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Replicase
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Moreover, Takeshita et al. (2012) solved the problem of the template-independent 3′-adenylation activity, which was required for the efficient viral RNA amplification in the host cells. They determined the structure of a complex that included Qβ replicase, a template RNA, a growing RNA complementary to the template RNA, and ATP. The structure represented the terminal stage of RNA polymerization and revealed that the shape and size of the nucleotide-binding pocket became available for ATP accommodation after the 3′-penultimate template-dependent C-addition (Takeshita et al. 2012).
Consideration of Glutamine Synthetase as a Multifunctional Protein
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
The summation of binding sites for metals, substrates, and feedback inhibitors seems extraordinarily large for each 50,000 dalton subunit. Then, in addition, the presence of the AMP modification site adds a dimension not seen with many other proteins. Within the framework of considering glutamine synthetase as a multifunctional protein, the adenylylation process is of particular interest. During the adenylylation and deadenylylation process, glutamine synthetase is, in essence, serving as a substrate for another enzyme reaction. The modification process in turn has a large effect on the conformation of glutamine synthetase and changes the binding of many other effectors. In this regard, glutamine synthetase binds and responds to several effectors, has its own important catalytic activity, and has a site that serves as a substrate for the adenyl transferase enzyme. These aspects alone make glutamine synthetase a complicated multifaceted enzyme, but in addition to these features is the consideration of whether glutamine synthetase can function as a regulator of protein synthesis.
Gentamicin
Published in 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, Kucers’ The Use of Antibiotics, 2017
Jesús Sojo-Dorado, Jesús Rodríguez-Baño
Adenylylation may be caused by at least five adenylyltransferases, designated ANT-2″, ANT-3′, ANT-4′, ANT-6, and ANT-9. ANT-4′ is further subdivided into two types. ANT-2″ can modify gentamicin and ANT-4′ can modify amikacin.
Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders
Published in Expert Opinion on Biological Therapy, 2022
Lara Marrone, Paolo M. Marchi, Mimoun Azzouz
Unfortunately, the characteristic small size of AAVs has limited the application of these vectors in the context of gene replacement therapy. Recombinant AAVs for gene therapy maintain their ITRs while being deprived of the core viral rep-cap genes, which are replaced by (i) a promoter, (ii) the therapeutic transgene sequence, and (iii) a poly-adenylation signal (Figure 1(a), right) [20]. This means that genes with coding sequences exceeding ~4 kb represent an oversized cargo for AAV vectors. Importantly, a number of monogenic diseases, including several disorders of the nervous system, would be excluded from the benefits of gene replacement therapy based on this limitation. Therefore, several strategies have been aimed at modifying oversized transgenes in order to adapt them to AAV-mediated delivery. Here, we review these different approaches and explore emerging alternatives. We additionally highlight the challenges linked to targeting the unique microenvironment of the nervous system, and provide insights into the research efforts currently directed at treating a number of neurological disorders via these methods.
Drug discovery through the isolation of natural products from Burkholderia
Published in Expert Opinion on Drug Discovery, 2021
Adam Foxfire, Andrew Riley Buhrow, Ravi S. Orugunty, Leif Smith
The biosynthetic gene cluster for production of Orn is well characterized [15]. Orn production is regulated by environmental iron concentration (Fur regulon) with optimal production reached at 4 µM environmental ferric iron, and production is generally negligible at concentrations above 15 µM. Additionally, growing Orn-producing strains in iron-rich media prevented later uptake of Orn by the strain [25]. Ornithine seems to be the limiting factor of Orn synthesis, and as such supplementation of media with 20 mM ornithine increases Orn synthesis by 2.5-fold. Although a putrescine (decarboxylated ornithine) residue is present in the final structure of Orn, supplementation of media with putrescine did not increase Orn synthesis. Whereas, supplementation of media with ornithine, arginine, and proline did increase the synthesis of Orn [25]. Interestingly, malleobactin (Figure 1(e)) biosynthesis is related to the biosynthetic pathway of Orn. Franke et al. [45] were able to reconstruct the biosynthesis of Orn from the malleobactin biosynthetic gene cluster by substitution of an adenylation domain of the Orn nonribosomal peptide synthetase (NRPS) into the related malleobactin NRPS.
Methodological considerations for measuring biofluid-based microRNA biomarkers
Published in Critical Reviews in Toxicology, 2021
Brian N. Chorley, Elnaz Atabakhsh, Graeme Doran, Jean-Charles Gautier, Heidrun Ellinger-Ziegelbauer, David Jackson, Tatiana Sharapova, Peter S.T. Yuen, Rachel J. Church, Philippe Couttet, Roland Froetschl, James McDuffie, Victor Martinez, Parimal Pande, Lauren Peel, Conor Rafferty, Frank J. Simutis, Alison H. Harrill
Another advantage of sequencing is the ability to detect modifications of the canonical sequence of miRNAs. As discussed previously, some of these detected sequence changes are due to technical sequencing errors; however, some have been consistently identified and validated by other methods (Morin et al. 2008; Neilsen et al. 2012; Gomes et al. 2013). Biologically, the existence of directed modification, such as adenylation or uridylation at the 3′ of some microRNAs, suggests that this region may be a focal point of regulation (Rissland et al. 2007; Menezes et al. 2018). In addition, isomiRs may be a result of differential cleavage of precursor miRNAs (Seitz et al. 2008; Hu et al. 2009). The endogenous biological functions of most isomiRs have proven elusive to date despite some evidence of regulatory roles (Cloonan et al. 2011). Most isomiR variants occur at the 3′ of the miRNA sequences, with templated and non-templated additions common (Wang et al. 2016; Wu et al. 2018). 5′ variants are predicted to change the miRNA seed and therefore may have significant influence on miRNA specificity (e.g. mammalian miR-142-3p, miR-101-5p, or mmu-miR-223-3p), whereas some 3′ variants may modulate miRNA stability or subcellular location (Telakivi and Flink 1985). Not surprisingly, 5′ isomiR variants are significantly less common than 3′ variants in most sequencing datasets (Wang et al. 2016) if it is speculated that these seed alterations may have greater biological impact.