Pepsin discovery

The carboxyl proteases are so called because they have two catalytically essential aspartate residues. They were formerly called acid proteases because most of them are active at low pH. The best-known member of the family is pepsin, which has the distinction of being the first enzyme to be named (in 1825, by T. Schwann). Other members are chymosin (rennin) cathepsin D Rhizopus-pepsin (from Rhizopus chinensis) penicillinopepsin (from Penicillium janthinel-lum) the enzyme from Endothia parasitica and renin, which is involved in the regulation of blood pressure. These constitute a homologous family, and all have an Mr of about 35 000. The aspartyl proteases have been thrown into prominence by the discovery of a retroviral subfamily, including one from HIV that is the target of therapy for AIDS. These are homodimers of subunits of about 100 residues.156,157 All the aspartyl proteases contain the two essential aspartyl residues. Their reaction mechanism is the most obscure of all the proteases, and there are no simple chemical models for guidance. 

As an example, we can consider the discovery and development of an antiviral drug. Inhibitors of the HIV protease, an enzyme essential for the maturation of the virus, can potentially cure HIV-infected people. The discovery process may consist of finding samples able to inhibit the viral aspartic protease over a certain threshold, while having little or no effect on another protease of the same class, such as pepsin. The hits will be submitted to further biological tests to identify leads, patentable compounds that are capable, for example, of inhibiting viral replication in cellular models. 

Wendell Stanley shared the Nobel Prize in chemistry in 1946 with John Northrop, awarded to them for their preparation of enzymes and virus proteins in a pure form, and with James Sumner for his discovery that enzymes can be crystallized. In 1926 Sumner had crystallized the enzyme urease in 1930 Northrop had crystallized pepsin and in 1935 Stanley had crystallized tobacco mosaic virus. Stanley s result and subsequent findings... 

Plant and other lectins have the ability to adhere strongly to microbial cell surfaces and lectins are responsible for the adhesion of Rhizobim trifotii to root hair cells of clover. Discovery of lectins which will bind other microbes may lead to the use of lectins as bridging agents to bind cells to inert support materials. Fletcher (83) studied the effects of proteins on the adhesion of a marine Pseudomonas sp. to polystyrene Petri dishes. Bovine serum albumin, gelatin, fibrinogen and pepsin (pKj — 5.8) all inhibit attachment at pH 7.6 when present either prior to or concurrently with the microbial cells. Bovine serum albumin decreased the adhesion of previously attached cells. 

It nevertheless appears from the work of Emmerling and of Kutscher that there is really a production of amino-adds in the prolonged digestions and that, both from the standpoint of time as well as of the nature of the products formed, this progress of hydrolysis differs unmistakably from that of pepsin. The fact that papain belongs rather to the class of trypdns is indicated by the discovery, made by Abderhalden, that papain... 

Naive physiologists had long believed that the mucous layer is a barrier to diffusion of acid and pepsin from the gastric contents to the mucosal surface, and therefore prevents attack on the surface by acid and pepsin. Norman Heatley, a junior colleague of Florey in the penicillin work, showed that a static layer of mucus does not inhibit diffusion of acid or pepsin. Heatley s demonstration was made before the discovery of active secretion of bicarbonate by the surface epithelial cells, and the function of the mucous layer as a dynamic entity had to be reevaluated after 1975. 

Immediately after Popielski s discovery became known, Ernst Rothlin of Zurich began a series of experiments comparing the effects of subcutaneous injections of histamine with the response of a dog s Pavlov pouch to a meal. In a few instances, as for example on 3 April 1920, Rothlin found that the concentration of pepsin in juice, as measured by the Mett method, was as high in two samples obtained after histamine stimulation as in three samples obtained after the dog had eaten. Nevertheless, Rothlin concluded that histamine is a less potent stimulus of pepsin than of acid secretion. ... 

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