate specificity, and the consequences of gene mutations. The roles of different vitamin D receptors and alternative bioactivation pathways are also discussed. Although significant progress has been made in understanding vitamin D bioactivation enzymes, further research is needed to fully comprehend the pleiotropic effects and the mechanisms of enzymatic activation in vitamin D-induced responses.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Chemistry, Organic
Qing Li, Wujun Liu, Zongbao K. Zhao
Summary: Fourteen NAD analogs based on proteogenic amino acids were synthesized with isolated yields ranging from 20-98% through the Zincke reaction in the presence of triethylamine. Some of the reduced analogs were found to effectively act as cofactors for a mutant cytochrome P450 enzyme to facilitate fatty acid hydroxylation.
TETRAHEDRON LETTERS
(2021)
Review
Biochemistry & Molecular Biology
Sian Thistlethwaite, Laura N. Jeffreys, Hazel M. Girvan, Kirsty J. McLean, Andrew W. Munro
Summary: BM3 is a catalytically self-sufficient flavocytochrome fusion protein that can be engineered to produce a variety of drug-like compounds. Through modification of key residues within the BM3 active site, its catalytic repertoire can be expanded to generate diverse metabolites.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Arsenij Kokorin, Vlada B. Urlacher
Summary: In this study, fusion of P450 BM3 from Bacillus megaterium and an alcohol dehydrogenase from Sphingomonas yanoikuyae improved the two-step oxidation of (+)-valencene and resulted in increased production of (+)-nootkatone.
Article
Chemistry, Analytical
Michael Riffle, Michael R. Hoopmann, Daniel Jaschob, Guo Zhong, Robert L. Moritz, Michael J. MacCoss, Trisha N. Davis, Nina Isoherranen, Alex Zelter
Summary: The study introduces Magnum and Limelight, an algorithm and software package for the identification and visualization of xenobiotic-protein adducts. Through validation and application, the methods and software enable accurate identification of xenobiotic-protein adducts and fill the gap in comprehensive data visualization tools in the field of open-mass searching.
ANALYTICAL CHEMISTRY
(2022)
Article
Engineering, Biomedical
Chase P. Monckton, Aidan Brougham-Cook, Gregory H. Underhill, Salman R. Khetani
Summary: In this study, researchers used high-throughput ECM microarrays and high content imaging to evaluate the attachment and differentiated functions of iPSC-derived human hepatocyte-like cells (iHep) on different liver ECM protein combinations. They discovered that the responses of iHep are regulated by the cooperation between ECM stiffness and protein composition. By selectively coating ECM proteins on materials with physiological stiffness, they achieved higher levels of mature functions in iHep cultures compared to primary human hepatocyte cultures, which has implications for drug screening, disease modeling, and regenerative medicine.
ACTA BIOMATERIALIA
(2022)
Review
Biochemistry & Molecular Biology
Annika Roeder, Saskia Huesken, Michael C. Hutter, Allan E. Rettie, Helmut Hanenberg, Constanze Wiek, Marco Girhard
Summary: The mammalian cytochrome P450 monooxygenase CYP4B1 has the ability to activate a wide range of xenobiotics, leading to tissue-specific toxicities. It can also hydroxylate fatty acids and fatty alcohols. Recent crystal structures of native rabbit CYP4B1 and the p.E310A variant have provided insights into its enigmatic role in xenobiotic and endobiotic metabolism, as well as its unusual heme-binding characteristics. Although CYP4B1 does not play a major role in hepatic P450-catalyzed drug metabolism, its expression patterns have been associated with various cancers and potential roles in cancer development. This review will summarize the current research on CYP4B1, focusing on its roles in endogenous and exogenous compound metabolism, structural properties, cancer association, and potential application in targeted cancer therapy with suicide gene approaches.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Rosa A. Luirink, Marlies C. A. Verkade-Vreeker, Jan N. M. Commandeur, Daan P. Geerke
Article
Toxicology
Jan B. Koenderink, Jeroen J. M. W. van den Heuvel, Ab Bilos, Galvin Vredenburg, Nico P. E. Vermeulen, Frans G. M. Russel
ARCHIVES OF TOXICOLOGY
(2020)
Editorial Material
Biochemistry & Molecular Biology
Herman Autrup, Frank A. Barile, Sir Colin Berry, Bas J. Blaauboer, Alan Boobis, Herrmann Bolt, Christopher J. Borgert, Wolfgang Dekant, Daniel Dietrich, Jose L. Domingo, Gio Batta Gori, Helmut Greim, Jan Hengstler, Sam Kacew, Hans Marquardt, Olavi Pelkonen, Kai Savolainen, Pat Heslop-Harrison, Nico P. Vermeulen
CHEMICO-BIOLOGICAL INTERACTIONS
(2020)
Editorial Material
Toxicology
Herman Autrup, Frank A. Barile, Sir Colin Berry, Bas J. Blaauboer, Alan Boobis, Herrmann Bolt, Christopher J. Borgert, Wolfgang Dekant, Daniel Dietrich, Jose L. Domingo, Gio Batta Gori, Helmut Greim, Jan Hengstler, Sam Kacew, Hans Marquardt, Olavi Pelkonen, Kai Savolainen, Pat Heslop-Harrison, Nico P. Vermeulen
TOXICOLOGY IN VITRO
(2020)
Article
Pharmacology & Pharmacy
Sandra Ortega Ugalde, Kerstin Wallraven, Alexander Speer, Wilbert Bitter, Tom N. Grossmann, Jan N. M. Commandeur
BIOCHEMICAL PHARMACOLOGY
(2020)
Article
Environmental Sciences
Herman Autrup, Frank A. Barile, Sir Colin Berry, Bas J. Blaauboer, Alan Boobis, Herrmann Bolt, Christopher J. Borgert, Wolfgang Dekant, Daniel Dietrich, Jose L. Domingo, Gio Batta Gori, Helmut Greim, Jan Hengstler, Sam Kacew, Hans Marquardt, Olavi Pelkonen, Kai Savolainen, Pat Heslop-Harrison, Nico P. Vermeulen
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES
(2020)
Article
Chemistry, Multidisciplinary
Paul Erhardt, Kenneth Bachmann, Donald Birkett, Michael Boberg, Nicholas Bodor, Gordon Gibson, David Hawkins, Gabrielle Hawksworth, Jack Hinson, Daniel Koehler, Brian Kress, Amarjit Luniwal, Hiroshi Masumoto, Raymond Novak, Phillip Portoghese, Jeffrey Sarver, M. Teresa Serafini, Christopher Trabbic, Nico Vermeulen, Steven Wrighton
Summary: This project, started over 15 years ago, aimed to create a glossary of drug metabolism terms specifically for medicinal chemists. Through extensive beta-testing, it engaged international audiences and expanded to enhance interdisciplinary communication. The current version maintains a chemical structure theme and tutorial comments to educate early stage researchers and investigators in today's collaborative drug discovery teams.
PURE AND APPLIED CHEMISTRY
(2021)
Correction
Toxicology
Liliana Capinha, Paul Jennings, Jan N. M. Commandeur
TOXICOLOGY LETTERS
(2021)
Article
Toxicology
Liliana Capinha, Paul Jennings, Jan N. M. Commandeur
Summary: The study demonstrates that three regioisomers of GSH-conjugates of TCE are formed in rat and human liver fractions, with different activities in human enzymes. Human liver fractions exhibit lower GSH-conjugation activity of TCE, suggesting a lower risk for TCE-associated nephrotoxic effects in humans compared to rats.
TOXICOLOGY LETTERS
(2021)
Letter
Toxicology
Frank A. Barile, Sir Colin Berry, Bas Blaauboer, Alan Boobis, Herrmann Bolt, Christopher J. Borgert, Wolfgang Dekant, Daniel Dietrich, Jose L. Domingo, Gio Batta Gori, Helmut Greim, Jan Hengstler, Sam Kacew, Hans Marquardt, Olavi Pelkonen, Kai Savolainen, Pat Heslop-Harrison, Aristides Tsatsakis, Nico P. Vermeulen
TOXICOLOGY LETTERS
(2021)
Letter
Toxicology
Frank A. Barile, Colin Berry, Bas Blaauboer, Alan Boobis, Herrmann M. Bolt, Christopher Borgert, Wolfgang Dekant, Daniel Dietrich, Jose L. Domingo, Corrado L. Galli, Gio Batta Gori, Helmut Greim, Jan G. Hengstler, Pat Heslop-Harrison, Sam Kacew, Hans Marquardt, Angela Mally, Olavi Pelkonen, Kai Savolainen, Emanuela Testai, Aristides Tsatsakis, Nico P. Vermeulen
Summary: The EU chemicals strategy for sustainability emphasizes the need for further regulation due to threats to human health and the environment. Concerns were raised by the German BfR regarding the scientific justification for this strategy. Any initiatives to improve consumer protection must be based on scientific knowledge and avoid confounding risk with other factors in policy-making.
ARCHIVES OF TOXICOLOGY
(2021)
Correction
Toxicology
Frank A. Barile, Sir Colin Berry, Bas Blaauboer, Alan Boobis, Herrmann Bolt, Christopher J. Borgert, Wolfgang Dekant, Daniel Dietrich, Jose L. Domingo, Gio Batta Gori, Helmut Greim, Jan Hengstler, Sam Kacew, Hans Marquardt, Olavi Pelkonen, Kai Savolainen, Pat Heslop-Harrison, Aristides Tsatsakis, Nico P. Vermeulen
TOXICOLOGY LETTERS
(2021)
Article
Chemistry, Multidisciplinary
Danny J. Scholten, Maikel Wijtmans, Stefan J. Dekker, Anna H. Vuuregge, Erik J. J. Boon, J. Chris Vos, Marco Siderius, Hanna Westbroek, Jacqueline E. van Muijlwijk-Koezen
Summary: Incorporating increased flexibility and adaptivity in courses can help freshmen take responsibility for their learning process, especially in the case of chemistry courses. Blended learning can enhance student engagement, but requires teachers to reconsider and redesign their course setup, largely depending on perceived practicality.
JOURNAL OF CHEMICAL EDUCATION
(2021)
Article
Toxicology
Liliana Capinha, Yaran Zhang, Anna-Katharina Holzer, Anna-Katharina Uckert, Melinda Zana, Giada Carta, Cormac Murphy, Jenna Baldovini, Zahra Mazidi, Johannes Grillari, Andras Dinnyes, Bob van de Water, Marcel Leist, Jan N. M. Commandeur, Paul Jennings
Summary: This study used six human derived cell models to investigate the effects of trichloroethylene (TCE) S-conjugates. The results showed that TCE S-conjugates induced Nrf2 pathway and unfolded protein response, which may explain the nephrotoxicity and neurotoxicity of TCE. This study expands our knowledge on the tissue specificity of TCE S-conjugates and highlights the value of human cell models and transcriptomics in mechanistic studies.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Toxicology
Liliana Capinha, Paul Jennings, Jan N. M. Commandeur
Summary: Bioactivation of trichloroethylene (TCE) through glutathione conjugation can cause adverse effects in the kidney and other extrahepatic tissues. Among the three regioisomeric conjugates formed, only 1,2-trans-DCVG and its corresponding cysteine-conjugate have been extensively studied. This study investigates the metabolism and cellular effects of 1,2-cis-DCVG and 1,2-cis-DCVC for the first time, revealing lower toxicity and slower formation rate for 1,2-cis-DCVC compared to 1,2-trans-DCVC.
TOXICOLOGY LETTERS
(2023)