Tetrahydrobiopterin and electron transfer in NO synthase

Daff, Simon and Gazur, Ben and Papale, Davide and McInnes, Craig and Morthala, Raghavendar R. and Gibson, Colin L. and Suckling, Colin J. (2012) Tetrahydrobiopterin and electron transfer in NO synthase. Nitric Oxide: Biology and Chemistry, 27 (supple). S5-S5. ISSN 1089-8603 (https://doi.org/10.1016/j.niox.2012.04.019)

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Mammalian NO synthase requires the cofactor tetrahydrobiopterin (H4B) to act as an electron donor during the activation of molecular oxygen at the heme site. After donating an electron, the resultant H4B radical is then required to abstract an electron from the ferrous NO complex, which is generated at the end of the catalytic reaction, in order to facilitate NO release. We have recently explored the structural requirements of NO synthase for the H4B cofactor by studying a range of novel cofactor analogues with highly modified structures. Substituents on the C6 and C7 positions of H4B are tolerated well, with surprisingly bulky pterins being able to bind and drive NO synthesis. The modified pterins have a wide range of activities and binding constants, but the main function of the cofactors in activating molecular oxygen appears to be independent of C6 and C7 modification as shown by rapid reaction studies. We have also assessed the possibility of direct electron transfer across the dimer interface between H4B molecules in the two NO synthase subunits. The H4B cofactors are within the range for facile electron transfer and present a possible mechanism for NO synthase to escape from the unreactive ferrous-NO complex, which is known to originate from product inhibition.