Summary: NAD dependent epimerase/dehydratase family
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NADH dehydrogenase (ubiquinone) Edit Wikipedia article
Complex I (EC 188.8.131.52) (also referred to as NADH:ubiquinone oxidoreductase or, especially in the context of the human protein, NADH dehydrogenase) is an enzyme of the respiratory chains of myriad organisms from bacteria to humans that falls under the H+ or Na+-translocating NADH Dehydrogenase (NDH) Family (TC# 3.D.1), a member of the Na+ transporting Mrp superfamily. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and, in eukaryotes, it is located in the inner mitochondrial membrane. NADH:ubiquinone oxidoreductases type I of bacteria and of eukaryotic mitochondria and chloroplasts couple electron transfer to the electrogenic transport of protons or Na+. It is one of the "entry enzymes" of cellular respiration or oxidative phosphorylation in the mitochondria.
|NADH:ubiquinone reductase (H+-translocating).|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
Complex I is the first enzyme of the mitochondrial electron transport chain. There are three energy-transducing enzymes in the electron transport chain - NADH:ubiquinone oxidoreductase (complex I), Coenzyme Q – cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV). Complex I is the largest and most complicated enzyme of the electron transport chain.
The reaction catalyzed by complex I is:
- NADH + H+ + CoQ + 4H+in→ NAD+ + CoQH2 + 4H+out
In this process, the complex translocates four protons across the inner membrane per molecule of oxidized NADH, helping to build the electrochemical potential difference used to produce ATP. Escherichia coli complex I (NADH dehydrogenase) is capable of proton translocation in the same direction to the established Δψ, showing that in the tested conditions, the coupling ion is H+. Na+ transport in the opposite direction was observed, and although Na+ was not necessary for the catalytic or proton transport activities, its presence increased the latter. H+ was translocated by the Paracoccus denitrificans complex I, but in this case, H+ transport was not influenced by Na+, and Na+ transport was not observed. Possibly, the E. coli complex I has two energy coupling sites (one Na+ independent and the other Na+dependent), as observed for the Rhodothermus marinus complex I, whereas the coupling mechanism of the P. denitrificans enzyme is completely Na+ independent. It is also possible that another transporter catalyzes the uptake of Na+. Complex I energy transduction by proton pumping may not be exclusive to the R. marinus enzyme. The Na+/H+ antiport activity seems not to be a general property of complex I. However, the existence of Na+-translocating activity of the complex I is still in question.
The reaction can be reversed – referred to as aerobic succinate-supported NAD+ reduction by ubiquinol – in the presence of a high membrane potential, but the exact catalytic mechanism remains unknown. Driving force of this reaction is a potential across the membrane which can be maintained either by ATP-hydrolysis or by complexes III and IV during succinate oxidation.
Complex I may have a role in triggering apoptosis. In fact, there has been shown to be a correlation between mitochondrial activities and programmed cell death (PCD) during somatic embryo development.
All redox reactions take place in the hydrophilic domain of complex I. NADH initially binds to complex I, and transfers two electrons to the flavin mononucleotide (FMN) prosthetic group of the enzyme, creating FMNH2. The electron acceptor – the isoalloxazine ring – of FMN is identical to that of FAD. The electrons are then transferred through the FMN via a series of iron-sulfur (Fe-S) clusters[how many?], and finally to coenzyme Q10 (ubiquinone). This electron flow changes the redox state of the protein, inducing conformational changes of the protein which alters the pK values of ionizable side chain, and causes four hydrogen ions to be pumped out of the mitochondrial matrix. Ubiquinone (CoQ) accepts two electrons to be reduced to ubiquinol (CoQH2).
Electron transfer mechanism
The proposed pathway for electron transport prior to ubiquinone reduction is as follows: NADH – FMN – N3 – N1b – N4 – N5 – N6a – N6b – N2 – Q, where Nx is a labelling convention for iron sulfur clusters. The high reduction potential of the N2 cluster and the relative proximity of the other clusters in the chain enable efficient electron transfer over long distance in the protein (with transfer rates from NADH to N2 iron-sulfur cluster of about 100 μs).
The equilibrium dynamics of Complex I are primarily driven by the quinone redox cycle. In conditions of high proton motive force (and accordingly, a ubiquinol-concentrated pool), the enzyme runs in the reverse direction. Ubiquinol is oxidized to ubiquinone, and the resulting released protons reduce the proton motive force.
Proton translocation mechanism
The coupling of proton translocation and electron transport in Complex I is currently proposed as being indirect (long range conformational changes) as opposed to direct (redox intermediates in the hydrogen pumps as in heme groups of Complexes III and IV). The architecture of the hydrophobic region of complex I shows multiple proton transporters that are mechanically interlinked. The three central components believed to contribute to this long-range conformational change event are the pH-coupled N2 iron-sulfur cluster, the quinone reduction, and the transmembrane helix subunits of the membrane arm. Transduction of conformational changes to drive the transmembrane transporters linked by a 'connecting rod' during the reduction of ubiquinone can account for two or three of the four protons pumped per NADH oxidized. The remaining proton must be pumped by direct coupling at the ubiquinone-binding site. It is proposed that direct and indirect coupling mechanisms account for the pumping of the four protons.
The N2 cluster's proximity to a nearby cysteine residue results in a conformational change upon reduction in the nearby helicases, leading to small but important changes in the overall protein conformation. Further electron paramagnetic resonance studies of the electron transfer have demonstrated that most of the energy that is released during the subsequent CoQ reduction is on the final ubiquinol formation step from semiquinone, providing evidence for the "single stroke" H+ translocation mechanism (i.e. all four protons move across the membrane at the same time). Alternative theories suggest a "two stroke mechanism" where each reduction step (semiquinone and ubiquinol) results in a stroke of two protons entering the intermembrane space.
The resulting ubiquinol localized to the membrane domain interacts with negatively charged residues in the membrane arm, stabilizing conformational changes. An antiporter mechanism (Na+/H+ swap) has been proposed using evidence of conserved Asp residues in the membrane arm. The presence of Lys, Glu, and His residues enable for proton gating (a protonation followed by deprotonation event across the membrane) driven by the pKa of the residues.
Composition and structure
NADH:ubiquinone oxidoreductase is the largest of the respiratory complexes. In mammals, the enzyme contains 44 separate water-soluble peripheral membrane proteins, which are anchored to the integral membrane constituents. Of particular functional importance are the flavin prosthetic group (FMN) and eight iron-sulfur clusters (FeS). Of the 44 subunits, seven are encoded by the mitochondrial genome.
The structure is an "L" shape with a long membrane domain (with around 60 trans-membrane helices) and a hydrophilic (or peripheral) domain, which includes all the known redox centres and the NADH binding site. The structure of the eukaryotic complex is not well characterised. However, the Sazanov group succeeded in solving the structures of the complex I hydrophilic domain from the bacterium Thermus thermophilus ( and complex I membrane domains from both the E. coli ( ) and T. thermophilus ( ) enzymes. In February 2013 the structure of an entire, intact complex I (from T. thermophilus) was published for the first time, again by the Sazanov group ( ). All thirteen of the E. coli proteins, which comprise NADH dehydrogenase I, are encoded within the nuo operon, and are homologous to mitochondrial complex I subunits. The antiporter-like subunits NuoL/M/N each contains 14 conserved transmembrane (TM) helices. Two of them are discontinuous, but subunit NuoL contains a 110 Å long amphipathic α-helix, spanning the entire length of the domain. The subunit, NuoL, is related to Na+/ H+ antiporters of TC# 2.A.63.1.1 (PhaA and PhaD).)
Three of the conserved, membrane-bound subunits in NADH dehydrogenase are related to each other, and to Mrp sodium-proton antiporters. Structural analysis of two prokaryotic complexes I revealed that the three subunits each contain fourteen transmembrane helices that overlay in structural alignments: the translocation of three protons may be coordinated by a lateral helix connecting them.
Complex I contains a ubiquinone binding pocket at the interface of the 49-kDa and PSST subunits. Close to iron-sulfur cluster N2, the proposed immediate electron donor for ubiquinone, a highly conserved tyrosine constitutes a critical element of the quinone reduction site. A possible quinone exchange path leads from cluster N2 to the N-terminal beta-sheet of the 49-kDa subunit. All 45 subunits of the bovine NDHI have been sequenced. Each complex contains noncovalently bound FMN, coenzyme Q and several iron-sulfur centers. The bacterial NDHs have 8-9 iron-sulfur centers.
A recent study by Roessler et al. (2010) used electron paramagnetic resonance (EPR) spectra and double electron-electron resonance (DEER) to determine the path of electron transfer through the iron-sulfur complexes, which are located in the hydrophilic domain. Seven of these clusters form a chain from the flavin to the quinone binding sites; the eighth cluster is located on the other side of the flavin, and its function is unknown. The EPR and DEER results suggest an alternating or “roller-coaster” potential energy profile for the electron transfer between the active sites and along the iron-sulfur clusters, which can optimize the rate of electron travel and allow efficient energy conversion in complex I.
A simulational study by Hayashi and Stuchebrukhov further identified the electron tunneling pathways in atomic resolution based on the tunneling current theory. The distinct pathways between neighboring Fe/S clusters primarily consist of two cysteine ligands and one additional key residue, which was supported by sensitivity of simulated electron transfer rates to their mutations and their conservation among various complex I homologues from simple bacteria to human beings. This result shows that the crucial part of complex I developed for optimal efficiency with specific key residues during early stages of the biological evolution and has been conserved since then. Internal water between protein subunits was identified as an essential mediator enhancing the overall electron transfer rate to achieve physiologically significant value.
|#||Human/Bovine subunit||Human protein||Protein description (UniProt)||Pfam family with Human protein|
|1||NDUFS7 / PSST / NUKM||NDUS7_HUMAN||NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial EC 184.108.40.206 EC 220.127.116.11||Pfam PF01058|
|2||NDUFS8 / TYKY / NUIM||NDUS8_HUMAN||NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial EC 18.104.22.168 EC 22.214.171.124||Pfam PF12838|
|3||NDUFV2 / 24kD / NUHMc||NDUV2_HUMAN||NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial EC 126.96.36.199 EC 188.8.131.52||Pfam PF01257|
|4||NDUFS3 / 30kD / NUGM||NDUS3_HUMAN||NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial EC 184.108.40.206 EC 220.127.116.11||Pfam PF00329|
|5||NDUFS2 / 49kD / NUCM||NDUS2_HUMAN||NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial EC 18.104.22.168 EC 22.214.171.124||Pfam PF00346|
|6||NDUFV1 / 51kD / NUBM||NDUV1_HUMAN||NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial EC 126.96.36.199 EC 188.8.131.52||Pfam PF01512|
|7||NDUFS1 / 75kD / NUAM||NDUS1_HUMAN||NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial EC 184.108.40.206 EC 220.127.116.11||Pfam PF00384|
|8||ND1 / NU1M||NU1M_HUMAN||NADH-ubiquinone oxidoreductase chain 1 EC 18.104.22.168||Pfam PF00146|
|9||ND2 / NU2M||NU2M_HUMAN||NADH-ubiquinone oxidoreductase chain 2 EC 22.214.171.124||Pfam PF00361, Pfam PF06444|
|10||ND3 / NU3M||NU3M_HUMAN||NADH-ubiquinone oxidoreductase chain 3 EC 126.96.36.199||Pfam PF00507|
|11||ND4 / NU4M||NU4M_HUMAN||NADH-ubiquinone oxidoreductase chain 4 EC 188.8.131.52||Pfam PF01059,Pfam PF00361|
|12||ND4L / NULM||NU4LM_HUMAN||NADH-ubiquinone oxidoreductase chain 4L EC 184.108.40.206||Pfam PF00420|
|13||ND5 / NU5M||NU5M_HUMAN||NADH-ubiquinone oxidoreductase chain 5 EC 220.127.116.11||Pfam PF00361, Pfam PF06455, Pfam PF00662|
|14||ND6 / NU6M||NU6M_HUMAN||NADH-ubiquinone oxidoreductase chain 6 EC 18.104.22.168||Pfam PF00499|
|Core accessory subunitsb|
|15||NDUFS6 / 13A||NDUS6_HUMAN||NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial||Pfam PF10276|
|16||NDUFA12 / B17.2||NDUAC_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12||Pfam PF05071|
|17||NDUFS4 / AQDQ||NDUS4_HUMAN||NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial||Pfam PF04800|
|18||NDUFA9 / 39kDa||NDUA9_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial||Pfam PF01370|
|19||NDUFAB1 / ACPM||ACPM_HUMAN||Acyl carrier protein, mitochondrial||Pfam PF00550|
|20||NDUFA2 / B8||NDUA2_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2||Pfam PF05047|
|21||NDUFA1 / MFWE||NDUA1_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1||Pfam PF15879|
|22||NDUFB3 / B12||NDUB3_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3||Pfam PF08122|
|23||NDUFA5 / AB13||NDUA5_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5||Pfam PF04716|
|24||NDUFA6 / B14||NDUA6_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6||Pfam PF05347|
|25||NDUFA11 / B14.7||NDUAB_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11||Pfam PF02466|
|26||NDUFB11 / ESSS||NDUBB_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial||Pfam PF10183|
|27||NDUFS5 / PFFD||NDUS5_HUMAN||NADH dehydrogenase [ubiquinone] iron-sulfur protein 5||Pfam PF10200|
|28||NDUFB4 / B15||NDUB4_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4||Pfam PF07225|
|29||NDUFA13 /A13||NDUAD_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13||Pfam PF06212|
|30||NDUFB7 / B18||NDUB7_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7||Pfam PF05676|
|31||NDUFA8 / PGIV||NDUA8_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8||Pfam PF06747|
|32||NDUFB9 / B22||NDUB9_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9||Pfam PF05347|
|33||NDUFB10 / PDSW||NDUBA_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10||Pfam PF10249|
|34||NDUFB8 / ASHI||NDUB8_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial||Pfam PF05821|
|35||NDUFC2 / B14.5B||NDUC2_HUMAN||NADH dehydrogenase [ubiquinone] 1 subunit C2||Pfam PF06374|
|36||NDUFB2 / AGGG||NDUB2_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial||Pfam PF14813|
|37||NDUFA7 / B14.5A||NDUA7_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7||Pfam PF07347|
|38||NDUFA3 / B9||NDUA3_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3||Pfam PF14987|
|39||NDUFA4 / MLRQc||NDUA4_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4||Pfam PF06522|
|40||NDUFB5 / SGDH||NDUB5_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial||Pfam PF09781|
|41||NDUFB1 / MNLL||NDUB1_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1||Pfam PF08040|
|42||NDUFC1 / KFYI||NDUC1_HUMAN||NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial||Pfam PF15088|
|43||NDUFA10 / 42kD||NDUAA_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial||Pfam PF01712|
|44||NDUFA4L2||NUA4L_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2||Pfam PF15880|
|45||NDUFV3||NDUV3_HUMAN||NADH dehydrogenase [ubiquinone] flavoprotein 3, 10kDa||-|
|46||NDUFB6||NDUB6_HUMAN||NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6||Pfam PF09782|
|Assembly factor proteins|
|47||NDUFAF1c||CIA30_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 1||Pfam PF08547|
|48||NDUFAF2||MIMIT_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2||Pfam PF05071|
|49||NDUFAF3||NDUF3_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3||Pfam PF05071|
|50||NDUFAF4||NDUF4_HUMAN||NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 4||Pfam PF06784|
- a Found in all species except fungi
- b May or may not be present in any species
- c Found in fungal species such as Schizosaccharomyces pombe
Bullatacin (an acetogenin found in Asimina triloba fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) (IC50=1.2 nM, stronger than rotenone). The best-known inhibitor of complex I is rotenone (commonly used as an organic pesticide). Rotenone and rotenoids are isoflavonoids occurring in several genera of tropical plants such as Antonia (Loganiaceae), Derris and Lonchocarpus (Faboideae, Fabaceae). There have been reports of the indigenous people of French Guiana using rotenone-containing plants to fish - due to its ichthyotoxic effect - as early as the 17th century. Rotenone binds to the ubiquinone binding site of complex I as well as piericidin A, another potent inhibitor with a close structural homologue to ubiquinone.
Acetogenins from Annonaceae are even more potent inhibitors of complex I. They cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding. Interestingly, Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.
Despite more than 50 years of study of complex I, no inhibitors blocking the electron flow inside the enzyme have been found. Hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal FeS cluster N2 and ubiquinone. It has been shown that long-term systemic inhibition of complex I by rotenone can induce selective degeneration of dopaminergic neurons.
Complex I is also blocked by adenosine diphosphate ribose – a reversible competitive inhibitor of NADH oxidation – by binding to the enzyme at the nucleotide binding site. Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively.
The antidiabetic drug Metformin has been shown to induce a mild and transient inhibition of the mitochondrial respiratory chain complex I, and this inhibition appears to play a key role in its mechanism of action.
The catalytic properties of eukaryotic complex I are not simple. Two catalytically and structurally distinct forms exist in any given preparation of the enzyme: one is the fully competent, so-called “active” A-form and the other is the catalytically silent, dormant, “deactive”, D-form. After exposure of idle enzyme to elevated, but physiological temperatures (>30 °C) in the absence of substrate, the enzyme converts to the D-form. This form is catalytically incompetent but can be activated by the slow reaction (k~4 min−1) of NADH oxidation with subsequent ubiquinone reduction. After one or several turnovers the enzyme becomes active and can catalyse physiological NADH:ubiquinone reaction at a much higher rate (k~104 min−1). In the presence of divalent cations (Mg2+, Ca2+), or at alkaline pH the activation takes much longer.
The high activation energy (270 kJ/mol) of the deactivation process indicates the occurrence of major conformational changes in the organisation of the complex I. However, until now, the only conformational difference observed between these two forms is the number of cysteine residues exposed at the surface of the enzyme. Treatment of the D-form of complex I with the sulfhydryl reagents N-Ethylmaleimide or DTNB irreversibly blocks critical cysteine residue(s), abolishing the ability of the enzyme to respond to activation, thus inactivating it irreversibly. The A-form of complex I is insensitive to sulfhydryl reagents.
It was found that these conformational changes may have a very important physiological significance. The deactive, but not the active form of complex I was susceptible to inhibition by nitrosothiols and peroxynitrite. It is likely that transition from the active to the inactive form of complex I takes place during pathological conditions when the turnover of the enzyme is limited at physiological temperatures, such as during hypoxia, or when the tissue nitric oxide:oxygen ratio increases (i.e. metabolic hypoxia).
Production of superoxide
Recent investigations suggest that complex I is a potent source of reactive oxygen species. Complex I can produce superoxide (as well as hydrogen peroxide), through at least two different pathways. During forward electron transfer, only very small amounts of superoxide are produced (probably less than 0.1% of the overall electron flow).
During reverse electron transfer, complex I might be the most important site of superoxide production within mitochondria, with up to 5% of electrons being diverted to superoxide formation. Reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by succinate dehydrogenase, glycerol-3-phosphate dehydrogenase, or dihydro-oorotate dehydrogenase in mammalian mitochondria) pass through complex I to reduce NAD+ to NADH, driven by the inner mitochondrial membrane potential electric potential. Although it is not precisely known under what pathological conditions reverse-electron transfer would occur in vivo, in vitro experiments indicate that it can be a very potent source of superoxide when succinate concentrations are high and oxaloacetate or malate concentrations are low.
Superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging. NADH dehdyrogenase produces superoxide by transferring one electron from FMNH2 to oxygen (O2). The radical flavin leftover is unstable, and transfers the remaining electron to the iron-sulfur centers. Interestingly, it is the ratio of NADH to NAD+ that determines the rate of superoxide formation.
Mutations in the subunits of complex I can cause mitochondrial diseases, including Leigh syndrome. Point mutations in various complex I subunits derived from mitochondrial DNA (mtDNA) can also result in Leber's Hereditary Optic Neuropathy. There is some evidence that complex I defects may play a role in the etiology of Parkinson's disease, perhaps because of reactive oxygen species (complex I can, like complex III, leak electrons to oxygen, forming highly toxic superoxide).
Although the exact etiology of Parkinson’s disease is unclear, it is likely that mitochondrial dysfunction, along with proteasome inhibition and environmental toxins, may play a large role. In fact, the inhibition of complex I has been shown to cause the production of peroxides and a decrease in proteasome activity, which may lead to Parkinson’s disease. Additionally, Esteves et al. (2010) found that cell lines with Parkinson’s disease show increased proton leakage in complex I, which causes decreased maximum respiratory capacity.
Recent studies have examined other roles of complex I activity in the brain. Andreazza et al. (2010) found that the level of complex I activity was significantly decreased in patients with bipolar disorder, but not in patients with depression or schizophrenia. They found that patients with bipolar disorder showed increased protein oxidation and nitration in their prefrontal cortex. These results suggest that future studies should target complex I for potential therapeutic studies for bipolar disorder. Similarly, Moran et al. (2010) found that patients with severe complex I deficiency showed decreased oxygen consumption rates and slower growth rates. However, they found that mutations in different genes in complex I lead to different phenotypes, thereby explaining the variations of pathophysiological manifestations of complex I deficiency.
Exposure to pesticides can also inhibit complex I and cause disease symptoms. For example, chronic exposure to low levels of dichlorvos, an organophosphate used as a pesticide, has been shown to cause liver dysfunction. This occurs because dichlorvos alters complex I and II activity levels, which leads to decreased mitochondrial electron transfer activities and decreased ATP synthesis.
The following is a list of humans genes that encode components of complex I:
- NADH dehydrogenase (ubiquinone) 1 alpha subcomplex
- NDUFA1 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kDa
- NDUFA2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kDa
- NDUFA3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 3, 9kDa
- NDUFA4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9kDa
- NDUFA4L – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like
- NDUFA4L2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2
- NDUFA5 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kDa
- NDUFA6 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6, 14kDa
- NDUFA7 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 14.5kDa
- NDUFA8 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8, 19kDa
- NDUFA9 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39kDa
- NDUFA10 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 10, 42kDa
- NDUFA11 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 11, 14.7kDa
- NDUFA12 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12
- NDUFA13 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13
- NDUFAB1 – NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa
- NDUFAF1 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 1
- NDUFAF2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 2
- NDUFAF3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 3
- NDUFAF4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 4
- NADH dehydrogenase (ubiquinone) 1 beta subcomplex
- NDUFB1 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kDa
- NDUFB2 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kDa
- NDUFB3 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa
- NDUFB4 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa
- NDUFB5 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa
- NDUFB6 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17kDa
- NDUFB7 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 7, 18kDa
- NDUFB8 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kDa
- NDUFB9 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kDa
- NDUFB10 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kDa
- NDUFB11 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11, 17.3kDa
- NADH dehydrogenase (ubiquinone) 1, subcomplex unknown
- NADH dehydrogenase (ubiquinone) Fe-S protein
- NDUFS1 – NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75kDa (NADH-coenzyme Q reductase)
- NDUFS2 – NADH dehydrogenase (ubiquinone) Fe-S protein 2, 49kDa (NADH-coenzyme Q reductase)
- NDUFS3 – NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)
- NDUFS4 – NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)
- NDUFS5 – NADH dehydrogenase (ubiquinone) Fe-S protein 5, 15kDa (NADH-coenzyme Q reductase)
- NDUFS6 – NADH dehydrogenase (ubiquinone) Fe-S protein 6, 13kDa (NADH-coenzyme Q reductase)
- NDUFS7 – NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20kDa (NADH-coenzyme Q reductase)
- NDUFS8 – NADH dehydrogenase (ubiquinone) Fe-S protein 8, 23kDa (NADH-coenzyme Q reductase)
- NADH dehydrogenase (ubiquinone) flavoprotein 1
- mitochondrially encoded NADH dehydrogenase subunit
- MT-ND1 - mitochondrially encoded NADH dehydrogenase subunit 1
- MT-ND2 - mitochondrially encoded NADH dehydrogenase subunit 2
- MT-ND3 - mitochondrially encoded NADH dehydrogenase subunit 3
- MT-ND4 - mitochondrially encoded NADH dehydrogenase subunit 4
- MT-ND4L - mitochondrially encoded NADH dehydrogenase subunit 4L
- MT-ND5 - mitochondrially encoded NADH dehydrogenase subunit 5
- MT-ND6 - mitochondrially encoded NADH dehydrogenase subunit 6
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- on YouTube
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- IST Austria: Sazanov Group MRC MBU Sazanov group
- Interactive Molecular model of NADH dehydrogenase (Requires MDL Chime)
- Complex I homepage
- Electron Transport Complex I at the US National Library of Medicine Medical Subject Headings (MeSH)
As of this edit, this article uses content from "3.D.1 The H+ or Na+-translocating NADH Dehydrogenase (NDH) Family", which is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License, but not under the GFDL. All relevant terms must be followed..
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
NAD dependent epimerase/dehydratase family Provide feedback
This family of proteins utilise NAD as a cofactor. The proteins in this family use nucleotide-sugar substrates for a variety of chemical reactions.
Thoden JB, Hegeman AD, Wesenberg G, Chapeau MC, Frey PA, Holden HM; , Biochemistry 1997;36:6294-6304.: Structural analysis of UDP-sugar binding to UDP-galactose 4-epimerase from Escherichia coli. PUBMED:9174344 EPMC:9174344
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001509
This domain is found in proteins that utilise NAD as a cofactor and use nucleotide-sugar substrates for a variety of chemical reactions [PUBMED:9174344]. One of the best studied of these proteins is UDP-galactose 4-epimerase which catalyses the conversion of UDP-galactose to UDP-glucose during galactose metabolism [PUBMED:11279032, PUBMED:10801319].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||catalytic activity (GO:0003824)|
|coenzyme binding (GO:0050662)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
A class of redox enzymes are two domain proteins. One domain, termed the catalytic domain, confers substrate specificity and the precise reaction of the enzyme. The other domain, which is common to this class of redox enzymes, is a Rossmann-fold domain. The Rossmann domain binds nicotinamide adenine dinucleotide (NAD+) and it is this cofactor that reversibly accepts a hydride ion, which is lost or gained by the substrate in the redox reaction. Rossmann domains have an alpha/beta fold, which has a central beta sheet, with approximately five alpha helices found surrounding the beta sheet.The strands forming the beta sheet are found in the following characteristic order 654123. The inter sheet crossover of the stands in the sheet form the NAD+ binding site . In some more distantly relate Rossmann domains the NAD+ cofactor is replaced by the functionally similar cofactor FAD.
The clan contains the following 198 members:2-Hacid_dh_C 3Beta_HSD 3HCDH_N adh_short adh_short_C2 ADH_zinc_N ADH_zinc_N_2 AdoHcyase_NAD AdoMet_MTase AlaDh_PNT_C Amino_oxidase ApbA AviRa B12-binding Bac_GDH Bin3 Bmt2 CheR CMAS CmcI CoA_binding CoA_binding_2 CoA_binding_3 Cons_hypoth95 DAO DapB_C DapB_N DFP DNA_methylase DOT1 DRE2_N DREV DUF1188 DUF1442 DUF1611_N DUF166 DUF1776 DUF2431 DUF268 DUF3410 DUF364 DUF43 DUF5129 DUF5130 DUF938 DXP_redisom_C DXP_reductoisom DXPR_C Eco57I ELFV_dehydrog Eno-Rase_FAD_bd Eno-Rase_NADH_b Enoyl_reductase Epimerase F420_oxidored FAD_binding_2 FAD_binding_3 FAD_oxidored Fibrillarin FMO-like FmrO FtsJ G6PD_N GCD14 GDI GDP_Man_Dehyd GFO_IDH_MocA GIDA GidB GLF Glu_dehyd_C Glyco_hydro_4 GMC_oxred_N Gp_dh_N GRAS GRDA HI0933_like HIM1 IlvN K_oxygenase KR LCM Ldh_1_N Lycopene_cycl Malic_M Mannitol_dh MCRA Met_10 Methyltr_RsmB-F Methyltr_RsmF_N Methyltrans_Mon Methyltrans_SAM Methyltransf_10 Methyltransf_11 Methyltransf_12 Methyltransf_14 Methyltransf_15 Methyltransf_16 Methyltransf_17 Methyltransf_18 Methyltransf_19 Methyltransf_2 Methyltransf_20 Methyltransf_21 Methyltransf_22 Methyltransf_23 Methyltransf_24 Methyltransf_25 Methyltransf_28 Methyltransf_29 Methyltransf_3 Methyltransf_30 Methyltransf_31 Methyltransf_32 Methyltransf_33 Methyltransf_34 Methyltransf_4 Methyltransf_5 Methyltransf_7 Methyltransf_8 Methyltransf_9 Methyltransf_PK MethyltransfD12 MetW Mg-por_mtran_C MOLO1 Mqo MT-A70 MTS Mur_ligase N2227 N6-adenineMlase N6_Mtase N6_N4_Mtase NAD_binding_10 NAD_binding_2 NAD_binding_3 NAD_binding_4 NAD_binding_5 NAD_binding_7 NAD_binding_8 NAD_binding_9 NAD_Gly3P_dh_N NAS NmrA NNMT_PNMT_TEMT NodS NSP11 NSP13 OCD_Mu_crystall Orbi_VP4 PARP_regulatory PCMT PDH Polysacc_syn_2C Polysacc_synt_2 Pox_MCEL Pox_mRNA-cap Prenylcys_lyase PrmA PRMT5 Pyr_redox Pyr_redox_2 Pyr_redox_3 Reovirus_L2 RmlD_sub_bind Rossmann-like rRNA_methylase RrnaAD Rsm22 RsmJ Sacchrp_dh_NADP SAM_MT SE Semialdhyde_dh Shikimate_DH Spermine_synth TehB THF_DHG_CYH_C Thi4 ThiF TPM_phosphatase TPMT TrkA_N TRM TRM13 TrmK tRNA_U5-meth_tr Trp_halogenase TylF Ubie_methyltran UDPG_MGDP_dh_N UPF0020 UPF0146 Urocanase V_cholerae_RfbT XdhC_C YjeF_N
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_93 (release 3.0)|
|Number in seed:||96|
|Number in full:||36991|
|Average length of the domain:||222.60 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||66.24 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||20|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 7 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Epimerase domain has been found. There are 899 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
Loading structure mapping...