AI Article Synopsis
- An increase in unknown enzymes due to genomics has led to a demand for improved methods to study them, particularly using enzyme inhibitors.
- The proposed strategy involves categorizing oxidoreductase genes into structural groups called pharmacofamilies, which helps identify common features in their binding sites.
- By utilizing NMR-based techniques for binding site mapping, researchers can efficiently design diverse inhibitor libraries that effectively target these enzymes.
Article Abstract
Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.chembiol.2004.02.012 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain.
Acta Neuropathol Commun
December 2024
Laboratory of Stem Cell Biology and Epigenetics, School of Basic Medical Sciences, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Highway, Pudong New Area, Shanghai, 201318, China.
Midbrain dopamine (mDA) neurons participate in a wide range of brain functions through an intricate regulation of DA biosynthesis. The epigenetic factors and mechanisms in this process are not well understood. Here we report that histone demethylase JMJD3 is a critical regulator for DA biosynthesis in adult mouse mDA neurons.
View Article and Find Full Text PDFExamination of common culture medium for human hepatocytes and engineered heart tissue: Towards an evaluation of cardiotoxicity associated with hepatic drug metabolism in vitro.
PLoS One
December 2024
Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan.
Cardiotoxicity associated with hepatic metabolism and drug-drug interactions is a serious concern. Predicting drug toxicity using animals remains challenging due to species and ethical concerns, necessitating the need to develop alternative approaches. Drug cardiotoxicity associated with hepatic metabolism cannot be detected using a cardiomyocyte-only evaluation system.
View Article and Find Full Text PDFPulmonary lysyl oxidase expression and its role in seeding Lewis lung carcinoma cells.
Clin Exp Metastasis
December 2024
Christopher S. Bond Life Sciences Center 540F, University of Missouri, 1201 E Rollins, Columbia, MO, 65211, USA.
Copper promotes tumor growth and metastasis through a variety of mechanisms, most notably as a cofactor within the lysyl oxidase (LOX) family of secreted cuproenzymes. Members of this family, which include LOX and LOX-like enzymes LOXL1-4, catalyze the copper-dependent crosslinking of collagens and elastin within the extracellular matrix (ECM). Elevated LOX expression is associated with higher incidence and worse prognosis in multiple cancers, including colorectal, breast, pancreatic, and head and neck.
View Article and Find Full Text PDFBase editing of in neurons alleviates symptoms in a mouse model of Parkinson's disease.
Elife
December 2024
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
Parkinson's disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons (DANs). Recent studies have reported the successful conversion of astrocytes into DANs by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to the rescue of motor symptoms in a chemically-induced mouse model of PD. However, follow-up studies have questioned the validity of this astrocyte-to-DAN conversion model.
View Article and Find Full Text PDFThe pan-cancer landscape of aldo-keto reductase1B10 reveals that its expression is diminished in gastric cancer.
Front Immunol
December 2024
Hunan Province Key Laboratory of Basic and Clinical Pharmacological Research on Gastrointestinal Tumors, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
Introduction: Aldo-keto reductase 1B10 (AKR1B10) is a multifunctional enzyme, which is important in cancer development and progression, but the landscape of AKR1B10 in pan-cancers and in tumor microenvironment is unclear.
Method: This study integrated the sequencing data of 33 cancer types, including gastric cancer, from TCGA project to explored the expression pattern and genetic and epigenetic alterations of AKR1B10. The association of AKR1B10 expression with clinical progression of cancers was evaluated by Kaplan-Meier analysis; the potential role of AKR1B10 in tumor microenvironment (TME) and immune-related gene expression were analyzed by PURITY, ESTIMATE, TIMER and CIBERSORT algorithms.
Want 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!