The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

The coagulation cascade: initiation, maintenance, and regulation

Calcium regulation of growth and differentiation of mouse epidermal cells in culture

Eleven distinct isoforms of phosphoinositide-specific phospholipase C (PLC), which are grouped into four subfamilies (beta, gamma, delta, and epsilon), have been identified in mammals. These isozymes catalyze the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] to inositol 1,4,5-trisphosphate and diacylglycerol in response to the activation of more than 100 different cell surface receptors. All PLC isoforms contain X and Y domains, which form the catalytic core, as well as various combinations of regulatory domains that are common to many other signaling proteins. These regulatory domains serve to target PLC isozymes to the vicinity of their substrate or activators through protein-protein or protein-lipid interactions. These domains (with their binding partners in parentheses or brackets) include the pleckstrin homology (PH) domain [PtdIns(3)P, beta gamma subunits of G proteins] and the COOH-terminal region including the C2 domain (GTP-bound alpha subunit of Gq) of PLC-beta; the PH domain [PtdIns(3,4,5)P3] and Src homology 2 domain [tyrosine-phosphorylated proteins, PtdIns(3,4,5)P3] of PLC-gamma; the PH domain [PtdIns(4,5)P2] and C2 domain (Ca2+) of PLC-delta; and the Ras binding domain (GTP-bound Ras) of PLC-epsilon. The presence of distinct regulatory domains in PLC isoforms renders them susceptible to different modes of activation. Given that the partners that interact with these regulatory domains of PLC isozymes are generated or eliminated in specific regions of the cell in response to changes in receptor status, the activation and deactivation of each PLC isoform are likely highly regulated processes.

Regulation of phosphoinositide-specific phospholipase C

The epidermis functions as a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes - the cornified layer, which forms the endpoint of epidermal differentiation and death. The cornified envelope replaces the plasma membrane of differentiating keratinocytes and consists of keratins that are enclosed within an insoluble amalgam of proteins, which are crosslinked by transglutaminases and surrounded by a lipid envelope. New insights into the molecular mechanisms and the physiological endpoints of cornification are increasing our understanding of the pathological defects of this unique form of programmed cell death, which is associated with barrier malfunctions and ichthyosis.

The cornified envelope: a model of cell death in the skin

Blood coagulation, skin-barrier formation, hardening of the fertilization envelope, extracellular-matrix assembly and other important biological processes are dependent on the rapid generation of covalent crosslinks between proteins. These reactions--which are catalysed by transglutaminases--endow the resulting supramolecular structure with extra rigidity and resistance against proteolytic degradation. Some transglutaminases function as molecular switches in cytoskeletal scaffolding and modulate protein-protein interactions. Having knowledge of these enzymes is essential for understanding the aetiologies of diverse hereditary diseases of the blood and skin, and various autoimmune, inflammatory and degenerative conditions.

Transglutaminases: crosslinking enzymes with pleiotropic functions

http://europepmc.org/articles/PMC1300553?pdf=render

Structural origins of fibrin clot rheology.

The human transglutaminase (TG) family consists of a structural protein, protein 4.2, that lacks catalytic activity, and eight zymogens/enzymes, designated factor XIII-A (FXIII-A) and TG1-7, that catalyze three types of posttranslational modification reactions: transamidation, esterification, and hydrolysis. These reactions are essential for biological processes such as blood coagulation, skin barrier formation, and extracellular matrix assembly but can also contribute to the pathophysiology of various inflammatory, autoimmune, and degenerative conditions. Some members of the TG family, for example, TG2, can participate in biological processes through actions unrelated to transamidase catalytic activity. We present here a comprehensive review of recent insights into the physiology and pathophysiology of TG family members that have come from studies of genetically engineered mouse models and/or inherited disorders. The review focuses on FXIII-A, TG1, TG2, TG5, and protein 4.2, as mice deficient in TG3, TG4, TG6, or TG7 have not yet been reported, nor have mutations in these proteins been linked to human disease.

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

https://science.sciencemag.org/content/sci/108/2802/280.full.pdf

Laszlo Lorand

Papers

Transglutaminases: crosslinking enzymes with pleiotropic functions

Structural origins of fibrin clot rheology.

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

On the Solubility of Fibrin Clots.

A filter paper assay for transamidating enzymes using radioactive amine substrates