Review
Biochemistry & Molecular Biology
Koji Umezawa, Isao Kii
Summary: The use of small molecule inhibitors for drug discovery is hindered by issues such as low selectivity, off-target effects, and failures in clinical trials. Non-canonical inhibitors targeting hidden pockets in proteins have gained attention, with the discovery of an inhibitor targeting a transient pocket in kinase DYRK1A. This discovery opens up the possibility for alternative targets in drug discovery, potentially leading to the development of more potent kinase inhibitors.
Article
Chemistry, Multidisciplinary
Kanta Kawai, Tasuku Hirayama, Haruka Imai, Takanori Murakami, Masatoshi Inden, Isao Hozumi, Hideko Nagasawa
Summary: In this study, we developed an activity-based fluorescence probe H-FluNox for monitoring the fluctuations of labile heme (LH) in cells. The probe exhibited high selectivity towards LH, enabling the discrimination of LH from labile Fe(II). By using this probe, we observed the acute release of LH upon NO stimulation and the accumulation of LH by inhibiting the heme exporter. Furthermore, the imaging studies using the probe provided insights into the heme-export activity of ATP-binding cassette subfamily G member 2 (ABCG2), the LH pooling ability of G-quadruplex, and the involvement of LH in ferroptosis.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Jose A. Amaya, David C. Lamb, Steven L. Kelly, Patrick Caffrey, Vidhi C. Murarka, Thomas L. Poulos
Summary: This study provides insights into the structural basis of substrate selectivity in the cytochrome P450 enzyme AmphL. A comparison with the closely related enzyme PimD reveals key catalytic structural features responsible for stereo- and regio-selective oxidation. The study also highlights the role of additional substrate interactions and -OH groups in correctly positioning the substrate and activating O-2. This research could contribute to the development of new macrolide antibiotics with enhanced antifungal and/or antiprotozoal efficacy.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Abhimanyu K. Singh, Sergio E. Martinez, Weijie Gu, Hoai Nguyen, Dominique Schols, Piet Herdewijn, Steven De Jonghe, Kalyan Das
Summary: The authors discovered a transient P-pocket created by HIV reverse transcriptase while sliding over a DNA substrate and developed a cryo-EM platform for lead optimization. By screening 300 drug-like fragments, they identified two leads that bind to the P-pocket, which is resilient to drug-resistance mutations and composed of structural elements from polymerase active site, primer grip, and template-primer. An engineered RT/DNA aptamer complex was utilized to trap the transient P-pocket and structures of the RT/DNA complex in the presence of an inhibitory fragment were determined.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Physical
Lulu Jiang, Yosuke Imanaka, Hiroshi Fujii
Summary: Tuning the electron-withdrawing effect of a ligand is crucial for developing efficient metal-complex catalysts. This study investigates the effects of steric and electron-withdrawing factors on the catalytic activity of an iron(iii) porphyrin catalyst for the hydroxylation reaction of a nonactivated alkane. The results show that while an increase in the electron-withdrawing effect enhances the reaction rate, excessive electron-withdrawing effects lead to a decrease in catalytic activity by affecting the formation rate of the reactive intermediate compound I. The steric effect of the meso-aryl group of the iron porphyrin is also found to be essential for efficient catalysis.
CATALYSIS SCIENCE & TECHNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Ilya Kolyadenko, Anastasia Scherbakova, Kirill Kovalev, Azat Gabdulkhakov, Svetlana Tishchenko
Summary: Laccases play an important role in catalyzing the oxidation of substrates and reducing oxygen to water. This study focused on optimizing the substrate-binding pocket and adjusting the oxygen reduction process of a two-domain laccase from Streptomyces griseoflavus. By substituting specific amino acid residues, the catalytic activity of the laccase towards ABTS and 2.6-DMP was greatly enhanced. It was also found that a certain residue (His 165) not only regulates oxygen access but also participates in proton transport.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Alisha Kamra, Sourav Das, Preeti Bhatt, Manju Solra, Tanmoy Maity, Subinoy Rana
Summary: Regulation of enzyme activity and biocatalytic cascades on compartmentalized cellular components is essential for cellular adaptation. A transient supramolecular glue with a controllable lifetime based on multivalent supramolecular interactions between surfactants and ATP has been introduced, allowing temporal control of catalytic activities similar to cellular nanoreactors. This system emulates heterogeneous cellular processes and provides opportunities for protocell construction and therapeutic interventions.
Review
Pharmacology & Pharmacy
Arthur G. Roberts, Jeffrey C. Stevens, Grazyna D. Szklarz, Emily E. Scott, Santosh Kumar, Manish B. Shah, James R. Halpert
Summary: This article summarizes four decades of work from Dr. James Halpert's laboratory, shaping the field of cytochrome P450, and providing insightful perspectives from the co-authors. This work will also inspire future drug metabolism scientists to make critical new discoveries in the cytochrome P450 field.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Multidisciplinary Sciences
Amanda K. Votvik, Asmund K. Rohr, Bastien Bissaro, Anton A. Stepnov, Morten Sorlie, Vincent G. H. Eijsink, Zarah Forsberg
Summary: Bacterial lytic polysaccharide monooxygenases (LPMOs) oxidize cellulose and chitin. Streptomyces coelicolor A3(2) encodes seven putative LPMOs, four of which oxidize chitin, two oxidize cellulose, and one is a non-characterized enzyme. A truncated version of the non-characterized LPMO called ScLPMO10D without a cell wall sorting signal (CWSS) was produced and its properties were studied. This study provides insights into the biological roles of LPMOs and allows for comparison with distantly related LPMOs with similar substrates.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Multidisciplinary
Soumya Samanta, Srijan Sengupta, Saptarshi Biswas, Sucheta Ghosh, Sudip Barman, Abhishek Dey
Summary: Heme dioxygenases play a crucial role in the biosynthesis of important biomolecules. In this study, the catalytic function of a ferrous heme dioxygen adduct was investigated using in situ resonance Raman spectroscopy. The results showed the accumulation of different species during the electrochemical ORR catalysis, mimicking the reaction of heme dioxygenases. This study provides important insights into the mechanism of biological catalysts and can inspire the design of more efficient artificial catalysts.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Pharmacology & Pharmacy
Mikina Takiyama, Takashi Matsumoto, Noriko Kaifuchi, Yasuharu Mizuhara, Eiji Warabi, Katsuya Ohbuchi, Kazushige Mizoguchi
Summary: Kampo medicines are widely used in Japan, but their potential to cause drug interactions is still unclear. This study investigated the inhibitory effects of goreisan, a Kampo medicine, on P-glycoprotein (P-gp) and cytochrome P-450 (CYP), which are associated with drug interactions. The results showed that goreisan extract has inhibitory activity against P-gp and that one of its ingredients, alisol A, exhibits an inhibitory effect on CYP3A. However, these effects are likely to be minor or negligible in vivo.
Article
Biochemistry & Molecular Biology
Ila A. Marathe, Stella M. Lai, Walter J. Zahurancik, Michael G. Poirier, Vicki H. Wysocki, Venkat Gopalan
Summary: The ribonucleoprotein form of archaeal RNase P consists of one catalytic RNA and five protein cofactors, which work together to recognize and cleave tRNA in a Mg2+-dependent manner. The addition of RPPs decreases the Mg2+ requirement and improves cleavage efficiency. Mg2+ and RPP proteins play essential roles in enhancing activity by inducing structural changes in RNA.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Analytical
J. Lamarche, K. Bierla, L. Ouerdane, J. Szpunar, L. Ronga, R. Lobinski
Summary: The reactivity of selenoprotein P with two metallodrugs (auranofin and cisplatin) was investigated through a series of purification techniques and sequencing, showing specific interactions between the protein and the drugs.
JOURNAL OF ANALYTICAL ATOMIC SPECTROMETRY
(2022)
Article
Ecology
A. A. Gaisina, A. A. Mekhtiev, A. N. Nurullayeva, G. M. Palatnikov, E. N. Shamilov
Summary: The suburbs of Baku, Azerbaijan have high levels of background gamma-radiation. This study investigated the impact of radiation on erythrocyte nuclear pathologies, levels of cytochrome P-450, and serotonin-modulating anticonsolidation protein (SMAP) in the tissues of hens living in settlements with different radiation levels. The results showed that higher radiation levels increased nuclear pathologies, upregulated tissue SMAP levels, and downregulated cytochrome P-450. Additionally, controlled dosage studies on rats found that SMAP administration provided significant protection to somatic cell nuclei from gamma-radiation.
Review
Pharmacology & Pharmacy
Joseph M. Cronin, Ai -Ming Yu
Summary: The development of medications requires a thorough understanding of their pharmacokinetic and pharmacodynamic properties. The study of ADME gene products and their functions has been revolutionized by recombinant DNA technologies. These technologies enable the investigation of drug metabolism and disposition, as well as the study of posttranscriptional regulation of ADME genes.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Biochemistry & Molecular Biology
Sabine Ottilie, Gregory M. Goldgof, Claudia Magalhaes Calvet, Gareth K. Jennings, Greg LaMonte, Jake Schenken, Edgar Vigil, Prianka Kumar, Laura-Isobel McCall, Eduardo Soares Constantino Lopes, Felicia Gunawan, Jennifer Yang, Yo Suzuki, Jair L. Siqueira-Neto, James H. McKerrow, Rommie E. Amaro, Larissa M. Podust, Jacob D. Durrant, Elizabeth A. Winzeler
ACS CHEMICAL BIOLOGY
(2017)
Article
Infectious Diseases
Thavy Long, Liliana Rojo-Arreola, Da Shi, Nelly El-Sakkary, Kurt Jarnagin, Fernando Rock, Maliwan Meewan, Alberto A. Rascon, Lin Lin, Katherine A. Cunningham, George A. Lemieux, Larissa Podust, Ruben Abagyan, Kaveh Ashrafi, James H. McKerrow, Conor R. Caffrey
PLOS NEGLECTED TROPICAL DISEASES
(2017)
Article
Infectious Diseases
Claudia Magalhaes Calvet, Jun Yong Choi, Diane Thomas, Brian Suzuki, Ken Hirata, Sharon Lostracco-Johnson, Liliane Batista de Mesquita, Alanderson Nogueira, Marcelo Meuser-Batista, Tatiana Araujo Silva, Jair Lage Siqueira-Neto, William R. Roush, Mirian Claudia de Souza Pereira, James H. McKerrow, Larissa M. Podust
PLOS NEGLECTED TROPICAL DISEASES
(2017)
Article
Chemistry, Medicinal
Francesco Saccoliti, Valentina Noemi Madia, Valeria Tudino, Alessandro De Leo, Luca Pescatori, Antonella Messore, Daniela De Vita, Luigi Scipione, Reto Brun, Marcel Kaiser, Pascal Maser, Claudia Magalhaes Calvet, Gareth K. Jennings, Larissa M. Podust, Roberta Costi, Roberto Di Santo
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Microbiology
Wenxu Zhou, Anjan Debnath, Gareth Jennings, Hye Jee Hahn, Boden H. Vanderloop, Minu Chaudhuri, W. David Nes, Larissa M. Podust
Article
Chemistry, Medicinal
Francesco Saccoliti, Valentina Noemi Madia, Valeria Tudino, Alessandro De Leo, Luca Pescatori, Antonella Messore, Daniela De Vita, Luigi Scipione, Reto Brun, Marcel Kaiser, Pascal Maser, Claudia M. Calvet, Gareth K. Jennings, Larissa M. Podust, Giacomo Pepe, Roberto Cirilli, Cristina Faggi, Annalise Di Marco, Maria Rosaria Battista, Vincenzo Summa, Roberta Costi, Roberto Di Santo
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Biochemistry & Molecular Biology
Roman M. Davydov, Gareth Jennings, Brian M. Hoffman, Larissa M. Podust
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2019)
Article
Biochemistry & Molecular Biology
Matthew D. DeMars, Nathan L. Samora, Song Yang, Marc Garcia-Borras, Jacob N. Sanders, K. N. Houk, Larissa M. Podust, David H. Sherman
JOURNAL OF BIOLOGICAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Da Shi, Kirti Kandhwal Chahal, Patricia Oto, Louis-Felix Nothias, Anjan Debnath, James H. McKerrow, Larissa M. Podust, Ruben Abagyan
ACS INFECTIOUS DISEASES
(2019)
Article
Microbiology
Brian Shing, Seema Singh, Larissa M. Podust, James H. McKerrow, Anjan Debnath
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Meeting Abstract
Biochemistry & Molecular Biology
Vandna Sharma, Brian Shing, Anjan Debnath, Larissa Podust
Meeting Abstract
Chemistry, Multidisciplinary
Joshua Corpuz, Larissa Podust, Matt Jaremko, Tony Davis, Michael Burkart
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
(2019)
Meeting Abstract
Biochemistry & Molecular Biology
Chenoa D. Arico, Larissa Podust, Hans-Joachim Knolker, Hugues Ouellet
Meeting Abstract
Biochemistry & Molecular Biology
Matthew D. DeMars, Song Yang, Fang Sheng, Nathan L. Samora, Sung Ryeol Park, Andrew N. Lowell, K. N. Houk, Larissa M. Podust, David H. Sherman
Article
Biochemistry & Molecular Biology
Drew R. Tietz, Larissa M. Podust, David H. Sherman, Thomas C. Pochapsky