The ɛ-(γ-Glutamyl)Lysine Crosslink and the Catalytic Role of Transglutaminases

Folk, J.E.; Finlayson, J. S.

doi:10.1016/s0065-3233(08)60217-x

Cited by 826 publications

(453 citation statements)

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“…Transglutaminase (Tgase) activity was evaluated using 20 µg of total proteins incubated at 37°C for 30 min in 125mM Tris pH 8, 2.5mM CaCl 2 , 10mM DTT, 200µg dimethylcasein and 2.25µCi [ 3 H] spermidine. After trichloroacetic acid-precipitation of proteins, Tgase specific activity was measured by counting radioactivity and is expressed as nmol of incorporated spermidine/h/mg of protein (Folk and Finlayson, 1977). Statistical analysis was performed by the GraphPad Prism Software using the one-way ANOVA with Bonferroni comparison and Student t-test.…”

Section: Tgm2 Mutagenesis Transfection and Assessment Of Transglutammentioning

confidence: 99%

Missense mutations in theTGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes

et al. 2007

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Transglutaminase 2 (TG2 or TGM2) is a multi-functional enzyme which catalyzes transamidation reactions or acts as a G-protein in intracellular signalling. Tgm2 -/-Mice lacking TG2 activity are glucose intolerant and show impairment of insulin secretion, suggesting an important physiological role for TG2 in the pancreatic β cell. We have previously described a TGM2 heterozygous missense mutation ((c.998A>G, p.N333S) in a 14 year-old patient with insulin-treated diabetes and in his diabetic father. The aim of this study was to further investigate the role of TG2 in early-onset type 2 diabetes. We analysed the TGM2 gene in 205 patients with clinically defined Maturity Onset Diabetes of the Young (MODY) or early-onset type 2 diabetes. We found two novel heterozygous mutations (c.989T>G, p.M330R; c.992T>A, p.I331N), which were not detected in 300 normoglycemic controls. All mutations were in residues which are located close to the catalytic site and impaired transamidating activity in vitro. Gene expression of TGM family genes and localization of TG2 in normal human pancreas indicated that TG2 is the only transglutaminase significantly expressed in human pancreatic islet cells. We conclude that reduced TG2 activity can contribute to disorders of glucose metabolism possibly via an impairment of insulin secretion. © 2007 Wiley-Liss, Inc. INTRODUCTIONTransglutaminase 2 (TG2; EC 2.3.2.13) is an ubiquitous enzyme with two well established, reciprocally regulated, activities: it cross-links proteins by virtue of its transamidating activity and acts as a G-protein in intracellular signalling (Griffin et al., 2002;Lorand and Graham, 2003). TG2 has been involved in several cellular processes such as cell adhesion and cell death, but its physiological role is still a matter of debate (Griffin et al., 2002;Lorand and Graham, 2003). In order to shed light on the function of TG2 in mammals, TG2 knock-out mice (Tgm2 -/-) have been generated (Bernassola et al., 2002;Nanda et al., 2001). Surprisingly, mice lacking TG2 activity do not show any major defects in apoptosis, but rather are glucose intolerant and show impairment of insulin secretion, suggesting a physiological role for TG2 in the pancreatic β cell (Bernassola et al., 2002). This is in keeping with previous studies showing that agents known to inhibit transglutaminase activity (e.g. monodansylcadaverine) can decrease glucose-stimulated insulin secretion from rat pancreatic islets in a dose-related manner (Sener et al., 1985, Bungay et al., 1986. In addition, we have described a TG2 heterozygous missense mutation p.N333S (c.998A>G) located in the TG2 catalytic site in a family clinically classified as maturity onset diabetes of the young (MODY; MIM# 606391) (Fig. 1A) (Bernassola et al., 2002). Thus, the aim of this study was to further investigate whether additional mutations in TG2 were also associated with early-onset type 2 diabetes (MIM# 125853). SUBJECTS AND METHODS Families with maturity onset diabetes of the young (MODY) or early onset type 2 diabetesWe studied the ...

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Section: Tgm2 Mutagenesis Transfection and Assessment Of Transglutammentioning

confidence: 99%

Missense mutations in theTGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes

et al. 2007

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“…Calcium ions play an important role in fibrin monomer aggregation [ 1,2] and fibrin stabilization by factor XIII [3] . They also partially protect fibrinogen against heat denaturation [4,5] .…”

Section: Introductionmentioning

confidence: 99%

Calcium‐binding properties of human fibrin(ogen) and degradation products

et al. 1979

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“…these enzymes have differences in substrate recognition, which must depend on different structures at a recognition subdomain at the active center (Fesus et al 1986). Comparison with recognition by proteinases have been searched to from the very early time, particularly in John E. Folk's lab at NIH, as summarized in 1977 in a well-known review by Folk and Fynlayson in Advances in Protein Chemistry (Folk and Fynlayson 1977;Gorman and Folk 1984), and has been confirmed thereafter by detection of the cysteine proteinase catalytic triad at the active site (Pedersen et al 1994) and by more recent comparison of properties of sequences targeted by transglutaminase and proteinases.…”

Section: The Years Of the Proteinmentioning

confidence: 99%