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The Use of Tracers in Transport Studies
Published in Joan Gil, Models of Lung Disease, 2020
Maya Simionescu, Nicolae Ghinea
This is a polymannose glycoprotein that has been widely used as a tracer because of its high peroxidatic activity. It contains at least seven major isoenzymes, all having ferric protoporphyrin IX as the prosthetic group with the nitrogen atom of a histidine residue as the proximal ligand. These various isoenzymes have different pIs (Tables 2–4) due to differences in the number of arginine residues; the acidic pI is characterisitic for the isoenzymes with lowest content of arginine (Shannon et al., 1966). The main isoenzyme, horseradish peroxidase-C (HRP-C), has a molecular weight of 44 kD and consists of 308 amino acid residues and 8 neutral carbohydrate side chains (Welinder, 1979) containing mannose, mannosamine, galactosamine, fucose, and xylose (Shannon et al., 1966). By chemical modifications, anionic and cationic derivatives of HRP have been produced (Rennke and Venkatachalam, 1979).
Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
N-acetyl-D-neuraminic acid (NeuAc; sialic acid) that can mediate or modulate a wide variety of physiological and pathological processes (Varki, 2008; Tao et al., 2010) is the precursor of a variety of drugs (e.g., for treatment of rheumatoid arthritis, septic shock, gastric ulcers, and other diseases). Several (chemo)enzymatic routes for the two-step synthesis of NeuAc have been described. The first step is the alkali-orN-acetyl-D-glucosamine(GlcNAc)-epimerase-catalyzed epimerization of GlcNAc to N-acetyl-D-mannosamine (ManNAc), followed by the production of Neu5Ac from ManNAc in presence of N-acetyl-D-neuraminic acid aldolase (opposite scheme). For this purpose, Lee et al. (2007) cloned and expressed genes from Anabaena sp. (GlcNAc-epimerase) and Escherichia coli (Neu5Ac aldolase) in E. coli BL21 (DE3); with the transformed E. coli cells that could be reused for more than 8 cycles a maximal productivity of 10.2 g NeuAc L−1∙h−1 was achieved. Gao et al. (2011; see also literature cited therein) used spore surface-displayed Neu5Ac aldolase (spores of B. subtilis, also reusable and an alternative to Neu5Ac aldolase immobilization); the productivity of this process was 4.9 g NeuAc L−1∙h−1.
The Development of Improved Therapeutics through a Glycan- “Designer” Approach
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The knowledge about glycan receptors allows a design of a tailored conjugate. An example here would be peptide with mannose glycan capable of binding to mannose-binding lectin (MBL) and leading to activation of complement system, macrophages, and dendritic cells. Conjugation of peptides or proteins with mannose is a very simple process and requires C-2 epimer of glucose as a substrate or a d-mannosamine. C-mannosylation consist of a unique C-C bond linking C1 of Man to C2 of the indole ring of tryptophan and its post-translational modification found in mammalian cells.
A glyco-engineering approach for site-specific conjugation to Fab glycans
Published in mAbs, 2023
Maria L. Jaramillo, Traian Sulea, Yves Durocher, Mauro Acchione, Melissa J. Schur, Anna Robotham, John F. Kelly, Marie-France Goneau, Alma Robert, Yuneivy Cepero-Donates, Michel Gilbert
N-azidoacetyl-D-mannosamine (ManNAz) was obtained from Sussex Research Laboratories. The synthesis of N-azidoacetylneuraminic acid (Neu5NAz) was performed using a recombinant form of the Pm1715 sialic acid aldolase from Pasteurella multocida. The reaction mix with the Pm1715 sialic acid aldolase included 20 mM ManNAz, 100 mM sodium pyruvate and 100 mM Tris pH 8.6, and was incubated at 37°C for 18 h. The CMP-Neu5NAz was obtained by adding a recombinant form of the CMP-NeuAc synthetase from Campylobacter jejuni as well as 13 mM CTP (1:1 ratio in the diluted reaction) and 63 mM MgCl2. The reaction was performed at 37°C for 1.5 h and the enzymes were removed by running the reaction mix on an Amicon Ultra-15 centrifugal filter unit with a 10,000 nominal molecular weight limit (NMWL). The filtrate was diluted 30-fold with water and applied to a 5 mL HiTrapQ HP column (7 runs total). The column was developed with a gradient of 0 to 0.25 M NH4HCO3 and the fractions containing CMP-Neu5NAz were identified by capillary electrophoresis analysis using a P/ACE MDQ system (Beckman Coulter) equipped with a diode array detector (electropherogram acquired at 271 nm). Capillaries were bare silica 50 µm × 60.2 cm with a detector at 50 cm, the running buffer was 25 mM sodium tetraborate, pH 9.4 and separations were performed at 27 kV for 30 min.
Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs
Published in Expert Opinion on Drug Delivery, 2018
Renuka Suresh Managuli, Sushil Yadaorao Raut, Meka Sreenivasa Reddy, Srinivas Mutalik
Singodia et al. [103] compared the MR targeting efficiency of O-palmitoyl mannose and 4-sulfated N-acetyl galactosamine (4-SO4GalNAc). It was observed that 4-SO4GalNAc coated liposomes showed enhanced uptake which could be attributed to strong hydrogen bonding with cysteine group of MR present on macrophage due to strong anionic charge of sulfate group. 4-SO4GalNAc forms eight hydrogen bond (six bond with sulfate group and two with N-acetyl galactosamine), in comparison to four hydrogen bond of mannose with C-type lectins of Mrs. Youngren et al., 2013 [104] fabricated selenium loaded mannosamine coated liposomes which showed increased uptake through M cells in Peyer’s patches due to interaction with MRs facilitated by positively charged mucoadhesive nature of mannosamine. MR is a specific target to mannosylated rather than glycosylated particles which is shown in a study by De Coen et al. [105]. Glycosylated nanogels were prepared by De Coen by cross-linking acetylated glycosylated block copolymer and pentafluorophenyl, whereas mannosylated nanogels were prepared by cross-linking acetylated mannosylethyl acrylamide and pentafluorophenyl. It was observed that mannosylated but not glycosylated nanogels efficiently target MR expressed on primary dendritic cell surface.
Carbohydrates great and small, from dietary fiber to sialic acids: How glycans influence the gut microbiome and affect human health
Published in Gut Microbes, 2021
Joanna K Coker, Oriane Moyne, Dmitry A. Rodionov, Karsten Zengler
In contrast to studies of infants and dietary sialic acids, where studies focus on microbiome composition but often do not address direct health impacts, studies of adults and dietary sialic acids focus mainly on health impacts and rarely assess microbiome composition. The ubiquity of sialic acids in mammalian glycoconjugates gives them a role in many physiological and pathological processes, from brain development to immune regulation, infections, heart disease, and diabetes.71 Many of these pathological processes have been associated with hypo-sialylation, or low Neu5Ac levels, of relevant molecules. Several studies have therefore looked at the effect of exogenous Neu5Ac-feeding on disease development and progression. Neu5Ac-feeding in apoE−/ – mice (a model of atherosclerosis through knockout of ApoE, a protein heavily involved in lipid circulation and metabolism)142 reduced atherosclerosis plaque area, as well as lipid liver deposition, triglyceride and cholesterol levels, and expression of inflammatory cytokines and intracellular adhesion factors in aorta endothelial cells and liver cells.92 In a different study, oral supplementation of the Neu5Ac precursor N-acetyl-D-mannosamine in mice on a high-fat diet (to study type II diabetes) resulted in a restoration of IgG sialylation and preserved insulin sensitivity.143 The mechanism of action in these studies is unknown and changes in the microbiome were not investigated in either case. However, given the established connections between the gut microbiome and atherosclerosis and diabetes144–146 and the impact sialic acids can have on the microbiome, an investigation of gut microbiome composition in response to Neu5Ac in these disease models would be intriguing.