Nitric oxide synthase electron transfer

Siddhanta U., Presta, A., Fan, B., Wolan, D., Rousseau, D. L., Stuehr, D.)., Domain swapping in inducible nitric-oxide synthase. Electron transfer occurs between flavin and heme groups located on adjacent subunits in the dimmer, J. Biol. Chem. 273 (1998), p. 18950-18958... 

E. Roles for Nitric Oxide Synthase Flavins in Electron Transfer... 

G. Role for Calmodulin in Controlling Electron Transfer in Nitric Oxide Synthase... 

Abu Soud, H. M., and Stuehr, D. J. (1993). Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer. Proc. Nad. Acad. Set. U.S.A. 90, 10769-10772. 

Feng C, Thomas C, Holliday MA, et al. Direct measurement by laser flash photolysis of intramolecular electron transfer in a two-domain construct of murine inducible nitric oxide synthase. J Am Chem Soc 2006 128 3808-11. 

Abu-Saud, H.M., Ichimori, K., Presta, A., and Stuehr, DJ. (2000) Electron transfer, oxygen binding, and nitric oxide feedback inhibition in endothelial nitric oxide synthase, J. Biol. Chem. 275, 17349-17357. 

Figure 11.4. Reaction catalyzedby Nitric oxide synthase (a), and arrangement of the coenzymes in the dimer (b). Electrons flow from NADPH and flavins of one snbnnit to the heme of the other. Arg denotes the snbstrate binding site. Tetrahydrobiopterin (BH4) also participates in electron transfer.

The property of NO of inhibiting mitochondrial electron transfer was first recognized in 1994 by two British research groups [14, 15] that reported the inhibition of brain and muscle cytochrome oxidase (complex IV) activity by low NO concentrations in a reversible and Oj-competitive manner. More related to the scope of this review is the NO inhibition of electron transfer at complex III, ubiquinol-cytochrome c reductase, the second NO-sensitive point in the respiratory chain, where inhibition of electron transfer between cytochromes b and c enhances mitochondrial H2O2 production [16]. Nitric oxide, produced by NO donors or by mitochondrial nitric oxide synthase (mtNOS), inhibits complex III electron transfer and increases Oy and H2O2 production in sub-mitochondrial particles and in mitochondria. Complex IV is more sensitive to NO inhibition (IC5o=O.l pM) than complex III (IC5o=O.2 pM). 

Hurshman, A.R. and M.A. Marietta (2002). Reactions catalyzed by the heme domain of inducible nitric oxide synthase Evidence for the involvement of tetrahydrobiopterin in electron transfer. Biochemistry 41, 3439-3456. 

Craig, D.H., S.K. Chapman, and S. Daff (2002). Calmodulin activates electron transfer through neuronal nitric-oxide synthase reductase domain by releasing an NADPH-dependent conformational lock. J. Biol Chem. Ill, 33987-33994. 

Knight, K. and N.S. Scrutton (2002). Stopped-flow kinetic studies of electron transfer in the reductase domain of neuronal nitric oxide synthase Reevaluation of the kinetic mechanism reveals new enzyme intermediates and variation with cytochrome P450 reductase. Biochem. J. 367,19-30. 

Control of Electron Transfer in Neuronal Nitric Oxide Synthase by Calmodulin, Substrate, Substrate Analogs, and Nitric Oxide... 

FIGURE I Role for calmodulin (CaM) in triggering interdomain electron transfer to the nitric oxide synthase (NOS) heme iron. Electrons derived from NADPH can transfer only into the flavin centers of CaM-free neuronal NOS (A). CaM binding to NOS occurs in response to elevated Ca concentrations, and this enables electrons to transfer from the flavins to the heme iron. Heme iron reduction is associated with increased NADPH oxidation and results in (B) superoxide (O2) production in the absence of L-arginine or (C) nitric oxide (NO) synthesis in the presence of L-arginine. FAD, Flavin-adenine dinucleotide FMN, flavin mononucleotide. 

FIGURE 2 Proposed dual mode for calmodulin (CaM) control of nitric oxide synthase (NOS) electron transfer. Neuronal NOS is composed of a reductase and an oxygenase domain, shown as two circles. CaM binding to NOS activates at two points in the electron transfer sequence (1) It increases the rate at which NADPH-derived electrons are transferred into the flavins, and (2) it enables the flavins to pass electrons to the oxygenase domain of NOS. Activation at the first point is associated with an increase in reductase domain-specific catalytic activities, such as electron transfer to cytochrome c or ferricyanide (FeCN ). Activation at the second point is associated with a reduction of NOS heme iron, an initiation of NO synthesis from L-arginine (Arg), or a reduction of Oj to form superoxide (O2) in the absence of substrate. FAD, Flavin-adenine dinucleotide FMN, flavin mononucleotide NO, nitric oxide. 

Fig 24.10. Nitric oxide synthase synthesizes the free radical NO. Like cytochrome P450 enzymes, NO synthase uses Fe-heme, FAD, and FMN to transfer single electrons from NADPH to O2. 

Stuehr DJ, Tejero J, Haque MM (2009) Structural and mechanistic aspects of flavoproteins electron transfer through the nitric oxide synthase flavoprotein domain. FEBS J 276 3959-3974... 

Feng C (2012) Mechanism of nitric oxide synthase regulation electron transfer and interdomain interactions. Coord Chem Rev 256 393-411... 

Garcin ED, Bruns CM, Lloyd SJ, Hosfield DJ, Tiso M, Gachhui R, Stuehr DJ, Tainer JA, Getzofif ED (2004) Structural basis for isozyme-specific regulation of electron transfer in nitric-oxide synthase. J Biol Chem 279 37918-37927... 

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