5.B.1 The gp91phox Phagocyte NADPH Oxidase-associated Cytochrome b558 (Phox) Family

The human phagocyte cytochrome b558 is a heterodimeric complex consisting of a heavy (β) chain (gp91phox) and a light (α) chain (p22phox) as well as several auxiliary subunits (Geisz and Leto, 2004). The β-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 heme-binding site in its N-terminal 280 residues, and (2) an FAD binding site (residues 338-344) as part of the C-terminal NADPH oxidase domain. The N-terminal domain has 6 putative transmembrane spanners (TMSs) and is the cytochrome binding site. It has been reported 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&149;-. The proposal that (gp91phox) has H+ channel activity has been effectively disputed and is now in doubt (DeCoursey 2003; DeCoursey et al. 2002, 2001, Morgan et al. 2002, 2007). Further, the voltage-gated proton channel (TC# 1.A.51) is expressed on phagosomes (Okochi et al., 2009 ). As a result, this family has been removed from class 1.A where it previously assumed the TC#1.A.20.

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 generating superoxide. Its activity is electrogenic, causing depolarization of the membrane potential, negative inside. Four histidines, two in TMS3 (his-101 and his-115) and two in TMS5 (his-209 and his-222), are known to ligand heme (Biberstine-Kinkade et al. 2001). p22phox (the α-chain) is not homologous to anything else in the databases and may not have catalytic activity.

The activity of gp91phox is accompanied by a fall in the internal pH. Efflux of H+ through a channel would be expected to provide charge compensation, preventing a large fall in the internal pH. 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. Differential cell surface expression of Nox1, Nox2 and Nox5 (for example) is accomplished via two pathways, a Sar1 (small GTPase)-dependent pathway and a Sar-independent pathway (Kiyohara et al. 2018).

gp91phox is homologous throughout its length to proteins from animals, slime molds, plants, fungi and bacteria. There are seven homologues in humans (Nox1-5 and Duox1 and 2). Homologues in all organisms form six phylogenetic clusters (Kimball and Saier, 2002). These include mitogenic oxidases of animals, the so-called respiratory burst oxidase proteins of plants, and the ferric reductases of yeast and plants. In all cases, electrons are probably transferred across the membrane (from in to out) forming superoxide. Sixteen homologues of the Phox family have been sequenced from A. thaliana. Homologues are also found in C. elegans and D. melanogaster. Duox enzyme activities in epithelia are inhibited by compounds that block Hv1, but inhibition occurs through Hv1-independent mechanisms, supporting the idea that Hv1 is not required for Duox activity (Gattas et al. 2019).

The overall electron transfer reaction catalyzed by gp91phox and some of its homologues is:

1. electron (in) → electron (out)

2. O2 (out) + electron (in) → O2- (superoxide) (out)

This family belongs to the Calmodulin/Calcineurin/KChIP (CaCa) Superfamily.



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TC#NameOrganismal TypeExample

The gp91phox/p22phox NADPH oxidase-associated, cytochrome b558, Nox2. TMS2 is important for stability and electron transfer (Picciocchi et al., 2011). The integral membrane flavocytochrome of Nox 2 transfers an electron from intracellular NADPH to extracellular O2, generating superoxide anion, O2- (Fisher 2009).


gp91phox (β-chain) of Homo sapiens (Nox2) (P04839)
p22phox (α-chain) of Homo sapiens (P13498)


Two component NADPH oxidase, one designated the heavy chain subunit, CCA70369, of 564 aas and 6 N-terminal TMSs plus 1 or 2 TMSs in the C-terminal domain, and the other designated the cytosolic protein p67phox, CCA67529, of 254 aas and either 0 or 4-5 TMSs (based on 4-5 moderate peaks of hydrophobicity) (Shikata et al. 2019). This latter protein shows limited sequence similarity with the P07213 protein (TC# 3.A.8.1.1) and the corresponding reagion of the homologous Q9MUK5 protein (TC# 3.A.9.1.1).

NADPH oxidase of Serendipita indica


NADPH oxidase of 775 aas and 10 - 12 TMSs in a 5-6 TMS plus another 5-6 TMS segment, separated by a hydrophilic domain. Algal NADPH oxidases, which produces superoxide near the cell membrane, can be of two types: one with 5-6 TMSs and another with 10 - 12 TMSs (Shikata et al. 2019).

NADPH oxidase of Galdieria sulphuraria (Red alga)


Nucleus/kidney/muscle/endothelial cell superoxide-generating NADPH oxidase (Nox4) (may regulate gene expression) (Cheng et al., 2001; Kuroda et al., 2005). Integrated analyses of heterodimerization, trafficking and catalytic activity have identified determinants for the NOX4-p22phox interaction such as heme incorporation into NOX4 and hot spot residues in TMSs 1 and 4 in p22phox; their effects on NOX4 maturation and ROS generation have been analyzed (O'Neill et al. 2018). The topology has been determined using a novel method that shows 6 TMSs with N- and C-termini facing the cytosol (Rousset et al. 2019).

Animals and slime molds

Kidney superoxide-generating NADPH oxidase of Homo sapiens

5.B.1.1.3Multiple tissue mitogenic oxidase, subunit 65 (Mox1 or Nox1) (alternative splicing yields a 191 aa protein with H+ channel activity) (Bánfi et al., 2000; Suh et al., 1999)Animals and slime moldsMitogenic oxidase (Nox1) of Homo sapiens
5.B.1.1.4Mitogenic NADPH oxidase 3, Nox3 (Cheng et al., 2001). Critical for formation of otoconia, mineral crystals in the inner ear; mutants are defective for motion and gravity sensing (Paffenholz et al., 2004).AnimalsNox3 of Homo sapiens (Q9HBY0)

NADPH oxidase 5 (Nox5) of 765 aas and 6 TMSs (Cheng et al., 2001).  It is found in the ER and peri-nuclear regions, but upon activation, migrates to the plasma membrane.  It's properties and involvment in human pathophysiology have been reviewed (Touyz et al. 2019).


Nox5 of Homo sapiens (Q96PH1)


Thyroid NADPH oxidase/peroxidase 1 (Dual oxidase 1; Duox1) with two EF band domains, responsive to Ca2+ regulation (De Deken et al., 2000; Edens et al., 2001).  Duox enzyme activities in epithelia are inhibited by compounds that block Hv1, but inhibition occurs through Hv1-independent mechanisms, supporting the idea that Hv1 is not required for Duox activity (Gattas et al. 2019).


Duox1 of Homo sapiens (Q9NRD9)


Thyroid NADPH oxidase/peroxidase 2 (Dual oxidase 2; Duox2) with two EF band domains, responsive to Ca2+ regulation (De Deken et al., 2000; Edens et al., 2001).  Duox enzyme activities in epithelia are inhibited by compounds that block Hv1, but inhibition occurs through Hv1-independent mechanisms, supporting the idea that Hv1 is not required for Duox activity (Gattas et al. 2019).


Duox2 of Homo sapiens (Q9NRD8)

5.B.1.1.8Respiratory burst oxidase proteins A-FPlantsRespiratory burst oxidase A of Arabidopsis thaliana

Respiratory burst oxidase homologue F, RBOHF, of 944 aas and 6 TMSs.  Calcium-dependent NADPH oxidase that generates superoxide. Generates reactive oxygen species (ROS) during incompatible interactions with pathogens and is important in the regulation of the hypersensitive response (HR). Involved in abscisic acid-induced stomatal closing and in UV-B and abscisic acid ROS-dependent signaling (Song et al. 2006; Desikan et al. 2006; Kwak et al. 2003).

RBOHF of Arabidopsis thaliana (Mouse-ear cress)


TC#NameOrganismal TypeExample

NADPH oxido-reductase of 450 aas and 7 TMSs.  These proteins have been characterized in prokaryotes as well as eukaryotes (Hajjar et al. 2017).


Putative oxido-reductase of Vibrio cholerae


Uncharacterized oxidoreductase of 445 aas and 6 N-terminal TMSs.

Putative oxidoreductase of Streptomyces sp.


Ferric reductase like transmembrane component of 220 aas and 6 TMSs.

Ferric reductase of Thermophagus xiamenensis


Uncharacterized protein of 441 aas and 6 N-terminal TMSs.

UP of Planctomycetes bacterium


Uncharacterized protein of 215 aas and 6 TMSs.

UP of Candidatus Curtissbacteria bacterium


Uncharacterized protein of 205 aas and 6 TMSs.

UP of Candidatus Saccharibacteria bacterium


Uncharacterized protein of 210 aas and 6 TMSs.

UP of Candidatus Nomurabacteria bacterium


Uncharacterized protein of 222 aas and 6 TMSs.

UP of Alicyclobacillus sendaiensis


Uncharacterized ferric reductase domain protein transmembrane component of 287 aas and 6 TMSs.

UP of Candidatus Moranbacteria bacterium


TC#NameOrganismal TypeExample

CDP-6-deoxy-delta-3,4-glucoseen reductase (Han et al. 1990).


CDP-6-deoxy-delta-3,4-glucoseen reductase of Yersinia pseudotuberculosis


Phenol hydroxylase (Yu et al. 2011).


Phenol hydroxylase of Acinetobacter calcoaceticus


Uncharacterized protein of 249 aas and possibly 4 TMSs in a 1 + 2 + 1 TMS arrangement.

UP of Parcubacteria group bacterium GW2011_GWA2_38_13b (groundwater metagenome)


TC#NameOrganismal TypeExample
5.B.1.4.1Ferric reductase/oxidase, FRO1PlantsFRO1 of Arabidopsis thaliana
5.B.1.4.2Iron chelate reductase, Fox1 (La Fontaine et al., 2002)AlgaeFox1 of Chlamydomonas reinhardtii (ABM66085)
5.B.1.4.3Fro1, ferric chelate reductase (Enomoto et al., 2007).PlantsFro1 of Lycopersicon esculentum (Q6EMC0)

Ferric reduction oxidase 2, Fro2 or Frd1, of 725 aas. Flavocytochrome that transfers electrons across the plasma membrane to reduce ferric iron chelates and form soluble ferrous iron in the rhizosphere. May be involved in the delivery of iron to developing pollen grains. Acts also as a copper-chelate reductase. Involved in glycine betaine-mediated chilling tolerance and reactive oxygen species accumulation (Robinson et al. 1999; Wu et al. 2005; Connolly et al. 2003; Einset et al. 2008).

Fro2 of Arabidopsis thaliana (Mouse-ear cress)


TC#NameOrganismal TypeExample

Plasma membrane Fe3+ and Cu2+ reductase, Fre1 (transfers electrons from NADPH in the cytoplasm to Fe3+ and Cu2+ in the extracellular millieu) (Rees and Thiele, 2007).  Thus, it, as well as Fre2 (TC# 5.B.1.7.2), mediate the reductive uptake of Fe3+-salts and Fe3+ bound to catecholate or hydroxamate siderophores. Fe3+ is reduced to Fe2+, which then dissociates from the siderophore and can be imported by the high-affinity Fe2+ transport complex in the plasma membrane. Also participates in Cu2+ reduction and Cu+ uptake (Dancis et al. 1992; Hassett and Kosman 1995; Lesuisse et al. 1996; Georgatsou et al. 1997; Shi et al. 2003).


Fre1 of Saccharomyces cerevisiae

5.B.1.5.2Vacuolar Fe3+ and Cu2+ reductase, Fre6 (transfers electrons from NADPH in the cytoplasm to Cu2+ in the vacuole) (Rees and Thiele, 2007). Yeast Fre6 of Saccharomyces cerevisiae

Fre2 Fe3+/Cu2+ oxidoreductase of 711 aas; similar in catalytic function to Fre1 (TC# 5.B.1.5.1), but induced only by Fe3+, not Cu2+ (Georgatsou et al. 1997; Yun et al. 2001).

Fre2 of Saccharomyces cerevisiae


Ferric reductase, FreB of 582 aas and 7 TMSs (Rehman et al. 2017).

FreB of Verticillium dahliae (Verticillium wilt)


Frp1 of 564 aas and 10 TMSs.

Metalloreductase responsible for reducing extracellular iron and copper prior to import (By similarity).

Catalyzes the reductive uptake of Fe3+-salts and Fe3+ bound to catecholate or hydroxamate siderophores. Fe3+ is reduced to Fe2+, which then dissociates from the siderophore and can be imported by the high-affinity Fe2+ transport complex in the plasma membrane. It may also participate in Cu2+ reduction and Cu+ uptake. Frp1 harbors a ferric reductase domain with three-candidate heme-binding ligands (Ahmad et al. 2022).

Frp1 of Schizosaccharomyces pombe (Fission yeast)


Frp2 of 564 aas and up to 11 TMSs, ferric/cupric reductase transmembrane component 2. It probably functions as does Frp1 (TC# 5.B.1.5.5) (Ahmad et al. 2022).

Frp2 of Schizosaccharomyces pombe (Fission yeast)


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample