D-pathway

Xu, J. Voth, G. A., Free energy profiles for H+ conduction in the D-pathway of Cytochrome c oxidase a study of the wild type and N98D mutant enzymes, Biochim. Bio-phys. Acta 2006,1757, 852-859. 

A reaction scheme frequently encountered in practice, the so-called square scheme mechanism, consists of the association of two EC reaction schemes as shown in Scheme 2.3 (which may as well be viewed as an association of two CE mechanisms). In the general case, the cyclic voltammetric response may be analyzed by adaptation and combination of the treatments given in Sections 2.2.1 and 2.2.2. A case of practical interest is when the follow-up reactions are fast and largely downhill. A and D are then stable reactants, whereas B and C are unstable intermediates. When the starting reactant is A (reduction process), the reaction follows the A-B-D pathway. The reoxidation preferred pathway is D-C-A. It is not the reverse of the forward... 

Fig. 33. Calculated activation energies relative to Cr(II) (top portion) compared to -log k, (bottom portion) where k are the experimental exchange-rate constants. No suitable D pathway could be located for Zn which is therefore omitted from the graph.

B8. Barter, P. J., Hopkins, G. J., and Calvert, G. D., Pathways for the incorporation of esterified cholesterol into very low density and low density lipoproteins in plasma incubated in vitro. Biochim. Biophys. Acta 713, 136-148 (1982). 

Both interchange (I) and dissociative (D) pathways represented by schemes (7.1), and (7.2) frequently lead to second-order rate expressions first-order in complex and first-order in incoming or attacking ligand. In a dilute solution, the observed second-order rate constant for the interchange path (7.1) is... 

It is obvious that the dissociative (D) pathway implies no assistance from the entering ligand since the entering ligand is not a stoichiometric component of the transition state. 

Fig. 11. A schematic illustration of subunits I (SUI) and II (SUII) of cytochrome c and ubiquinol oxidases. The proton pathways used for proton pumping and for the delivery of protons to the O2 binding site (thick black lines) are called the D- and K-pathways (named after the conserved residues Asp for the D-pathway and Lys for the K-pathway). Dashed lines depict the electron path from the substrate to the O2 binding site. In cytochrome c oxidases, electrons are delivered to the copper A center (Cua) from the substrate, cytochrome c, and then passed onto the low-spin heme (heme a) and finally to the binuclear center (heme 3-Cub). In ubiquinol oxidases, electrons are delivered directly to the low-spin heme (heme b) by the substrate, ubiquinol, and then to the binuclear center (heme 03-CuB).

Oprins, J.C., Van der Burg, C., Meijer, H.P., Munnik, T. and Groot, J.A., 2002, Tumor necrosis factor alpha potentiates ion secretion induced by histamine in a human intestinal epithelial cell line and in mouse colon involvement of the phospholipase D pathway. Gut 50 314—321. 

Omdahl JL, Bobrovnikova EA, Choe S, Dwivedi PP, and May BK (2001) Overview of regulatory cytochrome P450 enzymes of the vitamin D pathway. Steroids 66,381-9. 

Omdahl JL, Morris HA, and May BK (2002) Hydroxylase enzymes of the vitamin D pathway expression, function, and regxAdlion. Annual Reviews of Nutrition 22,139-66. 

Subunit III has no bound metal ions. Although it is the second-heaviest subunit, relatively little is known about its function. Its genetic deletion causes misassembly of the enzyme, while biochemical deletion decelerates proton transfer via the D-pathway (see below) in subunit I, and the subunit Ill-depleted enzyme becomes spontaneously inactivated after a number of turnovers, which is linked to loss of the Cub center. A role of subunit III as an oxygen reservoir has also been proposed. ... 

The so-called D-pathway in subunit I starts with a conserved aspartic acid near the iV-side, and continues into the middle of the membrane domain with a series of hydrophilic amino acids and several bound water molecules (Figure 3a). The latter were predicted by computational methods and were subsequently identified in the refined crystal structures. The D-pathway proper ends at a conserved glutamic acid residue at the bottom of a hydrophobic cavity, still some 10 A away from the site of O2 reduction (Figure 3a). Further proton conductivity to the latter site is not evident from the crystal stractures. The so-called K-pathway (mostly also in subunit I) is quite different. A conserved lysine residue either connects toward the A -side via a water molecule and a serine residue in subunit I (S255), or via a conserved glutamic acid residue (E62) in one of the membrane-spanning helices of subunit It. This pathway is lined by threonine and/or serine residues and appears to end at a key tyrosine moiety close to the O2 reduction site (Figure 3a, b). 

The electron originally at Cua becomes equilibrated approx. equally between heme a and Cua with the same kinetics as the F state is formed (Figure 4). This electron is finally transferred to the binuclear site, together with uptake of another proton via the D-pathway, and the O state is formed in ca. 2 3 ms. Different forms of the O state that differ in spectroscopic and kinetic parameters have long been described in the literature, but the stmctural basis for these differences remains unclear. Most recently Verkhovsky et al. reported a distinct difference in function, where reduction of the enzyme in state O was coupled to proton translocation only when snch rednction followed immediately after oxidation of the rednced enzyme by O2. The structure of the binuclear... 

It is known that the D-pathway transfers the pnmped protons, bnt it also transfers snbstrate protons to be consnmed at the binnclear site, at least those consnmed during the Pm F Oh reactions. Mutation of the lysine in the K-pathway (Figure 3a) hardly affects these reactions, but strongly inhibits reduction of heme and blocks the reversal... 

Again, the AS, represents the entropy of activation for the D pathway, while A,S, corresponds to the Id process.44... 

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