Ovalbumin digestion by human pepsins 1, 3 and 5.
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ABSTRACT:
SUBMITTER: Walker V
PROVIDER: S-EPMC1186250 | biostudies-other | 1978 Nov
REPOSITORIES: biostudies-other
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Project description:Plasmepsins are a group of diverse aspartic proteases in the malaria parasite Plasmodium Their functions are strikingly multifaceted, ranging from hemoglobin degradation to secretory organelle protein processing for egress, invasion, and effector export. Some, particularly the digestive vacuole plasmepsins, have been extensively characterized, whereas others, such as the transmission-stage plasmepsins, are minimally understood. Some (e.g. plasmepsin V) have exquisite cleavage sequence specificity; others are fairly promiscuous. Some have canonical pepsin-like aspartic protease features, whereas others have unusual attributes, including the nepenthesin loop of plasmepsin V and a histidine in place of a catalytic aspartate in plasmepsin III. We have learned much about the functioning of these enzymes, but more remains to be discovered about their cellular roles and even their mechanisms of action. Their importance in many key aspects of parasite biology makes them intriguing targets for antimalarial chemotherapy. Further consideration of their characteristics suggests that some are more viable drug targets than others. Indeed, inhibitors of invasion and egress offer hope for a desperately needed new drug to combat this nefarious organism.
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Project description:1. The pepsins and pepsinogens of the gastric mucosal extracts of two normal subjects, of seven patients with gastric adenocarcinoma and of two patients with duodenal ulcer have been investigated by agar-gel electrophoresis and by ion-exchange chromatography. 2. Of the eight zones of proteolytic activity that have previously been reported in normal human gastric juice, seven can be detected in activated fundic mucosal extracts. Of these seven, four can be attributed to discrete pepsins, numbered 1, 3a, 3 and 5. 3. Zone 7 results from the activity of one or more enzymes that are alkali-stable and are best referred to as gastric proteinases rather than as pepsins. Zone 7 is much more evident in mucosal extracts than in gastric juice. 4. Zones 4 and 6 may result respectively from the activity of a pepsin-inhibitor complex and of an unactivated zymogen. 5. It was not possible, by the chromatographic methods employed, to separate satisfactorily the individual pepsins from activated extracts or their precursors from unactivated extracts, so that the ascribing of a pepsin to a specific zymogen must be considered tentative. Even so, pepsin 3 appears to arise from at least two major precursors, if not from three, whereas pepsins 1 and 5 each arise from a single major precursor. 6. Pyloric mucosal extracts contain principally zone 5 but also zones 6 and 7. These zones in general behave similarly to the corresponding zones of fundic extracts, but pyloric pepsin 5 migrates slightly faster on agar-gel electrophoresis than does fundic pepsin 5 and is a different enzyme. Zones 1 to 4 are absent.
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Project description:1. The frequency of occurrence, under defined conditions, of the different human pepsins in the gastric juices of 50 normal subjects was investigated by agar-gel electrophoresis. 2. From a total of eight proteolytic zones located in the zymograms, no significant differences of occurrence existed between the sexes, or between subjects with or without gastric symptoms. 3. Two zones, numbered 3 and 5, occurred in all normal gastric juices. Zone 3 always exhibited the greatest proteolytic activity, then zone 5. The remaining enzymic zones were less well-marked and occurred less frequently. 4. A minor zone, 3a, was demonstrated within zone 3. The corresponding pepsin, 3a, has a mobility towards the anode 6-7% greater than has pepsin 3. 5. Of the eight zones, 1,2,3,3a and 5, at least, represent unique pepsins.
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Project description:Oxidized lipids containing a wide variety of potentially toxic compounds can be ingested through diet. However, their transformations during digestion are little known, despite this knowledge being essential in understanding their impact on human health. Considering this, the in vitro digestion process of highly oxidized soybean oil, containing compounds bearing hydroperoxy, aldehyde, epoxy, keto- and hydroxy groups, among others, is studied by 1H nuclear magnetic resonance. Lipolysis extent, oxidation occurrence and the fate of oxidation products both present in the undigested oil and formed during digestion are analyzed. Furthermore, the effect during digestion of two different ovalbumin proportions on all the aforementioned issues is also addressed. It is proved that polyunsaturated group bioaccessibility is affected by both a decrease in lipolysis and oxidation occurrence during digestion. While hydroperoxide level declines throughout this process, epoxy-compounds, keto-dienes, hydroxy-compounds, furan-derivatives and n-alkanals persist to a great extent or even increase. Conversely, α,β-unsaturated aldehydes, especially the very reactive and toxic oxygenated ones, diminish, although part of them remains in the digestates. While a low ovalbumin proportion hardly affects oil evolution during digestion, at a high level it diminishes oxidation and reduces the concentration of potentially bioaccessible toxic oxidation compounds.
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Project description:Allergy is a major public health concern, the main treatment for which is symptomatic relief with anti-inflammatory drugs. A key clinical challenge is to induce specific tolerance in order to control allergen-specific memory B and T cells, and specifically block effector cell responses. Our lab recently developed antigen-specific regulatory T-cell (Treg) therapies as a treatment for adverse responses. Recently, we created a chimeric antigen receptor (CAR) approach in which we engineered a target protein antigen, ovalbumin (OVA), linked with the transmembrane and signal transduction domains, CD28-CD3? to directly target B cells and sensitized mast cells in an allergy model. We named this receptor "BAR" for B-cell Antibody Receptor. Murine or human Tregs, transduced with a BAR containing OVA or control Tregs expressing an unrelated antigen, were successfully expanded in vitro and tested in the murine OVA-alum allergy model with measurable titers of anti-OVA IgE. Because BAR Tregs express the target antigen and could interact with specific IgE on sensitized mast cells, we first demonstrated that intravenously injected OVA-BAR Tregs did not directly lead to a drop in temperature or release of mediators in plasma indicative of anaphylaxis. Forty-eight hours later, mice were challenged intraperitoneally with 200??g OVA to induce an anaphylactic reaction, and temperature immediately measured for 30?min. We found that OVA-BAR Tregs protected mice from hypothermia, whereas mice given control BARs (expressing an unrelated antigen) or PBS showed substantial temperature drops indicative of anaphylaxis when systemically challenged with OVA. Importantly, this effect was also demonstrated in a passive anaphylaxis model in which mice that received anti-OVA IgE antibody were protected from hypothermia when treated with OVA-BAR Tregs prior to systemic OVA challenge. These results provide proof of principle that engineered allergen-specific T-regulatory cells can provide clinical protection against severe allergic reactions in individuals already IgE-sensitized to an allergen.
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Project description:1. The peptidase activities of pig pepsins A and C and human pepsin and gastricsin were compared. 2. The peptides studied had the general formula A Leu Val-His-B. Hydrolysis at 37 degrees C and pH 2.07 occurred at the amino side of the leucine residue for all the enzymes and all the peptides. 3. When A was Ac-Ala the peptides were hydrolysed under these conditions slowly by pig pepsin C only. 4. Pig pepsin A and human pepsin were unable to hydrolyse the tyrosine-containing peptides under the conditions tested. Gastricsin (human pepsin C) had about one-third of the activity of pig pepsin C with these substrates. 5. The increase in the rate of hydrolysis caused by the extension of the chain by a single alanine residue was most marked for pig pepsin A and human pepsin.
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Project description:A procedure was devised for isolating human pepsins 1, 2, 3 and 5 from gastric juice by repetitive column chromatography on DEAE-cellulose. The combined yields in four different experiments varied from 14% to 90% of the total peptic activity of the starting material. The isolated individual pepsins were shown to behave as single homogeneous proteins on agar-gel electrophoresis at pH 5.0 and on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. There is preliminary evidence, requiring further study, of two other pepsins, one migrating between pepsins 1 and 2 and the other a pepsin-3 component associating closely with pepsin 5 on chromatography.
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