NADH dehydrogenase

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Electron transport chain. NADH dehydrogenase is "I", at the left.

The structure of the peripheral domain of a NADH dehydrogenase related protein; bacterial FMN dehygrogenase PDB 2FUG. This structure omits a large transmembrane domain, which lies to the bottom of the image and extends to the right. This section of the complex lies in the mitochondrial matrix.

The electron carriers of the NADH dehydrogenease complex. Seven primary iron sulphur centers lie in a line down the peripheral arm of the complex to carry electrons from the site of NADH dehydration to ubiquinone. The iron sulphur group on the right is not found in the eukaryotic complex. Note: This image includes two errors. At the top, it should indicate NADH ---> NAD⁺ via a FMN electron carrier/cofactor. At the bottom, it should indicate Ubiquinone ---> Ubiquinol.

NADH dehydrogenase (EC 1.6.5.3) is an enzyme located in the inner mitochondrial membrane that catalyzes the transfer of electrons from NADH to coenzyme Q (CoQ). It is also called the NADH:quinone oxidoreductase.

[edit] Reaction

NADH Dehydrogenase is the first enzyme (complex I) of the mitochondrial electron transport chain.

NADH + H⁺ + CoQ + 4H⁺_in → NAD⁺ + CoQH₂ + 4H⁺_out

In this process, the complex translocates 4 protons across the inner membrane per molecule of oxidised NADH, helping to build the electrochemical potential used to produce ATP. The reaction is reversible and the exact catalytic mechanism remains unknown.

[edit] Composition and structure

NADH Dehydrogenase is the largest of the respiratory complexes, the mammalian enzyme containing 45 separate polypeptide chains. Of particular functional importance are the flavin prosthetic group and eight iron-sulfur clusters (FeS). Of the 45 subunits, seven are encoded by the mitochondrial genome ^{[1] [2]}. The structure is an "L" shape with a long membrane domain (with around 60 trans-membrane helices) and a hydrophilic peripheral domain, which includes all the known redox centres and the NADH binding site. Whereas the structure of the eukaryotic complex is not well characterised, the peripheral/hydrophilic domain of the complex from a bacterium (Thermus thermophilus) has been crystallised (PDB: 2FUG) ^[3].

[edit] Inhibitor

The best-known inhibitor of complex I is Rotenone (used as an organic pesticide). Rotenone and rotenoids are isoflavonoids occurring in several genera of tropical leguminosae plants such as Derris (Papilionaceae), Antonia (Loganiaceae) and Lonchocarpus (Fabaceae). There have been reports of rotenone-containing plants used by Indians to fish due to its ichthyotoxic effect, as early as the 17th century (Biet 1664 apud Moretti & Grenand 1982). 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.

Despite of more than 50 years of study of NADH:ubiquinone oxidoreductase no inhibitors dissecting the electron flow inside the enzyme were found. Hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal FeS cluster N2 and ubiquinone. Enzyme is also blocked by adenosine diphosphate ribose - reversible competitive inhibitor of NADH oxidation by the enzyme at the nucleotide binding site. Both hydrophylic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway respectively.

[edit] Active/de-active transition

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, “de-activated”, 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 de-active, but not the active form of Complex I was susceptible to inhibition by nitrosothiols and peroxynitrite ^[4] . It is likely that transition from the active to the deactive 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 ^[5]).

[edit] Pathology

Mutations in the subunits of complex I can cause mitochondrial diseases, including Leigh syndrome.

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 II, leak electron to oxygen, forming highly toxic superoxide). In fact, recent investigations suggest that reverse electron transfer through Complex I might be the most important site of superoxide production within mitochondria.

[edit] Genes

• 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)
• NDUFV1 - NADH dehydrogenase (ubiquinone) flavoprotein 1, 51kDa
• NDUFV2 - NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa
• NDUFV3 - NADH dehydrogenase (ubiquinone) flavoprotein 3, 10kDa
• 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

[edit] References

1. ^ Voet, D, & Voet, J. G, (2004) Biochemistry, 3rd Edition, John Wiley and Sons, pps 813-826
2. ^ Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE. (2006). "Bovine complex I is a complex of 45 different subunits". J.Biol.Chem. 281: 32724-32727. PMID 16950771. 
3. ^ Sazanov L.A., Hinchliffe P. (2006) Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus. Science 311, 1430-1436.
4. ^ Galkin A., Moncada S. (2007) S-nitrosation of mitochondrial complex I depends on its structural conformation. J.Biol.Chem., 282, 37448-37453, PMID 17956863
5. ^ Moncada S., Erusalimsky J.D. (2002) Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat.Rev.Mol.Cell.Biol., 3, 214-220, PMID 11994742

[edit] Additional images

ETC

[edit] External links

• Interactive Molecular model of NADH dehydrogenase (Requires MDL Chime)
• Complex I home page at The Scripps Research Institute
• MeSH Electron+Transport+Complex+I
• MeSH NADH+Dehydrogenase

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