Transglutaminases catalyze the posttranslational modification of proteins by transamidation of available glutamine residues. This action results primarily in the formation of epsilon-(gamma-glutamyl)lysine cross-links but includes the incorporation of polyamines into suitable protein substrates as well. The covalent isopeptide crosslink is stable and resistant to proteolysis, thereby increasing the resistance of tissue to chemical, enzymatic, and mechanical disruption. The plasma transglutaminase, factor XIIIa, is formed at sites of blood coagulation and impedes blood loss by stabilizing the fibrin clot. The squamous epithelium constituting the protective callus layer of skin is formed by the action of keratinocyte transglutaminase (TGK) and epidermal transglutaminase (TGE). The tissue transglutaminase (TGC) is a cytoplasmic enzyme present in many cells including those in the blood vessel wall. TGC function is unknown, although it could function to stabilize intra- and extra-cellular molecules in a wide v...

Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues.

A specialized tissue type, the keratinizing epithelium, protects terrestrial mammals from water loss and noxious physical, chemical and mechanical insults. This barrier between the body and the environment is constantly maintained by reproduction of inner living epidermal keratinocytes which undergo a process of terminal differentiation and then migrate to the surface as interlocking layers of dead stratum corneum cells. These cells provide the bulwark of mechanical and chemical protection, and together with their intercellular lipid surroundings, confer water-impermeability. Much of this barrier function is provided by the cornified cell envelope (CE), an extremely tough protein/lipid polymer structure formed just below the cytoplasmic membrane and subsequently resides on the exterior of the dead cornified cells. It consists of two parts: a protein envelope and a lipid envelope. The protein envelope is thought to contribute to the biomechanical properties of the CE as a result of cross-linking of specialized CE structural proteins by both disulfide bonds and N(epsilon)-(gamma-glutamyl)lysine isopeptide bonds formed by transglutaminases. Some of the structural proteins involved include involucrin, loricrin, small proline rich proteins, keratin intermediate filaments, elafin, cystatin A, and desmosomal proteins. The lipid envelope is located on the exterior of and covalently attached by ester bonds to the protein envelope and consists of a monomolecular layer of omega-hydroxyceramides. These not only serve of provide a Teflon-like coating to the cell, but also interdigitate with the intercellular lipid lamellae perhaps in a Velcro-like fashion. In fact the CE is a common feature of all stratified squamous epithelia, although its precise composition, structure and barrier function requirements vary widely between epithelia. Recent work has shown that a number of diseases which display defective epidermal barrier function, generically known as ichthyoses, are the result of genetic defects of the synthesis of either CE proteins, the transglutaminase 1 cross-linking enzyme, or defective metabolism of skin lipids.

/pdf/bricks-and-mortar-of-the-epidermal-barrier-2kvm8pin8b.pdf

Bricks and mortar of the epidermal barrier

Pyoderma gangrenosum is a rare but significant cause of ulcerations. It is a diagnosis of exclusion. Herein, we suggest diagnostic criteria and some historical perspectives on the diagnosis of pyoderma gangrenosum.

Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria.

Transglutaminases catalyze the posttranslational modification of proteins referred to as the R-glutaminyl peptide. a i rhc y glulur~~yl transferase reaction (EC 2.3.2.13). which leads to the formation of an isopeptide bond either within or between polypeptide chains. It appears that nature has not provided an enzyme for the cleavage of the transglutaminase cross-link in proteins. The action of these enzymes results therefore in the formation of "irreversibly" cross-linked, often insoluble supramolecular structures. In vertebrates, transglutaminases form a large protein family and have a wide distribution amongst tissues and body fluids. Proteins modified by transglutaminases are found throughout the organism, e. g. in fibrin clots formed in hemostasis and wound healing. in cell membranes of terminally differentiated erythrocytes. in extracellular matrices, and in the cornified envelope of the epidermis. Transglutaminases occur early in evolution and enzymes with a similar function to vertebrate transglutaminases have been found in invertebrates, in plants, in unicellular eucaryotes and in bacteria. While transglutaminases in higher animals always require Ca2+ for activity, thi? reqnirement is less stringent in plants and microorganism;. Recently, the p h a i y b11u~Lule u l a baclelial llar~aglulal~~iriast: was determined (1) and it was revealed that, these enzymes evolved as a separate lineage from the eucaryotic transglutaminases. For historical reasons several different names are used to describe a single transglutaminase gene product. The characterized gene products and the different designations are summarized in Table 1. The physiological function of the various transglutaminases is not well understood with the exception of the comparatively well characterized factor XIIIa. The widespread occurrence and high degree of conservation among transglutaminases could indicate that covalent protein cross-linking play? a more important role in nature than presently appreciated.

Transglutaminases: protein cross-linking enzymes in tissues and body fluids.

Gluten sensitivity typically presents as celiac disease, a common chronic small intestinal disorder. However, in certain individuals it is associated with dermatitis herpetiformis, a blistering skin disease characterized by granular IgA deposits in the papillary dermis. While tissue transglutaminase has been implicated as the major autoantigen of gluten sensitive disease, there has been no explanation as to why this condition appears in two distinct forms. Here we show that while sera from patients with either form of gluten sensitive disease react both with tissue transglutaminase and the related enzyme epidermal (type 3) transglutaminase, antibodies in patients having dermatitis herpetiformis show a markedly higher avidity for epidermal transglutaminase. Further, these patients have an antibody population specific for this enzyme. We also show that the IgA precipitates in the papillary dermis of patients with dermatitis herpetiformis, the defining signs of the disease, contain epidermal transglutaminase, but not tissue transglutaminase or keratinocyte transglutaminase. These findings demonstrate that epidermal transglutaminase, rather than tissue transglutaminase, is the dominant autoantigen in dermatitis herpetiformis and explain why skin symptoms appear in a proportion of patients having gluten sensitive disease.

https://rupress.org/jem/article-pdf/195/6/747/1138050/jem1956747.pdf

Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis.

Substrates of human and bovine epidermal transglutaminase (glutaminyl-peptide gamma-glutamyltransferase, R-glutaminyl-peptide:amine-gamma-glutamyltransferase, EC 2.3.2.13) were isolated and purified by ion exchange chromatography and preparative zone electrophoresis. These substrates of Mr 36,000, which we propose to call keratolinin, incorporated dansylcadaverine and were precipitated by antibody. Keratolinin is ultimately polymerized on the inner leaflet of the keratinocyte membrane to form the cornified envelope. Each Mr 36,000 substrate was dissociated by chaotropic agents or detergents into noncovalent subunits; the Mr of these subunits was 6,000-6,200 on electrophoresis in 15% acrylamide/1% NaDodSO4/6 M urea gels. Isoelectric focusing of human or bovine keratolinin revealed two moieties separated by 0.3-0.4 pH unit (human, 5.4/5.0; bovine, 6.3/6.0). The two proteins were readily resolved by chromatofocusing and each isoelectric moiety of bovine keratolinin incorporated dansylcadaverine by epidermal transglutaminase and calcium and reacted with identity to antiserum to soluble Mr 36,000 keratolinin. Antiserum to human keratolinin failed to crossreact with its bovine counterpart. Antiserum to involucrin did not crossreact with either keratolinin or epidermis by immunodiffusion. Human and bovine epidermal keratolinins are biochemically similar but immunochemically distinct proteins from the epidermis. Involucrin appears only in significant quantities in cell culture.

Keratolinin: the soluble substrate of epidermal transglutaminase from human and bovine tissue.

A 63-year-old white woman with perioral dermatitis, a sore tongue, and an erythematous dermatosis in the inframammary and perineal regions underwent surgical removal of a pancreatic glucagonoma The patient's plasma and pooled normal human plasma containing Sigma glucagon were fed to human keratinocyte cultures and increased arachidonic acid levels by 300% and 200%, respectively, when compared to pooled normal human plasma with no added commercial glucagon These experiments suggest that glucagon may increase inflammatory mediators such as arachidonic acid and its metabolites in the epidermis, causing the skin lesions seen in the glucagonoma syndrome

Glucagonoma syndrome: In vitro evidence that glucagon increases epidermal arachidonic acid

Epidermal and hair follicle transglutaminases crosslink structural proteins in the skin by epsilon-(gammaglutamyl)-lysine bonds. This crosslinking produces protein polymers that are extremely insoluble and, until recently, difficult to characterize.

Epidermal and hair follicle transglutaminases and crosslinking in skin.

Biochemistry of Transglutaminases and Cross-Linking in the Skin

To determine whether plasma 5-S-cysteinyldopa levels are useful in following up patients at risk for melanoma, we measured plasma 5-S-cysteinyldopa in patients with dysplastic nevus syndrome and/or malignant melanoma and in control subjects. In patients with dysplastic nevus syndrome, plasma 5-S-cysteinyldopa levels did not differ from those in control subjects. Conversely, patients with malignant melanomas had significantly higher plasma 5-S-cysteinyldopa levels than did controls. Those with localized cutaneous malignant melanoma and no distant metastases (Stages I and II disease) had 5-S-cysteinyldopa levels twofold greater than those of control subjects, whereas the levels of those with regional lymph node involvement (Stage III disease) were fourfold greater than those of control subjects. Levels of those with extraregional metastases (Stage IV disease) were 7- to 450-fold higher than those of control subjects. Moreover, plasma 5-S-cysteinyldopa levels correlated with the spread of disease and were useful in distmguishing primary melanoma and Stages III and IV melanoma. We conclude that plasma 5-S-cysteinyldopa may be an important tool for identifying melanoma at an earlier, more curable stage and for following up patients at risk for the development of melanoma, for example, those with dysplastic nevus syndrome.

Plasma 5-S-cysteinyldopa differentiates patients with primary and metastatic melanoma from patients with dysplastic nevus syndrome and normal subjects†

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