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Plant-Based Adjunct Therapy for Tuberculosis
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Lydia Gibango, Anna-Mari Reid, Jonathan L. Seaman, Namrita Lall
Several antigens that have been used in TB subunit vaccines include early secretory antigenic target-6 (ESAT6) and antigen 85B (Ag85B), which are conserved secreted proteins and have been shown to be immunogenic in animal models (Agger and Andersen, 2001; Stewart et al., 2019). Several hurdles have restricted the number of antigens used, such as the various different stages of infections that take place and the larger genome size of Mycobacterium tuberculosis. Other antigens that have been identified include sulfate adenylyltransferase subunit 2 (CysD), which is a non-secreted protein that forms part of the sulfur assimilation pathway and has been shown to be upregulated during latent infection and is conserved across several strains (Counoupas et al., 2016; Stewart et al., 2019).
RNA
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Further development of the Qβ sequencing occurred in the obstacles of the gene engineering approaches. As in the case of the MS2 RNA, the Qβ RNA was extended at the 3′-end with the polyA segment by terminal riboadenylate transferase purified from calf thymus (Gilvarg et al. 1974, 1975a) The polyadenylated Qβ RNA retained full infectivity in a spheroplast assay system. However, the progeny viruses did not contain polyA termini, indicating an in vivo rectification of the in vitro alteration (Gilvarg et al. 1975a). While the polyA-Qβ RNA functioned normally as messenger for the synthesis of virus-specific proteins, it had lost its capacity to serve as template for the Qβ replicase. The template function was restored, however, by phosphorolysis with polynucleotide phosphorylase. It was concluded that a host enzyme, perhaps polynucleotide phosphorylase, removed part or all of the adenylate residues prior to replication of the RNA in vivo (Gilvarg et al. 1975b). The Qβ RNA was elongated also with a 3′-terminal oligoC tract (Mekler and Billeter 1975). Meanwhile, polyA sequences were added to the 3′-terminus of the Qβ RNA by ATP:RNA adenylyltransferase from E. coli by Fiers’ team (Devos et al. 1976c). By tail lengths not exceeding 200 nucleotide residues, the physical properties of Qβ-RNA-polyA were only slightly different from those of the original RNA, but almost complete abolishment of template activity, even by short oligoA stretches, was found, in agreement with the conclusions of Weissmann’ team.
Biosynthesis and Genetics of Lipopolysaccharide Core
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
David E. Heinrichs, Chris Whitfield, Miguel A. Valvano
Recently, Valvano et al. (51) cloned the rfaE homolog from E. coli. This gene is part of an operon that includes glnE and orfXE of unknown function (52). glnE encodes the adenylyltransferase involved in the postranscriptional regulation of glutamine synthase, a central enzyme for nitrogen assimilation, although glnE itself is not regulated by nitrogen levels (52). It is intriguing but unclear why genes involved in LPS synthesis and nitrogen assimilation form an operon. rfaE encodes a 55-kDa protein of which the C-terminal 190 amino acids have strong similarities to the cytidylyltransferase superfamily, including the enzyme glycerol-3-phosphate cytidylyltransferase from Bacillus subtilis (TagD) and other enzymes with ADP transferase activity (53). The most conserved region in this superfamily resembles the ATP-binding HiGH (His-Ile-Gly-His) motif of class I aminoacyl-tRNA synthases. A BLASTP search using the E. coli RfaE C-terminal domain reveals strong similarities with Aut, a small protein identified in Ralstonia (Alcaligenes) eutrophus (54). An aut::Tn5 mutant is defective in autotrophic growth, but the phenotype includes morphological changes in the colony appearance. Valvano et al (51) showed that the aut::Tn5 mutant, unlike the wild-type strain, cannot grow in the presence of novobiocin and produces an LPS with an electrophoretic mobility in SDS-PAGE typical of heptose-deficient LPS. More importantly, the aut phenotypes are rescued with the E. coli rfaE. Collectively, these results strongly suggest that the aut homologs encode ADP-heptose synthases.
A study of inhibitors of d -glycero-β-d -manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei as a potential antibiotic target
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Suwon Kim, Seri Jo, Mi-Sun Kim, Dong Hae Shin
The carbohydrate ADP‐l‐glycero‐β‐d‐manno‐heptose (ADP‐l‐β‐d‐heptose) is a substantial precursor of the inner core oligosaccharide part and is synthesised through the ADP‐l‐β‐d‐heptose biosynthesis pathway, which includes five enzymes14. d‐Glycero‐β‐d‐manno‐heptose‐1‐phosphate adenylyltransferase (HldC) is the fourth enzyme in the biosynthesis pathway. In many bacterial species, the enzymatic function of HldC is achieved by a bifunctional enzyme HldE composed of ATP-dependent kinase and adenylyltransferase domains. The former acts in step 2 and the latter in step 4 of the biosynthesis pathway13. However, in B. pseudomallei, Neisseria meningitidis, N. gonorrhoeae, etc., the two domains of the HldE protein are encoded by separate genes, hldA (kinase) and hldC (adenylyltransferase)15. Since the blockage of the HldC catalytic activity prevents the biosynthesis of heptoses of the inner core oligosaccharide of LPS, it can be a potential antibiotic target13. Thus, we screened chemical compounds for inhibitors and tried to deduce their essential structural properties to bind with inhibitors.
New targets and therapeutics for neuroprotection, remyelination and repair in multiple sclerosis
Published in Expert Opinion on Investigational Drugs, 2020
Pablo Villoslada, Lawrence Steinman
In the past 5 years, impressive advances have been made in understanding the biology of axon damage, which is critical to develop effective therapies preventing axon loss [9]. After damage or transection, axons trigger an active degenerative process regulated by levels of nicotinamide adenine dinucleotide (NAD). This process is regulated by several key molecules that influence NAD levels, such as nicotinamide nucleotide adenylyltransferase 2 (NMNAT2), sterile alpha and TIR motif containing 1 (Sarm1), and phosphate starvation response 1 (PHR1) [87]. Downstream in the axon degeneration pathway, attempts to achieve neuroprotection have focused on targeting c-Jun N-terminal kinases (JNK), receptor-interacting serine/threonine-protein kinase 1(RIPK1), dual leucine zipper kinase (DLK, also known as MAP3K12), Serum Glucocorticoid Kinase (SGK), glycogen synthase kinase 3 (GSK3b) and the inhibitor of kappa B kinase (IKK). These kinases converge in the mitochondria and on calpain activation, leading to a calcium imbalance and cell death [88,89]. Therefore, several attempts have been made to develop neuroprotective agents that target several kinases in this pathway, such as Sarm1, DLK, RIPK1, SGK and JNK (Table 1) [90–94].
Influence of short-term changes in dietary sulfur on the relative abundances of intestinal sulfate-reducing bacteria
Published in Gut Microbes, 2019
Allison Dostal Webster, Christopher Staley, Matthew J. Hamilton, Merry Huang, Kathryn Fryxell, Raymond Erickson, Amanda J. Kabage, Michael J. Sadowsky, Alexander Khoruts
To assess the functional capacity for sulfate reduction among individual participants, the relative abundances of sulfate adenylyltransferase (EC 2.7.7.4) and adenylylsulfate reductase (EC 1.8.99.2) were specifically investigated among individual participants. While the relative abundance of sulfate adenylyltransferase was significantly greater in participant 02 (post-hoc P ≤ 0.020) than all other participants, no other significant differences among individuals or dietary arm were noted, and other genes known to be involved in dissimilatory sulfate reduction could not be identified. Ordination of gene abundances by Bray-Curtis dissimilarity showed some overlap in functional capacity among individuals, with statistically similar distributions of functional genes between Subjects 01 and 02, 02 and 03, and 03 and 04 (P ≥ 0.044, Bonferroni-corrected α = 0.008).