Bacteria Causing Gastrointestinal Infections
K. Balamurugan, U. Prithika in Pocket Guide to Bacterial Infections, 2019
The LT is structurally and functionally similar to the cholera toxin and is destroyed by heat and acid. It is a combination of A subunit and pentameric ring of 5B subunits. The B subunit binds to GM1 gangliosides of enterocytes and the A subunit causes G protein coupled activation of adenylate cyclase inside the enterocytes, leading to increased production of cyclic adenosine monophosphate (cAMP). These result in increased chloride secretion via cystic fibrosis transmembrane conductance regulator (CFTR) from the intestinal crypt cells of the small intestine resulting in voluminous diarrhea. The ST is not destroyed by heating even at 100°C, and their action is mediated through activation of guanylate kinase resulting in an increase of cyclic guanosine monophosphate (cGMP), leading to increased intestinal secretion from both small and large intestines.
Viral-Specific and Immune-Based Nonspecific Antiviral Therapies for CFS
Roberto Patarca-Montero in Treatment of Chronic Fatigue Syndrome in the Antiviral Revolution Era, 2014
Acyclovir is an acyclic analog of guanosine. The inhibitory activity of acyclovir is highly selective. The enzyme thymidine kinase (TK) of normal uninfected cells does not effectively use acyclovir as a substrate. However, TK encoded by the herpes simplex virus converts acyclovir into acyclovir monophosphate, a nucleotide analog. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. Acyclovir triphosphate interferes with herpes simplex virus DNA polymerase and inhibits viral replication. Acyclovir is preferentially taken up and selectively converted to the active triphosphate form by herpes virus-infected cells. Acyclovir triphosphate binds viral DNA polymerase, acting as a DNA chain terminator. Because acyclovir is taken up selectively by virus-infected cells, the concentration of acyclovir triphosphate is forty to 100 times higher in infected cells than in uninfected cells. Furthermore, viral DNA polymerase exhibits a ten- to thirtyfold greater affinity for acyclovir triphosphate than do cellular DNA polymerases. The higher concentration of the active triphosphate metabolite in infected cells plus the affinity for viral polymerases result in the very low toxicity of acyclovir for normal host cells.
Aciclovir and Valaciclovir
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
A number of phenomena account for the 300- to 3000-fold difference between toxicity of aciclovir for HSV and VZV and the host cell (Elion, 1982). The most important of these is the fact that aciclovir is selectively activated in HSV- or VZV-infected cells but remains virtually inactive in uninfected cells. HSV and VZV both encode a specific TK enzyme (Figure 213.2) that monophosphorylates the drug (Fyfe et al., 1978; Biron and Elion, 1980); aciclovir is not a substrate for host cellular TK (although phosphorylation does occur to a small extent by some other enzymes, possibly through the action of 5′ nucleotidase) (Cioe et al., 1992). Aciclovir monophosphate is then rapidly converted to aciclovir diphosphate and triphosphate by cellular enzymes. Guanylate kinase is responsible for converting aciclovir monophosphate to the diphosphate, an efficient process because the monophosphate form does not accumulate in cells (Miller and Miller, 1980). A number of cellular enzymes, including phosphoglycerate kinase, nucleoside diphosphate kinase, and phosphoenol pyruvate kinase, can convert aciclovir diphosphate to the active triphosphate form (Miller and Miller, 1982). The amount of aciclovir triphosphate formed in HSV- or VZV-infected cells is 40- to 100-fold greater than the amount formed in uninfected cells, and this difference is the principal reason for the excellent therapeutic ratio of aciclovir. In addition, the inhibition of cellular DNA polymerases alpha, delta, and epsilon by aciclovir triphosphate is significantly weaker than the inhibition of the viral DNA polymerase by the drug (Ilsley et al., 1995).
Gene networks associated with non-syndromic intellectual disability
Published in Journal of Neurogenetics, 2018
Soohyun Lee, Stephen Rudd, Jacob Gratten, Peter M. Visscher, Johannes B. Prins, Paul A. Dawson
PPI network analyses identified DLG3 (Disc large homolog 3), DLG4 (Disc large homolog 4) and CASK (calcium/calmodulin-dependent serine protein kinase 3), all of which are members of the membrane-associated guanylate kinase (MAGUK) superfamily, to be highly interconnected within this network (Supplementary Figure 2). Their direct/indirect binding partners include neuroligin-neurexin (encoded by NLGN and NRXN), NMDA receptors (encoded by GRIN1) and AMPA receptors and potassium channels (encoded by KCNA1), which form multimeric scaffolds for PPI and signal transduction. Of particular interest is the role of DLG4 in dopaminergic-glutamatergic systems. DLG4 provides a direct link between dopamine and glutamate receptors by multiple PPI and indirectly by crosstalk between their respective signalling pathways allowing reciprocal interaction between dopaminergic-glutamatergic systems (de Bartolomeis & Tomasetti, 2012). Dysfunction of dopamine and glutamate interaction has been implicated in the aetiology of schizophrenia (2014), and mutations in the genes DLG4, EPB41L1, GRIK2, GRIN1 and NRXN1 that we identified within the NS-ID network have also been linked with schizophrenia in the diseases ontology within the GeneGO database (Figure 2). The common aberration of dopaminergic and glutamatergic systems in schizophrenia (Network & Pathway Analysis Subgroup of Psychiatric Genomics Consortium, 2015) and NS-ID suggest that this network may be an underlying contributor to NS-ID.
The battle of lipid-based nanocarriers against blood-brain barrier: a critical review
Published in Journal of Drug Targeting, 2023
Kawthar K. Abla, Mohammed M. Mehanna
Claudins are a multigene family where claudin-5 is the most abundant isoform in the brain endothelial. They are of 20–27 kDa molecular weight, with four transmembrane spanning proteins, two extracellular loops, a cytoplasmic tail and PDZ binding motif within C-terminus allowing them to interact with the zonula occludens (ZOs) [24]. ZOs are membrane-associated guanylate kinase family cytoplasmic proteins. They have crucial PDZ domains that allow them to associate with transmembrane tight junctions, adherense junctions, and gap junctions. ZOs, on the opposite side, bind to the actin filaments (Figure 1) and provide a scaffolds-like structure connecting tight junction strands with the cytoskeleton [25].
Alterations in the expression pattern of RBC membrane associated proteins (RMAPs) in whole body γ-irradiated Sprague Dawley rats
Published in International Journal of Radiation Biology, 2023
Prabuddho Mukherjee, Kamendra Kumar, Bincy Babu, Jubilee Purkayastha, Sudhir Chandna
The p55 protein, which showed only a transient over-expression at 24 h following 7.5 Gy dose, belongs to the family of cytoskeletal and signaling proteins referred to as membrane associated guanylate kinase homologues (MAGUKs). It is a component of the protein 4.1-glycophorin C complex of RBC membranes, which regulates cellular shape and stability of the membrane (Chishti 1998). It is also a receptor for the binding of cytokine tumor necrosis factor (TNF), which plays a role in oxidative stress response by inducing MnSOD expression (Wong 1995). Its minimal but definitive change in expression at lethal dose warrants further study in both animal and human models.
Related Knowledge Centers
- Adenosine Diphosphate
- Catalysis
- Chemical Reaction
- Enzyme
- Guanosine Diphosphate
- Transferase
- Adenosine Triphosphate
- Guanosine Monophosphate
- Substrate
- Product