Catalysis And Thesis On PON1

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Thesis Draft Paraoxonase-1 (PON1) is a calcium-dependent enzyme which is able to hydrolyze various substrates. Some of the sustrates include homocysteine thiolactone (Jukubowski, 2000a), toxic organophosphates present in pesticides, such as paraoxon, parathion, and chlorpyrifos, compounds present in nerve gases like sarin and soman, as well as lactones (Amitai et al., 2006). For many years the activity of PON1 has been studied in relation to coronary artery disease, diabetes, and neurodegenerative diseases such as Alzheimer's and Parkinson's due to the perceived ability of PON1 to act as an antiatherogenic. While the research conclusions are contradictory regarding the role of PON1 in most diseases, a strong link has been demonstrated between PON1 activity and homocystein (hcy) and the risk of coronary artery disease (CAD) (Anderson et al., 2000). PON1 Structure and Catalysis The PON1 enzyme is part of the paraoxonase gene family which includes PON1, PON2, and PON3. IT RIDES ON HDL!! The PON1 gene is 355 residues long (Hassett et al., 1991) and contains two calcium ions, one participating in catalysis and the other maintaining the structure of the enzyme (Harel et al., 2004). Due to the wide range of substrates, the catalytic mechanism of PON1 was of interest. Three distinct crystal structures have been demonstrated. The first structure was crystallized at a pH of 4.5 and shows the PON1 variant as a six-bladed β-propeller covered by three α-helices (Harel et al., 2004). The second and third structure were determined at a pH of 6.5. The second structure contains an additional apolipoprotein, while the third structure reveals the enzyme with the compound 2-hydroxyquinoline, which is very sim... ... middle of paper ... ...s a better indicator of atherosclerosis than looking at the polymorphism (Jakubowski et al., 2001). For the majority of studies there is a negative correlation between the activity of PON1 and the level of serum Hcy. One study done showed lowered HTase activity in patients suffering from CAD than in the healthy control group. The HTase activity decreased as the number of affected vessels increased and in relation to the PON1 polymorphism genotype. The study also showed when comparing the CAD patients to the control group, the levels of HDL were decreased, while tHcy and oxidize LDL were increased (Koubaa et al., 2009). A separate study preformed with serum from hyperhomocysteinemic patients demonstrated similar results. The results showed that the activity of PON1 is significantly decreased in subjects with high concentrations of Hcy in serum (Holven et al., 2008).

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