Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign. In this Account, our research program that brings together the principles and methods of bioinorganic and medicinal chemistry are described, in an effort to bridge the gap between these fields and address an important class of medicinal targets. Fragment-based drug discovery (FBDD) is an important drug discovery approach that is particularly well suited for metalloenzyme inhibitor development. FBDD uses relatively small but diverse chemical structures that allow for the assembly of privileged molecular collections that focus on a specific feature of the target enzyme. For metalloenzyme inhibition, the specific feature is rather obvious, namely, a metal-dependent active site. Surprisingly, prior to our work, the exploration of diverse molecular fragments for binding the metal active sites of metalloenzymes was largely unexplored. By assembling a modest library of metal-binding pharmacophores (MBPs), we have been able to find lead hits for many metalloenzymes and, from these hits, develop inhibitors that act via novel mechanisms of action. A specific case study on the use of this strategy to identify a first-in-class inhibitor of zinc-dependent Rpn11 (a component of the proteasome) is highlighted. The application of FBDD for the development of metalloenzyme inhibitors has raised several other compelling questions, such as how the metalloenzyme active site influences the coordination chemistry of bound fragments, how one can identify the best fragments for a given metalloenzyme, and many others. Among the most significant, and concerning, questions for metalloenzyme inhibition are those that reside around issues of specificity and whether metalloenzyme inhibitors can be as selective and specific as other small molecule inhibitors (i.e., compounds that inhibit enzymes that do not utilize a metal at their active site). This also leads to the question of whether metalloenzyme inhibitors might interfere more broadly with the metallome. Efforts to address these and related questions are discussed, with the expectation that our findings will illuminate some of these topics, alleviate some of these concerns, and encourage greater interest in this important, undervalued class of drug targets.
 ...
PMID:A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes. 2871 3

Brassica napus is an important oilseed crop worldwide. Although seed weight is the main determinant of seed yield, few studies have focused on the molecular mechanisms that regulate seed weight in B. napus. In this study, the immature seeds of G-42 and 7-9, two B. napus doubled haploid (DH) lines with extremely different thousand-seed weight (TSW), were selected for a transcriptome analysis to determine the regulatory mechanisms underlying seed weight at the whole gene expression level and to identify candidate genes related to seed weight. A total of 2,251 new genes and 2,205 differentially expressed genes (DEGs) were obtained via RNA-seq (RNA sequencing). Among these genes, 1,747 (77.61%) new genes and 2020 (91.61%) DEGs were successfully annotated. Of these DEGs, 1,118 were up-regulated and 1,087 were down-regulated in the large-seed line. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database analysis indicated that 15 DEGs were involved in ubiquitin-mediated proteolysis and proteasome pathways, which might participate in regulating seed weight. The Gene Ontology (GO) database indicated that 222 DEGs were associated with the biological process or molecular function categories related to seed weight, such as cell division, cell size and cell cycle regulation, seed development, nutrient reservoir activity, and proteasome-mediated ubiquitin-dependent protein catabolic processes. Moreover, 50 DEGs encoding key enzymes or proteins were identified that likely participate in regulating seed weight. A DEG (GSBRNA2T00037121001) identified by the transcriptome analysis was also previously identified in a quantitative trait locus (QTL) region for seed weight via SLAF-seq (Specific Locus Amplified Fragment sequencing). Finally, the expression of 10 DEGs with putative roles in seed weight and the expression of the DEG GSBRNA2T00037121001 were confirmed by a quantitative real-time reverse transcription PCR (qRT-PCR) analysis, and the results were consistent with the RNA sequencing data. This work has provided new insights on the molecular mechanisms underlying seed weight-related biosynthesis and has laid a solid foundation for further improvements to the seed yield of oil crops.
 ...
PMID:RNA-seq transcriptome analysis of the immature seeds of two Brassica napus lines with extremely different thousand-seed weight to identify the candidate genes related to seed weight. 3123 18