Structures of Human Transglutaminase 2: Finding Clues for Interference in Cross-linking Mediated Activity

Abstract

Human transglutaminase 2 (TGase2) has various functions, including roles in various cellular processes such as apoptosis, development, differentiation, wound healing, and angiogenesis, and is linked to many diseases such as cancer. Although TGase2 has been considered an optimized drug target for the treatment of cancer, fibrosis, and neurodegenerative disorders, it has been difficult to generate TGase2-targeted drugs for clinical use because of the relatively flat and broad active site on TGase2. To design more specific and powerful inhibitors, detailed structural information about TGase2 complexed with various effector and inhibitor molecules is required. In this review, we summarized the current structural studies on TGase2, which will aid in designing drugs that can overcome the aforementioned limitations.

Proteomic profiling of epicardial fat in heart failure with preserved versus reduced and mildly reduced ejection fraction

“…In our study, TGM2 expressions are both down‐regulated in EAT and plasma levels of HFrEF/HFmrEF patients compared with HFpEF patients. Due to the function of apoptosis that keeping the integrity of the dying cells before cleared, down‐expression of TGM2 in HFrEF/HFmrEF patients may prevent the wastage of harmful intracellular components both by catalysing the cross‐linking of cytoskeletal proteins resulting in condensation of the cytoplasm and by mediating cross‐linking proteins of the extracellular matrix resulting in the irreversible formation of scaffolds 35 . Thereafter, down‐regulated TGM2 indicates worsen outcome in HF with reduced ejection fraction.…”

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

“…As mentioned above, with the exception of protein 4.2, all TGs catalyze a calcium-dependent crosslinking reaction that starts with a nucleophilic attack, by the thiol of the active cysteine, of a γ-carboxamide group of a glutamine residue forming a thioester intermediate with ammonia release (Figure 1B). Then, this intermediate reacts via the nucleophilic attack of an acyl acceptor (the ε-amino group of a lysine residue) leading to the formation of a covalent and degradationresistant intra-or inter-molecular ε-(γ-glutamyl)lysine isopeptide bond [38,42]. A similar reaction also occurs with a large number of amine donors, including naturally occurring di-and polyamines such as putrescine (PUT), spermidine (SPD), and spermine (SPM), leading to the formation of either N-mono(γ-glutamyl)-or N,N-bis(γ-glutamyl)-PUT, -SPD, or -SPM [43].…”

Transglutaminase 2 in diabetes mellitus: Unraveling its multifaceted role and therapeutic implications for vascular complications

“…In addition to Ca 2+ and nucleotides, the transamidase activity of TGase2 is subject to regulation by amine compounds, nitric oxide, and thiol compounds ( Table 1 ) 11 , 14 . Amine compounds, such as putrescine, monodansylcadaverine (MDC), 5-(biotinamido)pentylamine (BAPA), spermidine, and histamine, act as amine donors to inhibit transamidase activity by competing with natural substrates 17 , 37 , 38 . Nitric oxide also inhibits the transamidase activity through S-nitrosylation of the cysteine residue in the active site 39 .…”