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NADH dehydrogenase I, NuoA-N.  NuoL probably comprises part of the proton pathway (Nakamaru-Ogiso et al. 2010).  NuoL (ND5), NuoM (ND4) and NuoN (ND2) are all homologous to proton:sodium antiporters and may all play reoles in pumping protons using a similar mechanism (Sato et al. 2013).

NDH of E. coli NuoA-N

NADH dehydrogenase I
NDH of Paracoccus denitrificans Nqo1-14

NADH Dehydrogenase, NDH (Baradaran et al. 2013).  The x-ray structures of various complexes have been solved, and a coupling mechanism involving long range conformational changes has been proposed (Sazanov et al. 2013). The complex includes 16 subunits with nine iron-sulfur clusters, reduced by electrons from NADH. Employing the latest crystal structure of T. thermophilus complex I, Gupta et al. 2020 used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron-sulfur clusters and conformational transitions across complex I. The simulations revealed the molecular design principles linking redox reactions to quinone turnover and proton translocation in complex I. Using a zebrafish model of TB infection, Roca et al. 2022 found that tumor necrosis factor (TNF) induces reverse electron transport (RET) in mitochondrial complex I. This in turn drives the production of mitochondrial reactive oxygen species (mROS), causing macrophage necrosis. The complex I inhibitor metformin could be repurposed to inhibit TNF-induced mROS and necrosis in infected zebrafish and human macrophages, suggesting that this common antidiabetes drug may also be a useful adjunct therapy for TB (Roca et al. 2022).

NDH of Thermus thermophilus HB-8 Nqo1-15

Proton-translocating hydrogenase, H2ase
H2ase of Pyrococcus furiosus MbhA-N (PF1423-PF1436)

[Ni2+-4Fe-4S] H+ translocating, quinone-independent ferredoxin:H+ oxidoreductase, EchA-F (Hedderich and Forzi, 2005; Künkel et al., 1998; Welte and Deppenmeier 2013) The Ech hydrogenases of M. mazei and M. barkeri have been characterized and were shown to pump protons (Welte et al., 2010).  The EchC and EcnF subunits include [Fe4S4] centers, and that in the EchC subunit exhibits a pH dependency to suggest that it plays a role in proton pumping (Forzi et al. 2005).  EchE has the NiFe center that converts 2H+ to H2.  The transmembrane subuits are EchA and EchB (Welte and Deppenmeier 2013) The Ech hydrogenases of M. mazei and M. barkeri have been characterized and were shown to pump protons (Welte et al., 2010).  The EchC and EcnF subunits include [Fe4S4] centers, and that in the EchC subunit exhibits a pH dependency to suggest that it plays a role in proton pumping (Forzi et al. 2005).  EchE has the NiFe center that converts 2H+ to H2.  The transmembrane subuits are EchA and EchB (Welte and Deppenmeier 2013).

EchABCDEF of Methanosarcina barkeri
EchA (639 aas; 16-18 TMSs; CAA76117)
EchB (285 aas; 7 TMSs; CAA76118)
EchC (156 aas; 0 TMSs; CAA76119)
EchD (113 aas; 0 or 1 TMSs; CAA76120)
EchE (358 aas; 4 TMSs; CAA76121)
EchF (122 aas; 0 TMSs; CAA76122)

Carbon monoxide-induced, H+ translocating, quinone-independent, polyferredoxin (CooF):H+ oxidoreductase, H2ase (Fox et al., 1996a,b; Hedderich and Forzi, 2005) [oxidation of CO to CO2 by CO dehydrogenase results in transfer of electrons to polyferredoxin which reduces H2ase] (Soboh et al., 2002, 2004).

CooMKLXUH of Rhodospirillum rubrum
CooM (1265 aas; 32 TMSs; AAC45116)
CooK (323 aas; 7 TMSs; AAC45117)
CooL (142 aas; 4 TMSs; AAC45118)
CooX (166 aas; 4 TMSs; AAC45119)
CooU (172 aas; 0-4 TMSs; AAC45120)
CooH (361 aas; 2-4 TMSs; AAC45121)

Energy conserving probable carbon monoxide-inducible hydrogenase, CooMKLXUH (Martins et al. 2016).

CooMKLXUH of Desulfovibrio vulgaris

Proton-translocating NADH dehydrogenase I

NDH of Geobacter sulfurreducens
NuoA (142 aas) NP_954485
NuoB (170 aas) NP_951399
NuoC (162 aas) NP_951400
NuoD (390 aas) NP_951401
NuoE (173 aas) NP_951402
NuoF (591 aas) NP_951403
NuoG (677 aas) NP_954479
NuoH (329 aas) NP_954476
NuoI (176 aas) NP_954474
NuoJ (163 aas) NP_954473
NuoK (102 aas) NP_954472
NuoL (624 aas) NP_954471
NuoM (496 aas) NP_954470
NuoN (466 aas) NP_954469

The vertebrate H+-translocating NADH dehydrogenase (NDH) complex (45 subunits) (Cardol et al., 2004).  The 3-d structure of the 44 subunit complex (14 core subunits present in bacteria, plus 30 additional subunits) with a molecular weight of 1 MDa, has been solved at 5 Å resolution by single particle electron cryo-microscopy (Vinothkumar et al. 2014).The core subunits contain eight iron-sulphur clusters and 60 transmembrane helices. The structures of many of the supernumerary subunits were determined or modeled. The structure provided insight into the roles of the supernumerary subunits in regulation, assembly and homeostasis.  One such subunit, GRIM-19 or NDUFA13, (Q9P0J0 of the human homologue) is essential for membrane potential formation and NADH assembly (Lu and Cao 2008).  Stroud et al. 2016 showed that 25 of the 31 accessory subunits in the 45 subunit human NADH dehydrogenase complex are required for assembly of a functional complex, and 1 subunit is essential for cell viability. Quantitative proteomic analysis revealed that loss of each subunit affects the stability of other subunits residing in the same structural module (Stroud et al. 2016). Leber's hereditary optic neuropathy (LHON) in humans is associated with combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I (Caporali et al. 2018). It has been proposed that the quinone reaction cavity is indeed from the matrix-side region covered by the ND3 TMH1-2 loop (Masuya et al. 2021). Resting mitochondrial complex I from Drosophila melanogaster adopts a helix-locked state (Padavannil et al. 2023).

Metazoa, Chordata
NDH of Bos taurus (45 subunits)
PSST (20) (NuoB) (P42026)
TYKY (23) (NuoI) (P42028)
24 (NuoE) (P04394)
30 (NuoC) (P23709)
49 (NuoD) (P17694)
51 (NuoF) (P25708)
75 (NuoG) (P15690)
ND1 (36) (NuoH) (P03887)
ND2 (39) (NuoN) (P03892)
ND3 (13) (NuoA) (P03898)
ND4 (52) (NuoM) (P03910)
ND4L (11) (NuoK) (P03902)
ND5 (67) (NuoL) (P03920)
ND6 (19) (NuoJ) (P03924)
MWFE (7.5) (Q02377)
SDAP (8) (P52505)
B8 (Q02370)
B12 (Q02365)
B13 (P23935)
13a (P23934)
B14 (Q02366)
ESSS (14.5) (Q8HXG5)
PFFD (15) (Q02379)
B16.6 (Q95KV7)
B17.2 (O97725)
B18 (Q02368)
AQDQ (18) (Q02375)
PGIV (19) (P42029)
B22 (Q02369)
PDSW (22) (Q9DCS9)
39 (P34943)
B14.7 (Q8HXG6)
B15 (P48305)
ASHI (19) (Q02372)
KFYI (6)6 (Q02376)
MNLL (7) (Q02378)
AGGG (8) (Q02374)
B95,6 (Q02371)
MLRQ (9) (Q01321)
106 (P25712)
B14.5a (Q05752)
B14.5b (Q02827)
SGDH (16) (Q02380)
B17 (Q02367)
42 (P34942)

The fungal H+ translocating NADH dehydrogenase (NDH) complex (38 subunits; 35 included here) (Cardol et al., 2004).  The high resolution (3.6 - 3.9 Å) structure of the mitochondrial Yarrowia lipolytica enzyme, showing all central subunits that execute the bioenergetic functions, has been solved (see discussion for TC# 3.A.1 and Zickermann et al. 2015). The subunit inventory of mitochondrial complex I from the obligate aerobic yeast Yarrowia lipolytica involved a total of 37 subunits (Abdrakhmanova et al. 2004).

Fungi, Ascomycota
NDH of Neurospora crassa (35 subunits):
19.3 (NuoB) (O47950)
21.3c (NuoI) (Q12644)
24 (NuoE) (P40915)
31 (NuoC) (P23710)
49 (NuoD) (P22142)
51 (NuoF) (P24917)
78 (NuoG) (P24918)
ND1 (42) (NuoH) (P08774)
ND2 (66) (NuoN) (Q35140)
ND3 (NuoA) (Q35141)
ND4 (NuoM) (P15582)
ND4L (10) (NuoK) (P05509)
ND5 (80) (NuoL) (P05510)
ND6 (NuoJ) (P15959)
9.8 (Q6MFL8)
9.6 (P11943)
10.5 (Q07842)
10.63 (XP_331394)
29.9 (P24919)
14.8 (P42114)
11.73 (XP_324110)
11.53 (Q9P6T9)
13.53 (P7S1I2)
13.43 (Q8X0V6)
89.73 (Q7RZ09)
21 (P25711)
20.8 (P21976)
183 (Q875B9)
12.3 (Q03015)
40 (P25284)
21.3B (P25710)
73 (XP_322246)
20.13 (XP_332152)
20.9 (Q02854)

The higher plant H+ translocating NADH dehydrogenase (NDH) complex (41 subunits; 23 included here) (Cardol et al., 2004)
Viridiplantae, Streptophyta
NDH of Arabidopsis thaliana (32 subunits)
24 (NuoB) (Q42577)
25.5 (NuoI) (Q9FX83)
28.3 (NuoE) (O22769)
ND9 (22.6) (NuoC) (Q95748)
ND7 (44.6) (NuoD) (P93306)
53.5 (NuoF) (Q9FNN5)
81.5 (NuoG) (Q9FGI6)
ND1 (36) (NuoH) (NP_085565)
ND2 (55) (NuoN) (NP_085584)
ND3 (14) (NuoA) (NP_085553)
ND4 (55) (NuoM) (NP_085518)
ND4L (11) (NuoK) (NP_051111)
ND5 (74) (NuoL) (NP_085478)
ND6 (23.5) (NuoJ) (NP_085495)
7.5 (Q84MD9)
14 (O80800)
10.8 (Q8FIJ2)
7 (AK059007)
19.2 (Q9FLX7)
12.2 (Q9M9M6)
15 (Q9LHI0)
133 (Q8L3S7)
14 (Q9LZI6)
16.1 (Q8RWA7)
18 (Q9M9M9)
12 (Q8GXZ6)
17.1 (Q9FJW4)
12 (Q8LGE7)
13.6 (Q945M1)
12.5 (Q84W12)
44 (Q9SK66)

The green algal H+ translocating NADH dehydrogenase (NDH) complex (42 subunits; 33 included here) (Cardol et al., 2004)
Viridiplantae, Chlorophyta
NDH of Chlamydomonas reinhardtii (33 subunits)
18 (NuoB) (Q6V9B0)
23 (NuoI) (Q6V9B1)
27 (NuoE) (Q6V9B3)
25 (NuoC) (Q6V5O7)
43 (NuoD) (Q6V9A8)
50 (NuoF) (Q6V9B2)
75 (NuoG) (Q6UKY6)
ND1 (31.6) (NuoH) (P11658)
ND2 (42.4) (NuoN) (P08740)
14 (NuoA) (Q6V502)
ND4 (48.7) (NuoM) (P20113)
24.2 (NuoK) (Q84K56)
ND5 (59) (NuoL) (P08739)
ND6 (17.7) (NuoJ) (P10329)
7.53 (Q6Q1V4)
143 (Q6UKY4)
11 (Q6V9A9)
6.53 (Q6Q1V8)
18 (Q6UKY3)
133 (Q6UP30)
14 (Q6UKY9)
17 (Q6Q1W0)
11 (Q6TH88)
16 (Q6UP32)
18 (Q6UP31)
12 (Q6UKY7)
19 (Q6UP29)
12.93 (Q6V504)
13.93 (Q6UKY8)
17 (Q6V505)
38 (Q6V506)
23 (Q6QAY4)
13 (Q9UP28)

The NADH: ubiquinone oxidoreductase homologue using flavodoxin rather than NADH as electron donor (Weerakoon and Olson, 2008),
Flavodoxin: ubiquinone oxidoreductase of Campylobacter jejuni
NuoA Q0P849
NuoB Q0P850
NuoC Q0P851
NuoD Q9PM99
NuoG Q0P855
NuoI Q0P857
NuoJ Q0P858
NuoK Q0P859
NuoM Q0P861
NuoN Q0P862
Cj1575c (NuoE) Q0P853
Cj1574c (NuoF) Q0P854

The chloroplast NDH-1 complex with form subcomplexes, subcomplex: M (membrane). L (lumen), A and B (Peng et al., 2011).  The NDF6 (PNSB6) protein is essential for activity (Ishikawa et al. 2008).

Viridiplantae, Streptophyta
NDH complex of Arabidopsis thaliana chloroplasts
NdhA (Q37165) = NuoH in E. coli
NdhB (P0CC32) = NuoN in E. coli
NdhC (P56751) = NuoA in E. coli
NdhD (P26288) = NuoM in E. coli
NdhE (P26289) = NuoK in E. coli
NdhF (P56752) = NuoL in E. coli
NdhG (Q95695) = NuoJ in E. coli
NdhH (P56753) = NuoD in E. coli
NdhI (P56755) = NuoI in E. coli
NdhJ (P56754) =  NuoC in E. coli
NdhK (P56756) = NuoB in E. coli
NdhL (Q9CAC5)
NdhM (Q2V2S7)
NdhN (B3H5R4)
NdhO (Q9S829)
NDF1 (Q9S9N6)
NDF2 (C0Z2H4)
NDF4 (Q9LU21)
NDF6 (B3H6Z4)
NDH18 (Q9FG89)
PPL2 (O80634)
CYP20-2 (F4K2G0)
FKBP16-2 (F4JW56)
PQL (Q9XI73)   

The photosynthetic/respiratory NAD(P)H-quinone oxidoreductase subunits A - Q and S. NdhP and NdhQ are peptides of 42 and 39 aas, identified by cryoEM at 3.3 Å resolution (Schuller et al. 2019). NDH-1 (NdhA) shuttles electrons from reduced ferridoxin, via FMN and iron-sulfur (Fe-S) centers, to quinones in the respiratory and photosynthetic chains. The immediate electron acceptor for the enzyme in this species is believed to be plastoquinone. The system couples the redox reaction to proton translocation, and thus conserves the redox energy in a proton gradient (Schuller et al. 2019). Ferridoxin directly mediates electron transfer between photosystem I and complex I. Ferridoxin efficiently binds to complex I with subunit NdhS being the key component in this process (Schuller et al. 2019).

NAD(P)H-quinone oxidoreductase of Thermosynechococcus elongatus (strain BP-1)
NdhA, 372 aas, Q8DL32
NdhB, 515 aas, Q8DMR6
NdhC, 132 aas, Q8DJ02
NdhD1, 526 aas, Q8DKY0
NdhE, 101 aas, Q8DL29
NdhF1, 656 aas, Q8DKX9
NdhG, 200 aas, Q8DL30
NdhH, 394 aas, Q8DJD9
NdhI, 196 aas, Q8DL31
NdhJ, 168 aas, Q8DJ01
NdhK, 237 aas, Q8DKZ4
NdhL, 76 aas, Q8DKZ3
NdhM, 111 aas, Q8DLN5
NdhN, 150 aas, Q8DJU2
NdhO, 70 aas, Q8DMU4
NdhS, 110 aas, Q8DL61

Hydrogenase 4, Hyf. Catalyzes H2 production and H+/K+ exchange (Bagramyan et al., 2001; 2002).

Hydrogenase 4 (HyfABCDEFGHI) of E. coli
HyfA (P23481)
HyfB (P23482)
HyfC (P77858)
HyfD (P77416)
HyfE (P0AEW1)
HyfF (P77437)
HyfG (P77329)
HyfH (P77423)
HyfI (P77668)

Hydrogenase 3, Hyc. Catalyzes H2 production coupled to H+ export (Bagramyan et al., 2002). The HycC and HycD proteins span the membrane multiple times; FdhF is a molybdenum-dependent formate dehydrogenase while HycE (Hyd-3) is a NiFe hydrogenase (McDowall et al. 2014).

Hydrogenase 3, HycBCDEF of E. coli 
HycB (like HyfA) (P0AAK3)
HycC (like HyfB) (P16429) 
HycD (like HyfC) (P16430)
HycE (like HyfD) (P16431)
HycF (like HyfE) (P16432)
HycG (like HyfF) (P16433)
FdhF (FHL) (P07658)

Putative hydrogenase 4, HyfA-I. 

HyfA-I (H missing) of Leptospira interrogans 
HyfA (99aas) (Q8EXV0)
HyfB (573aas) (Q8EYE3)
HyfC (295aas) (Q8EYE2)
HyfD (519aas) (Q8F7D6)
HyfE (206aas) (Q8EYE1)
HyfF (402aas) (Q8EYD0)
HyfG (466aas) (Q8EYD9)
HyfI (273aas) (Q8EYD8)