Family 1.A.20 - The Phagocyte NADPH Oxidase-associated Cytochrome b558 Family       

Family ID: 52604

The human phagocyte cytochrome b558 is a heterodimeric complex consisting of a heavy (b) chain (gp91phox) and a light (a) chain (p22phox). The b-chain is a glycoprotein of 570 amino acyl residues called gp91phox, the product of the X-linked chronic granulomatous disease gene. The protein bears (1) the H+ channel in its N-terminal 280 residues, and (2) an FAD binding site (residues 338-344) as part of the C-terminal NADPH oxidase catalytic domain. The N-terminal domain has 6 putative transmembrane spanners (TMSs) and is believed to catalyze efflux of protons through an H+ channel that acts as a charge compensation pathway for the electrogenic generation of the superoxide radical, O2-. Arachidonate coordinately activates the oxidase and opens the channel. The N-terminal 230 residues contains all that is required for the arachidonate-activatable H+ channel. The involvement of histidine 115 in proton transport has been inferred from mutagenic studies. p22phox (the a-chain) is not homologous to anything else in the databases.

gp91phox is the terminal component of a respiratory chain that transfers single electrons from cytoplasmic NADPH to O2 on the external side of the plasma membrane. Its activity is electrogenic, causing depolarization of the membrane potential, negative inside, and its function is accompanied by a slight fall in the internal pH. Efflux of H+ through the channel provides charge compensation, preventing a large fall in the internal pH. The channel is opened by binding of arachidonic acid, the allosteric activator of the oxidase. In the presence of arachidonic acid, the direction of H+ flux is dictated by the pmf. The oxidase interacts with various cytosolic proteins that may regulate its activity.

gp91phox is homologous to the so-called respiratory burst oxidase proteins of plants. Six homologues of this enzyme have been sequenced and characterized from A. thaliana. Homologues are also found in C. elegans. The C-terminal domain of gp91phox is also homologous to bacterial flavohemoproteins (hemoglobin-like proteins) and yeast ferric reductases. However, the latter proteins do not possess the N-terminal transmembrane channel domain.