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Flavin to Heme Electron Transfer

However, the studies on the hinge and Tyrl43 provided no information on the electron transfer from flavin-semiqumone to b 2-heme, the step which rate limits the catalytic cycle. In some elegant experiments, Tegoni et al. (1998) showed that the variation of the rate constant (In et) for this step correlates well with variations in the driving force (AG). Thus, this slow intra-molecular electron transfer is almost certainly controlled by thermodynamics. Tegoni et al. (1998) also provided some evidence that the faster, flavohydroquinone - b 2-heme, electron transfer may also be under thermodynamic control although this remains to be conclusively demonstrated. [Pg.286]

The characterisation of the complexation between flavocytochrome b2 and cytochrome c has been the subject of many studies (see for example Short et al., 1998 Daff et al., 1996b and CapeillEre-Blandin, 1995). Work on the anomala flavocytochrome b2, for which there is no crystal structure, led to the conclusions that the cytochrome c binding site involved both the flavodehydrogenase and cytochrome domains (CapeillEre-Blandin and Albani, 1987) and that the complex was stabilised by electrostatic interactions (CapeillEre-Blandin, 1982). It is clear that similar conclusions hold true for the S. cerevisiae enzyme (Daff et al., 1996b) for which the crystal [Pg.286]

The failure of the Tegoni model provided the impetus for a new hypothesis of how flavocytochrome 4 2 nd cytochrome c interact with one another. An examination of the crystal structure of flavocytochrome i 2 (Xia and Mathews, 1990) reveals a reasonably uniform distribution of charge, however, several patches of surface acidity can be found. These areas were considered as possible locations for binding sites for cytochrome c by Short et al. (1998). The prime concern of these authors in locating such a binding site was that it should allow the b 2- s Q and the c-heme to be as close together as possible. In addition, they considered the sequence conservation [Pg.287]

The flavocytochrome b2 molecular surface which is buried and hidden from solvent on binding cytochrome c has a total area of 657. The model [Pg.288]

FIGURE 6. The Interaction of a Cytochrome c Molecule with a Single Flavocytochrome b Subunit as Predicted by Short et al. (1998). The two proteins are shown as ribbon diagrams. The heme groups are shown in stick representation. The interface region between the two proteins is indicated by the dotted line. [Pg.289]


The struetures of eight flavoprotein electron transfer complexes will be examined (Table 1). Four of these involve flavin to heme electron transfer, three involve electron transfer between flavin and an iron-sulfur center and one involves flavin to flavin electron transfer. These eomplexes provide a variety of domain types and arrangements, cofactor types and interdomain interaetions that can help define the factors important for the electron... [Pg.30]

Of the four catalytic activities stimulated by CaM, two activities (cytochrome c and ferricyanide reductions) were similarly stimulated in apo-NOS when compared to native NOS (Table I). This indicated that CaM s activation of these processes occurred through a mechanism not involving the flavin-to-heme electron transfer. Further analysis showed that CaM binding increased the rate of electron transfer from NADPH into the flavin centers by a factor of 20, revealing a direct activation of the reductase domain by CaM. [Pg.209]

In contrast, CaM s activation of NO synthesis and substrate-independent NADPH oxidase activity did appear to involve flavin-to-heme electron transfer, because these reactions were not activated in apo-NOS and were blocked in native NOS by agents that prevent heme iron reduction (Abu-Soud et al., 1994a). We conclude that CaM activates neuronal NOS at two points (Fig. 2) electron transfer into the flavins and interdomain electron transfer between the flavins and heme. Activation at each point is associated with an up-regulation of domain-specific catalytic functions. The dual regulation by CaM is unique and represents a new means by which electron transfer can be controlled in a metal-containing flavoprotein. [Pg.210]

Many aspects of the electron transfer reactions in P450 BM3 are now reasonably well understood, and the first mutagenesis experiments on the enzyme ruled out the involvement of a tryptophan residue adjacent to the heme in the flavin-to-heme electron transport process . However, even after two decades of study of this enzyme, several fundamental issues remain unresolved. Key among these are the reasons why the electron transfer reactions in the reductase domain of the enz5mie (and between FMN and heme) are so efficient by comparison with the eukaryotic P450 and CPR systems. Thus, further detailed rapid kinetic and structural studies are critical to gain a complete understanding of this efficient electron transfer system. [Pg.133]

FIGURE 15. Electron transfer pathways in FCB2. The best path for electron transfer from flavin to heme based on GREENPATH calculations. Dashed lines represent paths along hydrogen bonds and dotted lines represent a through-space jump. Path 1 involves a water molecule while path 2 does not. [Pg.62]

Electron flow through flavocytochrome bz has been extensively studied in both the S. cerevisiae (Tegoni et al., 1998 Daff et al., 1996a Chapman et al., 1994 Pompon, 1980) and H. anomala (CapeillEre-Blandin et al., 1975) enzymes. The catalytic cycle is shown in Figure 3. Firstly, the flavin is reduced by L-lactate a carbanion mechanism has been proposed for this redox step (Lederer, 1991). Complete (two-electron) reduction of the flavin is followed by intra-molecular electron transfer from fully-reduced flavin to heme, generating flavin semiquinone and reduced heme (Daff et al.. [Pg.280]

It would appear then that the redox properties of flavocytochrome 4>2 are well understood. While this is generally true, there are a number of aspects which remain controversial and it is these that will form the main focus of this article. There are three major questions which will be addressed (i) Does the transfer of redox equivalents from lactate to flavin really involve a carbanion intermediate (ii) What controls the intramolecular electron transfers from flavin to heme (iii) Where, on the surface of flavocytochrome 4>2> does cytochrome c bind prior to inter-molecular electron transfer ... [Pg.281]

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. [Pg.210]

These enzymes may contain other redox-active sites (iron-sulfur centers, hemes, and/or flavins), either in distinct domains of a single polypeptide or bound in separate subunits. These additional cofactors perform electron transfer from the molybdenum center to an external electron acceptor/donor. [Pg.396]

Figure 17.12 Direct electrocatal3ftic oxidation of D-fnictose at a glassy carbon electrode painted with a paste of Ketjen black particles modified with D-fructose dehydrogenase from a Gluconobacter species. The enzyme incorporates an additional heme center allowing direct electron transfer from the electrode to the flavin active site. Cyclic voltammograms were recorded at a scan rate of 20 mV s and at 25 + 2 °C and pH 5.0. Reproduced by permission of the PCCP Owner Societies, from Kamitaka et al., 2007. Figure 17.12 Direct electrocatal3ftic oxidation of D-fnictose at a glassy carbon electrode painted with a paste of Ketjen black particles modified with D-fructose dehydrogenase from a Gluconobacter species. The enzyme incorporates an additional heme center allowing direct electron transfer from the electrode to the flavin active site. Cyclic voltammograms were recorded at a scan rate of 20 mV s and at 25 + 2 °C and pH 5.0. Reproduced by permission of the PCCP Owner Societies, from Kamitaka et al., 2007.
At the initial step electrons are transferred from NADPH to the oxidized FAD, reducing it to FADH2. Disproportionation between flavins leads to the formation of two free radicals FADH and FMNH. Electron transfer from FMNH to the heme results in the reduction of Fe3+ to Fe2+, and the reduced heme becomes able to bind 02 to form the intermediate... [Pg.729]

Fig. 13. Schematic representation of the overall NOS architecture and summary of work presented in 139). Heterodimers were generated to test if electron transfer from the FMN domain proceeds via an inter- or intrasubunit process. When holo-NOS containing an inactive heme domain was dimerized with an active heme domain, activity was observed. However, when active holo-NOS was dimerized with the inactive heme domain, no activity was observed. These results indicate that the flavin domain of monomer A transfers electrons to the heme domain of monomer B. Fig. 13. Schematic representation of the overall NOS architecture and summary of work presented in 139). Heterodimers were generated to test if electron transfer from the FMN domain proceeds via an inter- or intrasubunit process. When holo-NOS containing an inactive heme domain was dimerized with an active heme domain, activity was observed. However, when active holo-NOS was dimerized with the inactive heme domain, no activity was observed. These results indicate that the flavin domain of monomer A transfers electrons to the heme domain of monomer B.
Role for calmodulin in control of heme reduction in NOS. (A) In the absence of bound calmodulin, electrons derived from NADPH can load into the flavins but cannot be transferred onto the heme iron. (B) On calmodulin binding, electrons transfer from the flavins onto the heme. In the absence of bound L-arginine, heme reduction generates superoxide (C), whereas in the presence of L-arginine, heme reduction can lead to NO synthesis. [Pg.161]

NADPH oxidation and NO synthesis by the enzyme, it supports a role for reduction of the heme iron in catalysis, and may explain why NOS functions only as an NADPH-dependent reductase in the absence of bound calmodulin (Klatt et ai, 1993). The mechanism of calmodulin gating is envisioned to involve a conformational change between the reductase and oxygenase domains of NOS, such that an electron transfer between the terminal flavin and heme iron becomes possible. Calmodulin may also have a distinct role within the NOS reductase domain, in that its binding dramatically increases reductase activity of the enzyme toward cytochrome c (Klatt et al., 1993 Heinzel et al., 1992). However, it is clear that several other NOS functions occur independent of calmodulin, including the binding of L-arginine and NADPH, and transfer of NADPH-derived electrons into the flavins (Abu-Soud and Stuehr, 1993). [Pg.161]

In the transfer of reducing equivalents from the pyridine nucleotide pool, flavoproteins carry out a central role of mediating the conversion of the obligatory 2-electron reductant to 1-electron receptors such as hemes and iron-sulfur redox centers. In such a role, the semiquinone form of the flavin serves as a pivotal intermediate. The reduction of flavins and flavoproteins by reduced pyridine nucleotides has been extensively studied since the initial work of Singer and Kearney which showed that flavin reduction can occur in a non-enzyme catalyzed manner. The reduction proceeds as a 2-electron process since the formation of a nicotinamide semiquinone (a necessary intermediate in a 1-electron process) has been... [Pg.126]


See other pages where Flavin to Heme Electron Transfer is mentioned: [Pg.285]    [Pg.286]    [Pg.293]    [Pg.42]    [Pg.285]    [Pg.286]    [Pg.293]    [Pg.42]    [Pg.359]    [Pg.363]    [Pg.611]    [Pg.159]    [Pg.47]    [Pg.285]    [Pg.1736]    [Pg.283]    [Pg.208]    [Pg.209]    [Pg.211]    [Pg.43]    [Pg.43]    [Pg.351]    [Pg.865]    [Pg.922]    [Pg.729]    [Pg.257]    [Pg.92]    [Pg.266]    [Pg.280]    [Pg.428]    [Pg.175]    [Pg.151]    [Pg.158]    [Pg.158]    [Pg.730]    [Pg.132]   


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