Trypsin deficiency

Emphysema usually presents with shortness of breath, dyspnea, and chronic cough. Pneumothorax may result from the bursting of an emphysematous bleb. The emphysema associated with o -anti trypsin deficiency is indistinguishable from nonfamilial forms, although chronic bronchitis and the associated cough occur less frequently than in other forms of emphysema. 

Vascular conditions have been associated with ,-anti trypsin deficiency, including panniculitis (an ulcerative, necrotizing skin condition) and cerebral aneurysm, among others. 

Sequencing of the human dj-antitrypsin gene in 1984 initiated an explosion in the study of this disease. Transgenic mice were created to study the effects of dj-anti trypsin deficiency, and cell culture studies of the regulation of the gene became possible. In 1992, D. A. Lomas and colleagues (Lomas et al., 1992) showed that the accumulation of abnormal dj-antitrypsin in the ER of the liver was the result of polymerization of dj-antitrypsin.This discovery set the stage for the study of the effects of this polymerized material on the liver, which it is hoped will allow the mechanism of liver disease associated with dj-antitrypsin deficiency to be determined. 

Perlmutter DH aj-Anti trypsin deficiency. Semin Liver Dis 18 217-225,1998. 

The diseases and disorders chosen for discussion and the order of presentation parallel subject matter taught in most first-year medical biochemistry. Chapters in the first part of the book, Nucleic Acids and Protein Structure, illustrate the relationships of protein structure and function with respect to collagen (Osteogenesis Imperfecta) and hemoglobin (Sickle Cell Anemia). The chapters Fragile X Syndrome and Hereditary Spherocytosis discuss key aspects of DNA and protein structure and their respective role in chromosomal and cytoskeletal structure. The chapter cardiac troponin and myocardial infarction provides an up-to-date demonstration of the usefulness of both structural proteins and enzymes as markers of cardiovascular disease, while the chapter cx Anti trypsin Deficiency discusses the important role of endogenous enzyme inhibitors. 

Playford, RJ., Freeman, T., Quinn, C. and Calam, J. (1990). Deficiency of a mucosal trypsin inhibitor in patients with ulcerative colitis. Gut 31, A1166. 

Proteinases and antiproteinases are part of the normal protective and repair mechanisms in the lungs. The imbalance of proteinase-antiproteinase activity in COPD is a result of either increased production or activity of destructive proteinases or inactivation or reduced production of protective antiproteinases. AAT (an antiproteinase) inhibits trypsin, elastase, and several other proteolytic enzymes. Deficiency of AAT results in unopposed proteinase activity, which promotes destruction of alveolar walls and lung parenchyma, leading to emphysema. 

The presence or absence of pancreatic enzymes can only be satisfactorily decided by intraduodenal intubation and direct examination of samples of small intestinal contents after the administration of a suitable stimulus to pancreatic secretion (Fll). It is not sufficient to look at one enzyme only, such as trypsin, since a specific deficiency of lipase can occur (Sll). Assessment of the degree of hydrolysis of fat in the stools is quite unreliable as a guide to pancreatic enzyme activity (CIO). 

Several examples of the binding of enzymes to poly(vinyl alcohol) are in the literature. These could possibly be used to treat enzyme deficiency diseases. In a recent example, trypsin was immobilized on poly(vinyl alcohol) fibers using maleic dialdehyde or bromal. While the reaction was more complete with bromal, the reaction with maleic dialdehyde gave a better support which showed decreasing activity with increasing enzyme content. The activity of the bromal activated system was independant of the enzyme content (52 ). Trypsin and papain were attached to poly(vinyl alcohol) by the reaction sequence shown in Equation 13. In this case, the crosslinked poly(vinyl alcohol) is treated by the 1,3-dioxalone derivative and then converted to either the isothiocyanate or the diazonium salt for coupling with the enzyme. The bound enzymes showed significant, altho reduced, activity in each case (53). 

The exact form in which non-crosslinked elastin is secreted from smooth muscle cells is yet to be clearly defined. Foster et al. (36) have suggested that a non-cross linked elastin (pro-elastin) is secreted from smooth muscle cells in a form that is approximately 120,000 to 140,000 daltons. They have suggested that proelastin is cleaved to smaller molecular weight forms of non-crosslinked elastin. It should be noted, however, that this view is not entirely supported by data from other laboratories. There are two reports on the use of isolated mRNA from chick aorta suggesting only a 70,000 dalton non-cross linked elastin is the major product of translation (37,38). There is also a recent report suggesting that aortic mRMA translates a 200,000 dalton putative elastin product (39). We have recently isolated a non-crosslinked elastin from the aortas of copper deficient chicks that appears to be 100,000 daltons (27). Its amino acid composition is similar to that for tropoelastin (Table III). A major problem in resolving these points is that the trypsin-like proteinase associated with elastin is not easily denatured or separated from the non-crosslinked forms of elastin. The proteinase is also not readily inhibited by commonly used inhibitors for trypsin-like proteinases (26). 

Those that are strictly proteinases - acting on a protein, rather than a peptide substrate - are discussed first. Members of the serpin family - notably ai-antitrypsin (also called Oi-antiproteinase), inhibit trypsin and similar proteases by binding to the active site. A deficiency of a,-antitrypsin, such as is seen in some genetic disorders expressing mutant -... 

Enteropeptidase cleaves between Lys-6 and Ile-7 to release a hexapeptide from the N-terminus. Trypsin autocatalytically activates trypsinogen and activates the other zymogens. The importance of the initial activation of trypsinogen to trypsin by enteropeptidase is manifested by children with congenital enteropeptidase deficiency who exhibit hypoproteinemia, anemia, failure to thrive, vomiting, and diarrhea. 

Protein C, like Factors II, VII, IX, and X, is a vitamin K-dependent protein. Activated protein C (PCa) can be derived by limited proteolysis of this zymogen by thrombin, trypsin, or by Russell s viper venom (VI). PCa, in contrast to the other vitamin K—activated ctors, exerts an anticoagulant activity by inhibiting Factors Va and Villa (Fll). A second activity identified for PCa is the release of plasminogen activator based on animal in vivo studies (CIO, Z2). These biochemical observations and the discovery of patients vnth recurrent thrombosis who are congenitally deficient in protein C make PCa a candidate for a central role in hemostasis (BIT). 

Increased uptake of large molecules can be expected in all pathologies where the gut is damaged or where the structure of the villi is changed. In patients with eczema and food allergy, the intestinal permeability of the probe molecule polyethylene glycol is increased [47], In infants with ai-antitrypsin deficiency, trypsin can be transported to the systemic circulation and reach the liver, causing inflammation and eventually fibrosis [48]. An increase in pinocytosis is also present in malnutrition. 

In the late 1970s and early 1980s—the time when P. falciparum could be cultured continuously in the laboratory—there was mounting evidence that the receptor for P. falciparum differed from that of P. vivax and P. knozvlesi. Several laboratories reported that a receptor for P. falciparum merozoites was sialic acid (N-acetylneuraminic acid) since human erythrocytes treated with neuraminidase or trypsin resisted invasion by P. falciparum merozoites and this was unlike the situation with P. vivax and P. knozvlesi where stripping by chymotrypsin but not trypsin blocked invasion. Further, Tn erythrocytes, which lack a glycosyltransfer-ase that results in cells deficient in sialic acid, were also refractory to invasion, as were En (a-) cells and when and S-s-U (-) cells, which were... 

Hubbard RC, McElvaney NG, Sellers SE, et al. Recombinant DNA-produced alpha 1-anti-trypsin administered by aerosol augments lower respiratory tract antineutrophil elas-tase defenses in individuals with alpha 1-antitrypsin deficiency. J. Glin. Invest., 1989 84(4) 1349-1354. 

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