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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
The study of the biosynthesis of Kdo was only made possible by the isolation of conditional mutants (16,23). Biochemical studies with these mutants were very important in providing direct evidence that LPS containing Kdo is essential for cell growth. The biosynthetic pathway of Kdo is shown in Figure 3 (24–26) and involves sequential reactions catalyzed by three enzymes: d-phosphoarabinose isomerase, Kdo-8-phosphate synthetase, and Kdo-8-phosphate phosphatase. Kdo is then convertd by a CMP-Kdo synthetase into cytidine-5′-monophosphate-Kdo (CMP-Kdo). The genes involved in Kdo biosynthesis in E. coli and Salmonella are not clustered. kdsA, encoding the Kdo-8-phosphate synthetase, maps at 27 min, and kdsB, encoding the CMP-Kdo synthetase, maps at 85 min. The gene for the phosphatase activity has not been identified. kdsA is located within a putative operon comprised of six open reading frames; the operon includes other genes not associated with LPS biosynthesis (27). kdsA is the last gene of this cluster and is transcribed from its own promoter. Experiments involving Northern blot analysis and operon fusions have shown that kdsA is subject to growth phase-dependent regulation at the transcriptional level with maximal expression achieved during early log phase (27). Protein sequence alignments of known Kdo-8-phosphate synthases with bacterial and fungal 3-deoxy-D-arabino-2-heptulosonate-7-phosphate synthases suggest that both classes of enzymes are structurally related and may belong to a family of 2-keto-3-deoxy-aldonic acid synthases (28). Intriguingly, a kdsA homolog has recently been cloned and sequenced from plant origin (W. Brabetz, personal communication). The plant homolog can functionally complement the KdsAts mutant of Salmonella, suggesting that Kdo-8-phosphate is synthesized in plants by an enzyme with structural and functional similarities to KdsA.
Galactosylated iron oxide nanoparticles for enhancing oral bioavailability of ceftriaxone
Published in Pharmaceutical Development and Technology, 2021
Muhammad Kawish, Tooba Jabri, Abdelbary Elhissi, Hina Zahid, Kanwal Muhammad Iqbal, Komal Rao, Jasra Gul, Muhammad Abdullah, Muhammad Raza Shah
Lactobionic acid (LBA) is an aldonic acid-derived through oxidation of lactose, showing potential as an excipient in food and pharmaceutical industries. The structure of LBA comprises of galactose moiety linked to gluconic acid via acetal linkage. LBA is a potential carrier for calcium supplements and is used to improve drug transport across biological barriers (Peshin and Kar 2017). The carboxylic moiety of LBA can interact with amine groups of proteins. Besides, the galactose moiety provides target specificity for hepatocellular carcinoma cells, offering enhanced anticancer effect (Craik and Malik 2013; Gerlach et al. 2013). Furthermore, galactose functionalized MNPs facilitates the delivery of hydrophobic drugs at the desired site of action (Liang et al. 2017). Despite the fact that galactose induces site-specificity against carcinoma cells, galactose moiety also exhibits the fastest absorption rate in the intestine, which is mediated through sodium-glucose linked transporter 1 (SGLT1), facilitates Na+-glucose co-transport (Cura and Carruthers 2011). The galactose moiety may give drugs an improved passage of intestinal transport through SGLT1 (Kaas and Craik 2010; Siu et al. 2018).