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RNA
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
When MS2 RNA was used as a substrate for the MazF interferase from Myxococcus xanthus, it was cleaved into two major bands of approximately 2.8 and 0.8 kb with many minor bands between them, suggesting that the MS2 RNA might contain a preferential cleavage site for the MazF, which was mapped (Nariya and Inouye 2008). The MazF activity to cleave the MS2 RNA was completely inhibited when it was preincubated with purified MazE, the antidote for the MazF (Yamaguchi et al. 2009). Working on the MazF homologs from Mycobacterium tuberculosis, Zhu et al. (2008) developed a new general method for the determination of the recognition sequences longer than three bases for the mRNA interferases with the use of the MS2 RNA as a substrate and CspA, an RNA chaperone, which prevented the formation of secondary structures in the RNA substrate. Using this method, it was found that pentad sequences, such as UU↓CCU, CU↓CCU, or U↓CGCU, were targets of the MazF homologs. Recently, tRNA was identified as a new target of one of the MazF homologs from M. tuberculosis (Schifano et al. 2016).
Asymmetric Reduction of C=N Bonds by Imine Reductases and Reductive Aminases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Matthias Höhne, Philipp Matzel, Martin Gand
Besides the identification of IREDs suitable for biocatalysis from natural resources, several protein engineering studies provided interesting enzymes useful for imine reduction and reductive amination. A few examples are listed below: The anchoring of Ir- and Ru metals via biotinylated pianostool ligands in the chiral environment of different streptavidin variants created artificial metallo enzymes with (R)- or (S)-selectivity for the production of the THIQ salsolidine (Dürrenberger et al., 2011). Formate is the hydrogen source in the catalyzed asymmetric transfer hydrogenation reactions. Further engineering studies of these hybrid catalysts are reviewed in Schrittwieser et al. (2015) and Schwizer et al. (2018).Starting with the opine dehydrogenase from Arthrobacter sp. 1C, extensive protein engineering changed the substrate spectrum to yield a reductive aminase variant for the synthesis of a tertiary amine, the antiarrhythmic drug vernakalant (Fig. 14.1). A variant carrying 29 substitutions was able to generate vernakalant with 80% de with complete conversion, if the amine is employed in 32-fold excess (Haibin et al., 2013; Schrittwieser et al., 2015).Substitution of six amino acids in the 2′-phosphate binding pocket inverted the cofactor specificity of the IRED from Myxococcus stipitatus from NADPH to NADH (Borlinghaus and Nestl, 2018).
Physiological and pathophysiological roles of hepoxilins and their analogs
Published in Drug Metabolism Reviews, 2023
Sara A. Helal, Fadumo Ahmed Isse, Samar H. Gerges, Ayman O. S. El-Kadi
There are several potential mechanisms for the action of 12 R-LOX/eLOX3 generated HXs, and these involve an action either via a putative membrane receptor called ichthyin or through the activation of peroxisome proliferator-activated receptors (PPARs). It is well known that PPARs are considered an important regulator in many processes in the skin including epidermal differentiation, proliferation, immune response, wound healing, and lipid metabolism. The expression levels of both PPARα and PPARγ are low in the skin compared to PPARδ levels but they are upregulated during the differentiation of keratinocytes (Hanley et al. 1998). HXs have been found to be an activator of PPARα due to their structural similarity to the known natural PPARα activator, 8S-HETE (Yu et al. 2007). In addition, HxB3, HxB4, HxD3, TrXB3, and TrXD3 produced by the prokaryote Myxococcus xanthus are identified to be PPARγ partial agonists and can increase its transcriptional activity (An et al. 2018). The formation of an activating ligand for PPARs by HXs is one possible mechanism of how the epidermal lipoxygenases 12 R-LOX and eLOX3 can play a pivotal role in epidermal differentiation.
Have marine natural product drug discovery efforts been productive and how can we improve their efficiency?
Published in Expert Opinion on Drug Discovery, 2019
In addition, HIV also exhibits high genetic variability, and thus develops resistance to existing drugs and escapes host immune responses elicited by AIDS vaccine candidates. In another example, the phenylspirodrimane stachybotrin D, Figure 4, isolated from the marine sponge-associated fungus Stachybotrys chartarum, showed inhibition against the HIV-1 virus, as well as showed similar inhibitory effects on HIV-1 replication of wild type and several NNRTI-resistant HIV-1 strains [15]. In addition, bengamide A (a seven-membered lactam), Figure 4, isolated from the marine sponge-associated bacterium Myxococcus virescens, inhibits HIV replication in vitro and in primary cells with EC50s of 15–32 nM [16]. Bengamide A acts by inhibiting the cellular NF-κB signaling pathway. The synthetic derivative of bengamide A (LAF389), Figure 4, was tested as an anti-cancer agent in phase I of the clinical trials, but the study was terminated due to cardiovascular and pulmonary toxicities [16].
Investigational drug therapies for coeliac disease – where to from here?
Published in Expert Opinion on Investigational Drugs, 2018
James Haridy, Diana Lewis, Evan D. Newnham
The long gliadin peptide exhibits strong resistance to breakdown by endogenous proteases, pepsin, and intestinal brush border peptidases. This is largely owing to the significant glutamine (Gln) and proline (Pro) content of gliadin, which remain stable with resistance exhibited despite contact with gastric, intestinal, and pancreatic proteases. Prolyl endopeptidases (PEPs), expressed in other mammals and microbes, effectively cleave and detoxify gluten particles in vivo [29]. Endogenous levels of PEPs expressed in humans are generally minimal and not sufficient for detoxifying gluten peptides. Recombinant PEPs derived from a number of microbes have been developed, with four reaching human trials to date including Latiglutenase, AnPEP, Caricain, and STAN1. Further, PEPs derived from Flavobacterium mengospticum and Myxococcus xanthus have been found to be capable of proline proteolytic activity, however are unable to function in the acidic pH of the stomach and duodenum [29].