To get insight into the origin of pyrimidine specificity of ribonuclease A, a study of the enzyme interaction with the substrate analogs having a modified nucleobase was undertaken. Pyridine and pyrimidine cyclophosphates were obtained by phosphorylation of 2'(3')-O-dibutyl stannylidene derivatives of nonprotected nucleosides in high yields. The results of kinetic and NMR studies suggested that a substrate should be locked in anti-conformation in the productive enzyme-substrate complex as it was shown for the crystalline complexes of the enzyme with pyrimidine nucleotides by X-ray analysis. The interaction between carbonyl group in position 2 of substrate nucleobase and proton accepting group of the protein (NH of Thr45) was found to be a prerequisite for the specific recognition of a substrate by the enzyme. The rate constants for transformation of lactam form (slow) and lactim form (fast) of pyrimidine substrates were estimated.
Download full-text PDF |
Source |
|---|
Publication Analysis
Top Keywords
Similar Publications
mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.
Cell Rep
January 2025
Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA; Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Tri-Institutional PhD Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:
One critical aspect of cell proliferation is increased nucleotide synthesis, including pyrimidines. Pyrimidines are synthesized through de novo and salvage pathways. Prior studies established that the mammalian target of rapamycin complex 1 (mTORC1) promotes pyrimidine synthesis by activating the de novo pathway for cell proliferation.
View Article and Find Full Text PDFPYGO2 promotes resistance to chemotherapy via reducing apoptosis and G2/M cell cycle arrest in esophageal carcinoma cells.
Med Oncol
January 2025
Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran.
5-FU is a widely used chemotherapy drug for esophageal carcinomas, but therapy failure has been observed in 5-FU-resistant patients. Overcoming this resistance is a significant challenge in cancer treatment, requiring identifying and targeting important resistance mechanisms. PYGO2 expression is crucial in developing resistance to various chemotherapy drugs.
View Article and Find Full Text PDFIntegrating machine learning and structure-based approaches for repurposing potent tyrosine protein kinase Src inhibitors to treat inflammatory disorders.
Sci Rep
January 2025
State Key Laboratory of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China.
Tyrosine-protein kinase Src plays a key role in cell proliferation and growth under favorable conditions, but its overexpression and genetic mutations can lead to the progression of various inflammatory diseases. Due to the specificity and selectivity problems of previously discovered inhibitors like dasatinib and bosutinib, we employed an integrated machine learning and structure-based drug repurposing strategy to find novel, targeted, and non-toxic Src kinase inhibitors. Different machine learning models including random forest (RF), k-nearest neighbors (K-NN), decision tree, and support vector machine (SVM), were trained using already available bioactivity data of Src kinase targeting compounds.
View Article and Find Full Text PDFThe climb toward intracranial efficacy: Zorifertinib in EGFR-mutant NSCLC with CNS metastases in the EVEREST trial.
Med
January 2025
Division of Neuro-Oncology, Stanford University, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA. Electronic address:
The phase III EVEREST trial evaluating zorifertinib in the treatment of metastatic EGFR-mutant NSCLC was groundbreaking in its specific inclusion of patients with brain metastases. Zorifertinib prolonged systemic and intracranial progression-free survival compared with first-generation EGFR inhibitors, yet questions remain about its efficacy and toxicity compared with osimertinib.
View Article and Find Full Text PDFEffect of Genetic Variants on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Involvement of , and .
Int J Mol Sci
December 2024
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa (IIS-Princesa), 28006 Madrid, Spain.
Statins are the primary drugs used to prevent cardiovascular disease by inhibiting the HMG-CoA reductase, an enzyme crucial for the synthesis of LDL cholesterol in the liver. A significant number of patients experience adverse drug reactions (ADRs), particularly musculoskeletal problems, which can affect adherence to treatment. Recent clinical guidelines, such as those from the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2022, recommend adjusting rosuvastatin doses based on genetic variations in the and genes to minimize ADRs and improve treatment efficacy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!