The Distribution and Characterisation of Aspartic Proteinases in Human Tissues

Reid, William Alexander (1987) The Distribution and Characterisation of Aspartic Proteinases in Human Tissues. MD thesis, University of Glasgow.

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The aspartic proteinases are members of a family of enzymes, the catalytic activity of which depends on the presence of two aspartic residues in the active site. This thesis concerns four members of this group - pepsin, gastricsin, cathepsin D and slow moving protease (SMP). The defining characteristics, nomenclature and general biochemistry of the aspartic proteinases are reviewed in Chapter 1 and an attempt is made to clarify the various systems which have been used to classify this group of enzymes. Assay and purification methods, the structure and mechanism of action of the enzymes and their immunological properties are outlined. Pure supplies of these enzymes are not commercially available and Chapter 2 describes the method by which these were obtained and how anti sera were developed. The anti sera are used to show that cathepsin D and SMP, previously thought to be identical, are separate enzymes. In Chapter 3 the immunohistochemical methods are introduced and their use in determining the distribution of the above enzymes in normal gastroduodenal mucosa is described, at both light and electron microscopic level. It is shown that pepsinogen is mainly confined to the gastric body, while progastricsin co-localises with pepsinogen but is also present in the gastric antrum and duodenum. Cathepsin D is demonstrated in parietal cells, in gastric antral glands and cells in the lamina propria, while SMP is demonstrated mainly in the surface epithelium of the stomach. These studies raise the general problem of the effects diffusion may have on the localisation of tissue antigens. This problem appears not to have been widely discussed in the literature and is dealt with in Chapter 4, in which diffusion was studied by immunolocalisation of pepsinogen and progastricsin in autolysing gastric mucosa and confirmed experimentally by immunolabelling of antigens introduced into various normal tissues. Enzyme activity at low pH has long been recognised in seminal fluid. In Chapter 5 this is shown to be due to the presence of gastricsin, apparently identical to that in normal gastric juice. The zymogen, progastricsin, was localised to the acinar cells of the prostate, which appear to secrete and presumably synthesise it. In Chapter 6, the distribution of aspartic proteinases in normal tissues apart from stomach, duodenum and prostate is discussed. No evidence of pepsinogen or progastricsin was found in other tissues, while cathepsin D appears widely distributed both in macrophages and in epithelial cells. SMP appears to be confined to the surface membrane or cilia of a few tissues, such as chorionic villi and respiratory epithelium, but its presence even in these tissues could be derived from the red blood cells, on the membranes of which it is demonstrated. Studies on the distribution of the aspartic proteinases are extended to the fetal stomach in Chapter 7, where it is shown that SMP is the dominant enzyme from 12 weeks gestation onwards, while progastricsin becomes prominent by about 17 weeks, when pepsinogen and cathepsin D also appear. Some attempt is made to relate the order of their appearance to the molecular evolution of aspartic proteinases. The rest of the thesis deals with the presence and distribution of the aspartic proteinases in neoplastic tissues. In Chapter 8, it is shown that gastric carcinomas produce aspartic proteinases, namely cathepsin D (100%), SMP (50%), progastricsin (30%) and pepsinogen (6%). There appears to be no relation to prognosis and both intestinal and diffuse types of carcinoma contain aspartic proteinases. In Chapter 9, the studies which showed progastricsin in normal prostatic epithelium, described in Chapter 5, are extended to carcinomas, up to 40% of which produce progastricsin. Progastricsin co-localises with acid phosphatase but is, however, less widely distributed. In Chapter 10 the distribution of aspartic proteinases in non-gastric tumours is described. While pepsinogen is highly specific to gastric carcinomas, progastricsin occasionally occurs in tumours of some other sites, especially pancreas, while cathepsin D is found in almost all tumours studied. SMP appears to be present in certain tumours, mainly kidney. In Chapter 11, progastricsin is more fully studied in metastatic tumours, firstly in local lymph node secondaries near primary gastric carcinomas and secondly in deposits further afield, both in lymph node and liver, from a range of primaries in different sites. It is shown that in most cases the presence of progastricsin in a lymph node metastasis of adenocarcinoma indicates a primary in the stomach or in pancreas but that occasionally metastases from other sites contain progastricsin. While progastricsin was commonly found in liver metastases, the correlation with a primary in stomach did not reach statistical significance. These results could be useful to the diagnostic histopathologist in determining the primary site from which a given metastasis has originated. The final discussion (Chapter 12) incorporates recent evidence that the pol gene of the HIV I virus codes for an aspartic proteinase and that retroviral proteinase activity is inhibited by the aspartic proteinase inhibitor, pepstatin. Knowledge of the distribution of the aspartic proteinases might therefore be relevant to possible treatment of AIDS with aspartic proteinase inhibitors.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Medicine
Date of Award: 1987
Depositing User: Enlighten Team
Unique ID: glathesis:1987-77618
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53

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