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Cytomegalovirus
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Ganciclovir is a nucleoside analogue drug with antiviral activity against sensitive strains of CMV [102]. For activity, the drug must be phosphorylated by a CMV phosphotransferase enzyme encoded by the UL97 gene. The phosphotransferase converts ganciclovir to ganciclovir monophosphate, which in turn is phosphorylated to ganciclovir triphosphate by cellular enzymes. The triphosphate form exerts antiviral activity via inhibition of the DNA polymerase enzyme, by interfering with elongation of viral DNA. Because of the critical role of the phosphotransferase, mutations in the UL97 gene result in ganciclovir resistance [103]. These resistant CMV isolates have been reported in a variety of patient populations, especially in individuals who have received prolonged antiviral therapy. Ganciclovir resistance can also occur in strains with mutations in the CMV DNA polymerase gene.
The Mannitol Enzyme II of the Bacterial Phosphotransferase System: A Functionally Chimaeric Protein with Receptor, Transport, Kinase, and Regulatory Activities
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
Milton H. Saier, John E. Leonard
Figure 1 shows the pathway for the initiation of D-mannitol catabolism in E. coli. The sugar is transported across the membrane and concomitantly phosphorylated by a PTS-mediated mechanism. In this process the phosphoryl group of phosphoenolpyruvate is transferred sequentially from phosphoenolpyruvate to Enzyme I and HPr, the two energy coupling proteins of the phosphotransferase system. Phospho-HPr then binds to the cytoplasmic surface of the Enzyme II,Mtl and free mannitol, in the extracellular medium, approaches the sugar binding site on the outer face of the enzyme. Group translocation of the sugar through the membrane corresponds to the simultaneous transport and phosphorylation of the substrate, with the release of D-mannitol-1-phosphate in the cytoplasm. The byproduct of this reaction is pyruvate. Cytoplasmic mannitol-1-phosphate is then oxidized to fructose-6-phosphate in a process catalyzed by mannitol-1-phosphate dehydrogenase in which NAD+ serves as the electron acceptor. While the general energy coupling proteins of the PTS, Enzyme I, and HPr, are coded for by the ptsl and ptsH genes, respectively, which comprise the pts operon,9,10 the Enzyme IIMtl and the mannitol-1-phosphate dehydrogenase are coded for by the mtlA and mtlD genes, respectively, which comprise the mtl operon.11,12,13 Substantial differences between the protein constituents of the PTS in the two principal organisms under study, E. coli and S. typhimurium, have not been revealed by available investigations.
Growth Factor Receptors as Proto Oncogenes or Oncogene Products
Published in Velibor Krsmanović, James F. Whitfield, Malignant Cell Secretion, 2019
No definitive information is yet available for any of the known receptor tyrosine kinases as to what residues are directly involved in ligand binding. Biochemical and genetic evidence indicates that ligand binding to these receptors induces a conformational change which results in receptor oligomerization and transmembrane signal transduction.19-21 The result of this process is the induction of the intrinsic protein tyrosine-specific phosphotransferase activity of the intracellular domain.
Proteomic response in Streptococcus gordonii DL1 biofilm cells during attachment to salivary MUC5B
Published in Journal of Oral Microbiology, 2021
Carolina Robertsson, Gunnel Svensäter, Zoltan Blum, Magnus E Jakobsson, Claes Wickström
Also, among the novel biofilm cell proteins was the multiple-sugar metabolism transmembrane permease F (MsmF), a transmembrane helical protein [27]. Based on reduced uptake and fermentation of a variety of carbohydrates in an MsmF-mutant, S. mutans MsmF was confirmed to be involved in the low-affinity multiple-sugar metabolism (msm) [36]. Several mono- and disaccharides have been identified as substrates for the msm system in S. mutans [37]. A phosphotransferase system (PTS) deficient mutant of S. mutans was found to switch to msm, which in turn reduced the total carbohydrate transport and metabolism in the cells [38]. A shift towards the low-affinity msm system may benefit biofilm lifestyle cells by reducing the flow through the central carbon metabolism and thereby protecting the biofilm against harmful acidification.
Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy
Published in Expert Opinion on Drug Discovery, 2019
Induced protein degradation by small molecules, an alternative to occupancy-driven inhibition, has steadily grown as an attractive, promising drug discovery avenue over the last two decades. Perturbation of homeostasis and turnover of specific proteins by means of induced degradation is an event-driven strategy (Table 1), thus comparable to other down-regulation methods such as gene silencing and editing [1,2]. Rather than simply inhibiting phosphotransferase activity through steady-state occupancy of binding sites (active or allosteric), the small molecules serve as non-stoichiometric cofactors in cycles of catalytic degradation of the targeted proteins, an irreversible process. Thus, small-molecule inducers of protein degradation would be anticipated to show dramatically different activities relative to their traditional counterparts on both the molecular and cellular levels.
An evaluation of tofacitinib for the treatment of psoriatic arthritis
Published in Expert Opinion on Pharmacotherapy, 2019
Hunar Abdulrahim, Hisham Sharlala, Adewale O. Adebajo
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinase enzymes that transduce signals arising from cytokine and growth factors via the JAK-STAT pathway [23]. There are four JAK isoforms currently recognized: JAK1, JAK2, JAK3, and TYK2 [23]. Within each of these four structural domains, there are seven homologous regions (JH 1–7). JH1 (kinase domain) is the primary phosphotransferase in which ATP is bound, both autophosphorylating the JAK complex and phosphorylating Signal Transducers And Activators of Transcription (STATs) [24]. In the signaling pathway, type I/II cytokines bind to their receptors and activate JAKs, which phosphorylate and activate STATs initiating downstream signaling cascades. The phosphorylated STATs (pSTATs) form either homo or heterodimers that translocate into the nucleus where they bind their related promoter elements to regulate transcription of target genes [25].