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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Involvement of NADPH in the interaction between heme oxygenase-1 and cytochrome P450 reductase.

Heme oxygenase-1 (HO-1) catalyzes the physiological degradation of heme at the expense of molecular oxygen using electrons donated by NADPH-cytochrome P450 reductase ( CPR). In this study, we investigated the effect of NADP(H) on the interaction of HO-1 with CPR by surface plasmon resonance. We found that HO-1 associated with CPR more tightly in the presence of NADP(+) (K(D) = 0.5 microm) than in its absence (K(D) = 2.4 microm). The HO-1 mutants, K149A, K149A/K153A, and R185A, showed almost no heme degradation activity with NADPH- CPR, whereas they exhibited activity comparable to that of the wild type when sodium ascorbate was used. R185A showed a 100-fold decreased affinity for CPR compared with wild type, even in the presence of NADP(+) (K(D) = 36.3 microm). The affinities of K149A and K149A/K153A for CPR were decreased 7- and 9-fold (K(D) = 16.8 and 21.8 microm), respectively. In contrast to R185A, the affinities of K149A and K149A/K153A were improved by the addition of NADP(+) (K(D) = 5.2 and 9.6 microm, respectively), as was the case with wild type. Computer modeling of the HO-1/ CPR complex showed that the guanidino group of Arg(185) is located within the hydrogen bonding distance of 2'-phosphate of NADPH, suggesting that Arg(185) contributes to the binding to CPR through an electrostatic interaction with the phosphate group. On the other hand, Lys(149) is close to a cluster of acidic amino acids near the FMN binding site of CPR. Thus, Lys(149) and Lys(153) appear to interact with CPR in such a way as to orient the redox partners for optimal electron transfer from FMN of CPR to heme of HO-1.[1]

References

  1. Involvement of NADPH in the interaction between heme oxygenase-1 and cytochrome P450 reductase. Higashimoto, Y., Sakamoto, H., Hayashi, S., Sugishima, M., Fukuyama, K., Palmer, G., Noguchi, M. J. Biol. Chem. (2005) [Pubmed]
 
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