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Methene bridge carbon atom elimination in oxidative heme degradation catalyzed by heme oxygenase and NADPH-cytochrome P-450 reductase
Authors:J C Docherty  G D Firneisz  B A Schacter
Institution:Department of Medicine, University of Manitoba, and Manitoba Institute of Cell Biology, 100 Olivia Street, Winnipeg, Manitoba R3E 0V9, Canada
Abstract:Physiological heme degradation is mediated by the heme oxygenase system consisting of heme oxygenase and NADPH-cytochrome P-450 reductase. Biliverdin IX alpha is formed by elimination of one methene bridge carbon atom as CO. Purified NADPH-cytochrome P-450 reductase alone will also degrade heme but biliverdin is a minor product (15%). The enzymatic mechanisms of heme degradation in the presence and absence of heme oxygenase were compared by analyzing the recovery of 14CO from the degradation of 14C]heme. 14CO recovery from purified NADPH-cytochrome P-450 reductase-catalyzed degradation of 14C]methemalbumin was 15% of the predicted value for one molecule of CO liberated per mole of heme degraded. 14CO2 and 14C]formic acid were formed in amounts (18 and 98%, respectively), suggesting oxidative cleavage of more than one methene bridge per heme degraded, similar to heme degradation by hydrogen peroxide. The reaction was strongly inhibited by catalase, but superoxide dismutase had no effect. 14C]Heme degradation by the reconstituted heme oxygenase system yielded 33% 14CO. Near-stoichiometric recovery of 14CO was achieved after addition of catalase to eliminate side reactions. Near-quantitative recovery of 14CO was also achieved using spleen microsomal preparations. Heme degradation by purified NADPH-cytochrome P-450 reductase appeared to be mediated by hydrogen peroxide. The major products were not bile pigments, and only small amounts of CO were formed. The presence of heme oxygenase, and possibly an intact membrane structure, were essential for efficient heme degradation to bile pigments, possibly by protecting the heme from indiscriminate attack by active oxygen species.
Keywords:To whom correspondence should be addressed at the Manitoba Institute of Cell Biology  
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