The Role of Kinase Inhibitors in Cancer Therapies

Protein kinases are enzymes that transfer a phosphate group to the threonine, serine, or tyrosine residues of the target protein, regulating its activity. The activity of these enzymes are very important and strictly regulated in the cell as they promote cell proliferation, survival, and migration. In the case of any dysregulation of these enzymes, they can be associated with cancer initiation and progression. Small-molecule kinase inhibitors approved by the FDA for their improved clinical benefits are currently used in targeted therapy for the treatment of various cancers. So far, there are 62 FDA-approved therapeutic agents targeting different protein kinases, eight of which were approved in 2020. Today, kinase inhibitors are used as FDA approved cancer agents and newly developed ones are evaluated in clinical trials. Those protein kinase inhibitors can be grouped as growth factor receptor inhibitors, Ras/Raf/Mek inhibitors, phosphoinositide 3-kinase (PI3K) and cyclin dependent kinase inhibitors, other targets, and agents such as protein kinase c and 3 phosphoinositide-dependent kinase 1. In this chapter, these kinases, their pathways, and their inhibitors will be discussed in detail

Genome-scale metabolic representation of Amycolatopsis balhimycina

Infection caused by methicillin-resistant Staphylococcus aureus (MRSA) is an increasing societal problem. Typically, glycopeptide antibiotics are used in the treatment of these infections. The most comprehensively studied glycopeptide antibiotic biosynthetic pathway is that of balhimycin biosynthesis in Amycolatopsis balhimycina. The balhimycin yield obtained by A. balhimycina is, however, low and there is therefore a need to improve balhimycin production. In this study, we performed genome sequencing, assembly and annotation analysis of A. balhimycina and further used these annotated data to reconstruct a genome-scale metabolic model for the organism. Here we generated an almost complete A. balhimycina genome sequence comprising 10,562,587 base pairs assembled into 2,153 contigs. The high GC-genome (similar to 69%) includes 8,585 open reading frames (ORFs). We used our integrative toolbox called SEQTOR for functional annotation and then integrated annotated data with biochemical and physiological information available for this organism to reconstruct a genome-scale metabolic model of A. balhimycina. The resulting metabolic model contains 583 ORFs as protein encoding genes (7% of the predicted 8,585 ORFs), 407 EC numbers, 647 metabolites and 1,363 metabolic reactions. During the analysis of the metabolic model, linear, quadratic and evolutionary programming algorithms using flux balance analysis (FBA), minimization of metabolic adjustment (MOMA), and OptGene, respectively were applied as well as phenotypic behavior and improved balhimycin production were simulated. The A. balhimycina model shows a good agreement between in silico data and experimental data and also identifies key reactions associated with increased balhimycin production. The reconstruction of the genome-scale metabolic model of A. balhimycina serves as a basis for physiological characterization. The model allows a rational design of engineering strategies for increasing balhimycin production in A. balhimycina and glycopeptide production in general

Soil Salinity and pH Drive Soil Bacterial Community Composition and Diversity Along a Lateritic Slope in the Avon River Critical Zone Observatory, Western Australia

Soils are crucial in regulating ecosystem processes, such as nutrient cycling, and supporting plant growth. To a large extent, these functions are carried out by highly diverse and dynamic soil microbiomes that are in turn governed by numerous environmental factors including weathering profile and vegetation. In this study, we investigate geophysical and vegetation effects on the microbial communities of iron-rich lateritic soils in the highly weathered landscapes of Western Australia (WA). The study site was a lateritic hillslope in southwestern Australia, where gradual erosion of the duricrust has resulted in the exposure of the different weathering zones. High-throughput amplicon sequencing of the 16S rRNA gene was used to investigate soil bacterial community diversity, composition and functioning. We predicted that shifts in the microbial community would reflect variations in certain edaphic properties associated with the different layers of the lateritic profile and vegetation cover. Our results supported this hypothesis, with electrical conductivity, pH and clay content having the strongest correlation with beta diversity, and many of the differentially abundant taxa belonging to the phyla Actinobacteria and Proteobacteria. Soil water repellence, which is associated with Eucalyptus vegetation, also affected beta diversity. This enhanced understanding of the natural system could help to improve future crop management in WA since the physicochemical properties of the agricultural soils in this region are inherited from laterites via the weathering and pedogenesis processes

PENTOSE PHOSPHATE PATHWAY FLUX ANALYSIS FOR GLYCOPEPTIDE ANTIBIOTIC VANCOMYCIN PRODUCTION DURING GLUCOSE-LIMITED CULTIVATION OF Amycolatopsis orientalis

In vivo pentose phosphate pathway (PPP) enzymes such as glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), and transaldolase (TAL) activities as well as ATP- and ADP-level variations of Amycolatopsis orientalis were investigated with respect to glucose concentration and incubation period. G6PDH, 6PGDH, and TAL activities of A. orientalis reached maximum levels at 48 hr for all glucose concentrations used, after which the levels began to decline. G6PDH, 6PGDH, and TAL activities showed positive correlation with the glucose concentration up to 15 g/ L, while further increases had an opposite effect. Intracellular AM level showed a positive correlation with glucose concentrations, while ADP level increased up to 15 g/ L. ATP concentration of A. orientalis increased rapidly at 48 hr of incubation, as was the case also for G6PDH, 6PGDH, and TAL activities, although the incubation period corresponding to maximum values of ADP shifted to 60 hr Production of the glycopeptide antibiotic vancomycin increased with the increases in glucose concentrations up to 15 g/ L, by showing coherence in the rates of oxidative and nonoxidative parts of the PPP