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Title: Structural studies on proteins involved in angiogenesis
Author: Mitsiki, Eirini
ISNI:       0000 0001 3412 6953
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2007
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Angiogenesis, the sprouting of new capillaries from pre-existing microvasculature, is a key phenomenon for many physiological and athological processes. Physiological angiogenesis occurs during embryogenesis and for a healthy adult it occurs during wound healing and the female ovarian/menstrual cycle. Uncontrolled or dysfunctional angiogenesis on the other hand, has been shown to be associated with ischemia of the heart, atherosclerosis, rheumatoid arthritis and tumour growth and metastasis. Control of angiogenesis occurs via a signal network of activators and repressors, known as angiogenesis-stimulating factors (angiogenic factors) and angiogenesis inhibitors (angiostatins). PrC?teins involved in this key process include nucleoside phosphorylases as well as the tissue inhibitors ofmetalloproteinases (TIMPs). Nucleoside phosphorylases catalyse the reversible phosphorolysis of purine and pyrimidine nucleosides, a reaction of key importance for the nucleotide salvage pathway. Pyrimidine phosphorylases (PyNPs), which cleave the glycosidic bond of pyrimidines readily catalyses the reversible phosphorolysis (having primarily a catabolic function) of thymidine and 2'-deoxyuridine to their respective base and to 2-deoxy-D-ribose-l-' phosphate, as well as that of some pyrimidine analogues. Thymidine phosphorylase (TP) was found to induce the eH] thymidine incorporation, endothelial cell migration in vitro and angiogenesis in vivo. This is achieved by retaining a constant and correct supply of deoxyribonucleoside triphosphates (dNTPs) for DNA repair and replication. TP has also been shown to play a crucial role in pathological angiogenesis; TP overexpression has been related to various carcinomas while TP deficiency has been related to certain clinical conditions. Here we report the crystal structures of hTP in two fonns: unbound (native hTP) and bound with a small molecule inhibitor, 5IUR, which greatly resembles the chemotherapeutic agent currently used, 5FUR. Additionally, mutagenesis and enzymatic activity assays provide some novel infonnation on the significance of certain active site residues and their role in the phosphorolytic reaction catalysed by hTP. Extracellular matrix (ECM), which surrounds tissues and organs, has been shown to influence cell behaviour. Turnover of ECM components is therefore a crucial process for the control of cellular behaviour. It is essential in morphogenesis and tissue remodeling, which occur during embryonic development, wound healing and angiogenesis, while ., misregulation of ECM components turnover, has been linked to a series of pathological conditions. Enzymes involved in proteolytic systems that ECM turnover include the matrix-degrading proteinases known as Matrix Metalloproteinases (MMPs) or matrixins. The role of these molecules is highly controlled under physiological conditions, primarily by endogenous inhibitors, known as the tissue inhibitors of metalloproteinases (TIMPs). TIMPs have attracted a lot of interest due to their potential use in therapeutics. Understanding the structural features that are essential for TIMP potency against MMPs is thus of outmost importance. A bioinformatic analysis of an 'ancestral' TIMP form, TIMP from Drosophila melanogaster (dTIMP) allows the understanding of the evolutionary relati<;mships thatlink TIMPs .from different species, and raises questions about the significance of certain conserved TIMP features.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available