Article
Chemistry, Medicinal
Ebru Cetin, Ali Rana Atilgan, Canan Atilgan
Summary: Antibiotic resistance is a global health problem caused by mutations that render drugs ineffective. This study aims to understand the working mechanisms of resistant mutants of Escherichia coli dihydrofolate reductase using molecular dynamics simulations. The findings suggest that the entire enzyme is synchronized with the substrate, and mutations affect the hydrogen bond dynamics. The mutants are categorized based on the observed mechanisms.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Himadri S. Sarkar, Takato Mashita, Toshiyuki Kowada, Satoshi Hamaguchi, Toshizo Sato, Kento Kasahara, Nobuyuki Matubayasi, Toshitaka Matsui, Shin Mizukami
Summary: The authors developed a series of photoswitchable inhibitors selective for Escherichia coli dihydrofolate reductase (eDHFR) by modifying the structure of a previously reported compound, azoMTX. The addition of bulky bis-alkylated arylazopyrazole groups increased selectivity towards eDHFR over human DHFR. The new ligands showed nearly complete Z-to-E photoconversion and high thermostability, allowing for real-time control of eDHFR activity by switching the illumination light wavelengths.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biology
Yanmin Zhang, Sourav Chowdhury, Joao Rodrigues, Eugene Shakhnovich
Summary: A new compound CD15-3 was discovered to inhibit both the wild type and TMP-resistant variants of E. coli DHFR; CD15-3 showed delayed resistance compared to TMP in in vitro evolution; Resistance to CD15-3 was attributed to gene duplication of efflux pumps, resulting in weak resistance.
Article
Microbiology
T. Parks Remcho, Sravanthi D. Guggilapu, Phillip Cruz, Glenn A. Nardone, Gavin Heffernan, Robert D. O'Connor, Carole A. Bewley, Thomas E. Wellems, Kristin D. Lane
Summary: WR99210 selectively targets Plasmodium parasites, with compound 1 effective against Plasmodium falciparum at low concentrations, while compound 2 is ineffective. Structural evaluations revealed compound 1 as WR99210 and compound 2 as a dihydrotriazine regioisomer, with different binding capabilities to the parasite's enzyme.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Chemistry, Medicinal
Ebru Cetin, Tandac F. Guclu, Isik Kantarcioglu, Ilona K. Gaszek, Erdal Toprak, Ali Rana Atilgan, Burcu Dedeoglu, Canan Atilgan
Summary: In this study, the researchers investigated the interaction and inhibition mechanisms of a newly proposed DHFR inhibitor, 4´-deoxy methyl trimethoprim (4´-DTMP). They found that the kinetic differences in the inhibitory effects between 4´-DTMP and trimethoprim (TMP) can be attributed to the polar modification in 4´-DTMP, which induces additional interactions with the enzyme. These changes propagate through the hydrogen bond networks in the whole enzyme. The study also highlighted the importance of avoiding segmentation of the loop domain in inhibitor-bound DHFR.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Jiahua Deng, Qiang Cui
Summary: This study analyzes the contributions of second-shell residues in an efficient enzyme and finds that they mainly impact catalytic efficiency by perturbing the apo state and substrate binding. Mutations of these residues also modulate the active site hydration level, influencing the energetics of phosphoryl transfer. These mechanistic insights can inform strategies for improving enzyme design and engineering beyond the current focus on the first coordination shell.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Infectious Diseases
Stephanie J. Ambrose, Ruth M. Hall
Summary: Accurate identification of individual genes is essential for tracking the spread of antibiotic resistance genes, with trimethoprim resistance genes being increasingly found in genome sequences. This study explains common issues and pitfalls in dfrA gene identification and compiles complete information on dfrA genes/DfrA proteins in Gram-negative bacteria, proposing a method to prevent future duplication of gene numbers and confusion.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Bilkis Mehrin Moni, Joanna A. Quaye, Giovanni Gadda
Summary: Enzymes require flexible regions for catalysis, and the mobile regions of enzymes include gates that regulate the passage of molecules in and out of the active site. Q80 in loop 3 of the enzyme NQO plays a mechanistically essential role in NADH binding, but does not significantly affect quinone binding and hydride transfer.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Hao Gu, Takasumi Kato, Hiroyuki Kumeta, Yasuhiro Kumaki, Takashi Tsukamoto, Takashi Kikukawa, Makoto Demura, Hiroaki Ishida, Hans J. Vogel, Tomoyasu Aizawa
Summary: The study investigated the antimicrobial mechanism of CP1, a model antimicrobial peptide, by analyzing the structure of recombinant CP1 and its C-terminal truncated analogue in a membrane-mimetic environment. The results showed that the C-terminal region of CP1 played an important role in its antimicrobial activity.
Article
Multidisciplinary Sciences
Madhu Sudan Manna, Yusuf Talha Tamer, Ilona Gaszek, Nicole Poulides, Ayesha Ahmed, Xiaoyu Wang, Furkan C. R. Toprak, DaNae R. Woodard, Andrew Y. Koh, Noelle S. Williams, Dominika Borek, Ali Rana Atilgan, John D. Hulleman, Canan Atilgan, Uttam Tambar, Erdal Toprak
Summary: The study shows that 4'-desmethyltrimethoprim (4'-DTMP) inhibits both bacterial dihydrofolate reductase (DHFR) and a common TMP-resistant variant, slowing down the evolution of antibiotic resistance in E. coli.
NATURE COMMUNICATIONS
(2021)
Article
Ecology
David Kneis, Claudele Lemay-St-Denis, Stella Cellier-Goetghebeur, Alan X. Elena, Thomas U. Berendonk, Joelle N. Pelletier, Stefanie Hess
Summary: In this study, shotgun metagenomics was used to estimate the abundance of dfrB gene variants in aquatic environments. The results showed that dfrB1, dfrB2, dfrB3, dfrB4, dfrB5, and dfrB7 were more prevalent in wastewater microbiomes, while dfrB9, dfrB10, and dfrB13 were more prevalent in freshwater. This suggests that natural freshwater communities serve as a major reservoir for the recently discovered dfrB gene variants.
Review
Food Science & Technology
Dilek Eltemur, Peter Robatscher, Michael Oberhuber, Matteo Scampicchio, Alberto Ceccon
Summary: Nuclear magnetic resonance (NMR) spectroscopy is a promising technique for the analysis of bovine milk due to its non-destructive nature, minimal sample preparation requirements, and comprehensive approach. This review provides an overview of the applications of NMR techniques in assessing the quality and authenticity of bovine milk, highlighting key studies and emphasizing the versatility and significance of NMR spectroscopy in milk metabolomics research.
Article
Chemistry, Physical
Zefan Zhang, Christian Hilty
Summary: The reversible adsorption of CO2-derived species to graphene quantum dots in CO2 electroreduction reaction was characterized using nuclear spin hyperpolarized NMR. The study found a significant difference in the relaxation rates of bound and free species, indicating reversible binding. pH-dependent adsorption and desorption rate constants were measured, along with the average binding distance.
Article
Biochemistry & Molecular Biology
Jiacong Li, Mingxia Yang, Weijia Li, Chujie Lu, Deyu Feng, Zhuo Shang, Chengyuan Wang, Wei Lin
Summary: This study reveals the structure of the non-canonical MTHFR MSMEG_6649 and demonstrates that it has a larger binding groove with FAD compared to canonical MTHFR. The NADH-binding site in MSMEG_6649 is similar to the FAD binding site in canonical MTHFR, suggesting NADH plays the same role in catalysis. Critical residues involved in NADH and substrate binding were identified, providing insights for understanding the catalytic mechanism and potential drug targets.
BIOCHEMICAL JOURNAL
(2023)
Article
Chemistry, Medicinal
Hongyi Zhou, Hongnan Cao, Jeffrey Skolnick
Summary: In modern drug discovery, virtual ligand screening (VLS) is commonly used to reduce time and cost before experimental ligand screening. A new approach called FRAGSITE improves VLS precision and recall by integrating ligand fragment scores with global ligand similarity scores, outperforming state-of-the-art methods and showing better performance on challenging sets.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)