Enzymes utilising ferryl intermediates

P-450 is also able to catalyse reductive reactions. Thus if the enzyme becomes activated in the absence of substrate it can react as an oxidase, reducing oxygen to superoxide, peroxide and water. Whether such an uncoupled reaction can occur in vivo, however, is not clear [219], At low concentrations of oxygen, P-450 can act as a reductase. Thus it is able to initiate lipid peroxidation either directly via reduction of lipid hydroperoxides or via reducing CCI4 to CHCI3 [217], 

Progressive fibro-proliferative diseases (e.g. liver cirrhosis, pulmonary fibrosis, rheumatoid arthritis) result in a dramatic increase in collagen synthesis [227], This is preceded by inflammation that correlates with an increased activity of proline and lysine hydroxylase [228], Although they are unlikely to be the primary initiators of these diseases the increased activities of these enzymes may cause other problems. For example, in vitro the enzyme can turn over in the absence of a peptide substrate (but the presence of the 2-oxoglutarate cofactor). In this case stoichiometric amounts of ascorbate are required, probably to reduce the ferryl ion back to ferrous [229]. In vivo, lower concentrations of ascorbate are utilised [229,230], possibly to reactivate the enzyme after a non-productive activation (for example in the presence of a peptide that can bind to the active site, but cannot be hydroxylated). As the amount of proline-hydroxylase activity increases in the fibro-proliferative diseases, the concentration of ascorbate might not be sufficient to reduce these inactive complexes, resulting in the formation of potentially reactive ferryl intermediates. 

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Fig. 5. Mechanism of action of dinuclear non-haem iron enzymes utilising ferryl intermediates. Mechanisms for ribonucleotide reductase and methane mono-oxygenase adapted from that of Que [72]. Compound I and compound II define intermediates at the same oxidation state as the equivalent peroxidase intermediate (see Fig. 2). X is an unknown group suggested to bridge between the two iron atoms and form a cation radical. The nature of the electron required for the reduction of ribonucleotide reductase compound II is not clear - it is possible that this intermediate can also oxidise tyrosine [72].

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