Abstract
Transglutaminases (TGases) are Ca2+-dependent enzymes capable of catalysing transamidation of glutamine residues to form intermolecular isopeptide bonds. Nine distinct TGases have been described in mammals, and two of them (types 2 and 3) are regulated by GTP/ATP. TGase2 hydrolyses GTP and is therefore a bifunctional enzyme. In the present study, we report that TGase5 is also regulated by nucleotides. We have identified the putative TGase5 GTP-binding pocket by comparative amino acid sequence alignment and homology-derived three-dimensional modelling. GTP and ATP inhibit TGase5 cross-linking activity in vitro, and Ca2+ is capable of completely reversing this inhibition. In addition, TGase5 mRNA is not restricted to epidermal tissue, but is also present in different adult and foetal tissues, suggesting a role for TGase5 outside the epidermis. These results reveal the reciprocal actions of Ca2+ and nucleotides with respect to TGase5 activity. Taken together, these results indicate that TGases are a complex family of enzymes regulated by calcium, with at least three of them, namely TGase2, TGase3 and TGase5, also being regulated by ATP and GTP.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / pharmacology
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Adenosine Triphosphate / physiology*
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Amino Acid Sequence
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Aminoacyltransferases / antagonists & inhibitors
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Animals
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Binding Sites
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Calcium / physiology
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Calcium-Binding Proteins / antagonists & inhibitors
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Cell Line
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Enzyme Activation / physiology
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GTP Phosphohydrolases / metabolism
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GTP-Binding Proteins / antagonists & inhibitors
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GTP-Binding Proteins / metabolism
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Guanosine Triphosphate / metabolism
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Guanosine Triphosphate / pharmacology
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Guanosine Triphosphate / physiology*
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Guinea Pigs
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Humans
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Keratinocytes / enzymology
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Models, Molecular
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Molecular Sequence Data
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Protein Glutamine gamma Glutamyltransferase 2
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Sequence Alignment / methods
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Transglutaminases / antagonists & inhibitors
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Transglutaminases / biosynthesis
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Transglutaminases / chemistry
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Transglutaminases / metabolism
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Transglutaminases / physiology*
Substances
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Calcium-Binding Proteins
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Guanosine Triphosphate
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Adenosine Triphosphate
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Aminoacyltransferases
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transamidases
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transglutaminase 5
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Protein Glutamine gamma Glutamyltransferase 2
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TGM3 protein, human
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Transglutaminases
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GTP Phosphohydrolases
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GTP-Binding Proteins
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Calcium