Abstract
Biological electron transfers often occur between metal-containing cofactors that are separated by very large molecular distances. Employing photosensitizer-modified iron and copper proteins, we have shown that single-step electron tunneling can occur on nanosecond to microsecond timescales at distances between 15 and 20 Å. We also have shown that charge transport can occur over even longer distances by hole hopping (multistep tunneling) through intervening tyrosines and tryptophans. In this perspective, we advance the hypothesis that such hole hopping through Tyr/Trp chains could protect oxygenase, dioxygenase, and peroxidase enzymes from oxidative damage. In support of this view, by examining the structures of P450 (CYP102A) and 2OG-Fe (TauD) enzymes, we have identified candidate Tyr/Trp chains that could transfer holes from uncoupled high-potential intermediates to reductants in contact with protein surface sites.
Highlights
Many vital biological transformations involve the incorporation of one or two O-atoms from molecular oxygen into organic substrates
Enzymes that utilize oxygen must coordinate the delivery of four protons and four electrons to O2 in order to prevent the formation of harmful molecular oxidants (O2−, HO2 H2O2, and HO), collectively known as reactive oxygen species (ROS)
We will advance the hypothesis that there are potentially protective radical chains in P450 and 2OG-Fe; but first we will review what we know about the factors controlling hopping through aromatic amino acids in multistep electron tunneling constructs designed in azurin, a prototypal cupredoxin
Summary
Many vital biological transformations involve the incorporation of one (monooxygenases) or two (dioxygenases) O-atoms from molecular oxygen into organic substrates. For enzymes with broad substrate specificities, or when operating in the presence of xenobiotic compounds, the fidelity of substrate oxidation is less than 100%, with potentially damaging consequences (Chen et al 2008; De Matteis et al 2012; Denisov et al 2007a; Grinkova et al 2013; Saban et al 2011; Staudt et al 1974) This circumstance is manifested as an increased molar ratio of O2 consumption to substrate hydroxylation (uncoupling). We suggest that radical transfer pathways are employed to deliver strongly oxidizing holes (E°∼1 V versus NHE) from ferryl complexes in active sites to less fragile regions of oxygenases In this perspective, we will advance the hypothesis that there are potentially protective radical chains in P450 and 2OG-Fe; but first we will review what we know about the factors controlling hopping through aromatic amino acids in multistep electron tunneling constructs designed in azurin, a prototypal cupredoxin
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