Digestive enzyme, protein inhibitors

Pancreatic secretion for many, if not most, species is regulated in order to insure adequate protein digestion. Correspondingly, protease inhibitors have a greater impact on pancreatic secretion than do inhibitors of amylase and lipase (Toskes, 1986). The secretory response of the exocrine pancreas to protease inhibitors can be rapid (< 10 min), does not involve parallel increases in the secretion of all enzymes (Holm et al., 1992), and is probably mediated by a signaling pathway (see below). 

Why this elaborate mechanism for getting active digestive enzymes into the gastrointestinal tract Synthesis of the enzymes as inactive precursors protects the exocrine cells from destructive proteolytic attack. The pancreas further protects itself against self-digestion by making a specific inhibitor, a protein called pancreatic trypsin inhibitor (p. 231), that effectively prevents... 

Takada, K., et al. 1991. Effect of pH, dietary proteins and trypsin inhibitors on hydrolytic rate of human granulocyte colony-stimulating factor (G-CSF) by rat digestive enzymes. J Pharmacobio-dyn 14 363. 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

The cereal dual function a-amylase/trypsin inhibitor proteins are cysteine-rich, disulphide-rich, double-headed, 13-16 kDa, dual function inhibitor proteins that inhibit both of the digestion enzymes a-amylase and trypsin [290-325] (Table 11). Thus the Zea (com) member of this family, com Hageman factor inhibitor (CHFI), is a double-headed 14 kDa protein that inhibits a-amylase and the serine proteases trypsin and blood clotting Factor Xlla [323-324] (Table 11). The structures of the bifunctional a-amylase/trypsin inhibitor proteins from Eleusine (ragi) (RBI) [292-295] and Zea (com) (CHFI) [325] have been determined. These proteins are structurally similar to the lipid transfer proteins, being composed of a bundle of 4 a-helices together with a short [3-sheet element connected by loops, the a-amylase- and protease-inhibitory domains being separately located [325]. 

Some of the proteins are toxic in nature. Ricin present in castor bean is extremely toxic to higher animals in very small amounts. Enzyme irvhibitors such as trypsin inhibitor bind to digestive enzyme and prevent the availability of the protein. Lectin, a toxic protein present commonly in legumes, agglutinates red blood cells. A bacterial toxin causes cholera, which is a protein. Snake venom is protein in nature. 

The enzymes called proteases are necessary for the digestion of proteins. A newly proposed treatment for acquired immune deficiency syndrome (AIDS) involves the use of protease inhibitors, and as AIDS is an immunodeficiency disease, with cancer sometimes described in the same way, there may be a connection. (AIDS is by most accounts caused by the retrovirus HIV, and cancer may in some instances be traced to retroviruses.)... 

The alimentary canal in nematodes also contains proteins that inhibit digestive enzymes of the host (primarily proteases see ref. 141) or prevent coagulation of host blood (138). The structures of some of these protease inhibitors have been identified (142,143). 

Biochemical and nutritional aspects of seaweed proteins have been reported. Enzymatic degradation of algal fibers could be attempted to improve protein digestibility (Fleurence, 1999) and also to prepare bioactive peptides. A great deal of interest has been developed nowadays to isolate antihypertensive bioactive peptides, which act as angiotensin-con-verting enzyme (ACE) inhibitors because of their numerous health beneficial effects (Wijesekara and Kim, 2010). 

In the same year, there appeared a paper by Larry D. Byers and Richard V Wolfenden, in which they described that (L)-benzylsuccinic acid is an inhibitor ofthe digestive enzyme carboxypeptidase A, which splits off phenylalanine from the C-terminal end of proteins. [10] Of particular related importance was, that a few years earlier, William Lipscomb had elucidated the structure of this enzyme by X-ray analysis. It was thus possible to buUd a spatial model showing the interaction between the enzyme and its substrate. Cushman and Ondetti developed the idea that in the active site of the enzyme there was a pocket housing the phenylalanine residue, and that the succinyl residue was complexed by zinc. (L)-Benzylsuccinic acid binds in a similar mode and thereby inhibits carboxypeptidase A (Fig. 5.10). 

The nutritional value of a protein also depends on its digestibility here again, plant proteins tend to be inferior to animal proteins. Their poor digestibility results from (1) the presence of peptide bonds which are relatively resistant to the digestive enzymes, (2) the presence of enzyme inhibitors such as the trypsin inhibitor present in soya beans (page 177), and (3) the presence of fibre which hinders the access of proteolytic enzymes (page 130). 

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