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Transglutaminases
Published in Elling Kvamme, Glutamine and Glutamate in Mammals, 1988
The designation “transglutaminase” was first used by Waelsch and co-workers in 1959.10 They described a Ca2+-dependent transamidation reaction followed by ammonia liberation and incorporation of amines such as histamine or putrescine into proteins (e.g., casein) in the guinea pig liver and other tissues.
Proteases as Biocatalysts for the Synthesis of Model Peptides
Published in Willi Kullmann, Enzymatic Peptide Synthesis, 1987
In the 1950s a series of studies were performed, in particular by Fruton and his collaborators, which dealt with enzymatic peptide synthesis via transamidation. (Studies on this topic are discussed in detail in Reference 4). However, those investigations were stimulated more by the idea of a possible participation of proteases in the pathway of protein biosynthesis rather than by any intention to synthesize peptides on a preparative scale. Certainly, this was neither the primary aim of Wieland, Determann, and co-workers when in the 1960s they tried to elucidate the molecular mechanisms of the plastein reaction (vide infra, Chapter 9).
Clinical development of an anti-GPC-1 antibody for the treatment of cancer
Published in Expert Opinion on Biological Therapy, 2022
Saikat Ghosh, Pie Huda, Nicholas Fletcher, Douglas Campbell, Kristofer J. Thurecht, Bradley Walsh
Proteoglycans are composed of glycosylated proteins with covalently attached glycosaminoglycan (GAG) chains [1]. In 1990, David et al. reported their seminal investigation of a novel membrane-associated proteoglycan present in human lung fibroblasts [2]. The cDNA of the proteoglycan was cloned and sequenced by the research group and the core protein was found to contain short hydrophobic amino acid sequences at its C-terminus without a proper cytoplasmic domain. Both these features were reminiscent of membrane-bound phosphatidylinositol-anchored proteins. At the time, the process of phospholipid anchoring through an enzyme-catalyzed transamidation reaction was known as glypiation. This led to proposal of the name ‘Glypican’ by David et al. for the newly discovered ‘glypiated proteoglycan.’
Transglutaminase 2 as a therapeutic target for neurological conditions
Published in Expert Opinion on Therapeutic Targets, 2021
Jeffrey W. Keillor, Gail V.W. Johnson
TG2 is one of nine human transglutaminases, eight of which are catalytically active. As a calcium-activated transamidase, TG2 catalyzes the deamidation or transamidation of acyl-donor glutamine substrates [23], via acyl-transfer mechanisms resembling those of the cysteine proteases [24]. Deamidation results in the hydrolysis of substrate glutamine residues to glutamate residues (Figure 1A). Transamidation results in either the incorporation of small biological amines into the protein (Figure 1B), or the crosslinking of proteins, if the acyl-acceptor substrate is the ε-amino group of a peptide bound lysine (Figure 1C) [23]. In addition to calcium, GTP [25] and the redox state [26] of TG2 also play roles in determining its activity as a transamidase. Both oxidation and GTP binding result in inhibition of TG2 transamidase activity [25,26].
Emerging PEGylated non-biologic drugs
Published in Expert Opinion on Emerging Drugs, 2019
Eun Ji Park, Jiyoung Choi, Kang Choon Lee, Dong Hee Na
The number of the attached PEG molecules and the PEGylation sites are also major factors in the formation of heterogeneous conjugates [50–52]. However, these problems could be solved in small non-biologic drugs through site-specific PEGylation. In peptides, a common approach to site-specific PEGylation is to target thiol group of free cysteine inserted into the desired position which does not interfere with biological activity [53]. The thiol-specific PEGylation is performed by using thiol-reactive PEGs activated with maleimides, pyridyl disulfide, vinyl sulfone, and iodoacetamide [54]. Another popular approach is the targeting of the N-terminal amine by using aldehyde-activated PEG, based on the difference in reactivity between the N-terminal α-amine (pKa = 7.6–8.0) and the ε-amine of the Lys residue (pKa = 10.0–10.2) [55–57]. This approach was successfully applied for the development of pegfilgrastim (Neulasta®), a PEGylated version of recombinant methionyl human granulocyte colony-stimulating factor [58,59]. Recently, new advances in site-specific PEGylation have been achieved by the use of enzymes such as microbial transglutaminase, which catalyzes transamidation reactions of a protein substrate leading to a modification of the side chains of glutamine and lysine residues [60]. The site-specific PEGylation approaches used in proteins can be applied to the peptide molecules [21].