China
Africa
Explore chapters and articles related to this topic
The Role of Conjugating Enzymes in the Biliary Excretion of Bilirubin
Published in Karel P. M. Heirwegh, Stanley B. Brown, Bilirubin, 1982
In 1938 Gunn described a mutant strain of Wistar rats which exhibit hereditary hyperbilirubinemia,53 the defect is inherited as an autosomal recessive character. Malloy and Loewenstein showed that the jaundice of these rats was due to an inability to convert “indirect” (unconjugated) bilirubin to “direct” (conjugated) bilirubin and thus to excrete bilirubin in bile.54 Following the identification of the biliary pigment as bilirubin glucuronide it was quickly established that the jaundice of the Gunn rat was due to a deficiency of bilirubin UDP-glucuronyltransferase in the liver, kidney, and gastrointestinal tract.55,56 It was later shown that glucosyl- and xylosyltransferase activities were also deficient.34 All other liver function tests and liver histology are normal. Schmid and colleagues showed that these animals were able to excrete conjugated bilirubin normally and that nonjaundiced litter mates of icteric rats had a reduced ability to form glucuronides with o-aminobenzoate and menthol but the defect is less severe.57 The ability of the Gunn rat to glucuronidate other substances is reduced in some, but not all instances, the extent of the defect being partially dependent on the genetic background of the Gunn rat. Many studies55–57 have reported extensive defects in the conjugation of o-aminophenol which can be partially corrected in vitro by diethylnitrosa-mine58 and alkyl ketones.59 It has been suggested that the conjugating defect in the Gunn rat with respect to bilirubin was related to the fact that it forms an acyl rather than an ethereal glucuronide. This is unlikely as Javitt60 has been able to demonstrate that the biliary excretion rates of phenoldibromphthalein and diphenylacetic acid, which forms ethereal and acyl glucuronides, respectively, are similar.
Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes
Published in Experimental Lung Research, 2018
Xiao Na Ge, Idil Bastan, Sung Gil Ha, Yana G. Greenberg, Jeffrey D. Esko, Savita P. Rao, P. Sriramarao
HSPGs play a multifunctional role in inflammation largely due to their highly diverse HS chains that interact with a variety of ligands, including pro-inflammatory mediators such as cytokines, chemokines and growth factors.10,11 Increased HSPG deposition has been noted in patients with asthma4,5 and in experimental models of allergic asthma5,6 correlating with disease severity. HS chains of HSPGs can be highly heterogeneous with respect to length as well as the degree and pattern of sulfation, which are critical determinants of ligand binding and functional role during inflammation.12,34 In the current study, we found that expression of Hs2st (mRNA and protein) is decreased in WT mice after exposure to Alternaria alternata, while expression of Ndst1 was unaltered. Expression levels of HSPG biosynthetic enzymes are known to be altered during inflammatory conditions. For example, inflammatory cytokines such as IFNγ and TNFα can induce Ndst1 expression in endothelial cells increasing sulfation of HS along with a corresponding increase in sequestration of RANTES at the apical surface of endothelial cells and leukocyte chemotaxis.26 In the context of AAI, previous studies have shown that expression of xylosyltransferase-1, β1,3-glucuronosyltransferase-1, chondroitin-4, and chondroitin-6 sulfotransferase genes is increased in OVA-challenged rats.5
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
Isolation of occidiofungin from a xylosyltransferase mutant strain demonstrated that the presence of the xylose on the NAA was not important for antifungal activity against Candida spp [85]. Interestingly, the biosynthetic gene cluster for occidiofungin contains two thioesterases [86]. One is an independently expressed thioesterase named OcfN, and the other is a C-terminal TE domain of the OcfD NRPS. The presence of both thioesterases expanded the conformational variants of occidiofungin and presumably OcfN has evolved to be part of the biosynthetic gene cluster due to its ability to produce structural variants that enhance antifungal activity against some fungi.
The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity
Published in mAbs, 2018
Natasha A. Pereira, Kah Fai Chan, Pao Chun Lin, Zhiwei Song
In addition to CHO cells, alternative expression platforms such as plants have also been reported for production of recombinant antibodies.90 Unlike CHO cells, glycoproteins produced from plants lack α1,6-fucose, β1,4-galactose and α2,3-sialic acid. Plant N-glycans typically contains a Man3GlcNAc2 core modified with β1,2-xylose and α1,3-fucose. Large complex type N-glycans with mammalian Lea structure containing α1,4-fucose and β1,3-galactose residues were sometimes observed.91 Antibody N-glycans produced in plants are predominantly GnGnXF3 structures containing the unwanted residues β1,2-xylose and core α1,3-fucose.92,93 These sugars are immunogenic to humans, and serum antibodies against core xylose and core α1,3-fucose have been detected in healthy human blood donors.94 Strategies to overcome this immunogenicity include use of RNAi knockdown of α1,3-fucosyltransferase (FucT) and β1,2-xylosyltransferase (XylT) in plants95,96 and FucT/XylT-knockout lines.97,98 An afucosylated anti-CD30 monoclonal antibody with G0 structure was produced using glycoengineered aquatic plant Lemna minor and shown to have improved ADCC over the same CHO cell-produced antibody.95 Anti-HIV 2G12 produced in XylT/FucT-knockdown N. benthamiana was found to be homogeneous G0 structures with terminal N-acetylglucosamine and lacking both xylose and α1,3-fucose residues.96 Further glycoengineering in XylT/FucT knockdown N. benthamiana by expressing a modified human β1,4-galactosyltransferase was reported to produce anti-HIV monoclonal antibodies with fully β1,4-galactosylated N-glycans and improved virus neutralization potency.99