Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.3 (complex I)
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NADH: ubiquinone reductase (electron transfer complex I) has been isolated from Neurospora crassa mitochondria as a monodisperse protein-phospholipid-Triton X-100 complex (1:0.04:0.15, by weight). The enzyme is in the monomeric state, has a protein molecular weight of 610,000 and consists of about 25 different subunits. Membrane crystals of the enzyme complex have been prepared by adding mixed phospholipid-Triton X-100 micelles and then removing the Triton by dialysis. Diffraction patterns of the negatively stained membrane crystals extend to about 3.9 nm, with a unit cell size of 19 nm X 38 nm and gamma = 90 degrees. The two-sided plane group packing corresponding to pgg is p22(1)2(1). By combining four sets of tilted views, a low-resolution three-dimensional structure of the protein has been calculated. The structure shows that NADH: ubiquinone reductase extends 15 nm across the membrane, projecting 9 nm from one membrane side and 1 nm from the opposite side. Only about one-third of the total protein mass is located in the membrane. The structure of NADH: ubiquinone reductase is compared with that of ubiquinol: cytochrome c reductase determined by electron microscopy of membrane crystals.
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PMID:Three-dimensional structure of NADH: ubiquinone reductase (complex I) from Neurospora mitochondria determined by electron microscopy of membrane crystals. 295 29

Respiratory complex I (NADH:ubiquinone oxidoreductase) is an L-shaped multisubunit protein assembly consisting of a hydrophobic membrane arm and a hydrophilic peripheral arm. It catalyses the transfer of two electrons from NADH to quinone coupled to the translocation of four protons across the membrane. Although we have solved recently the crystal structure of the peripheral arm, the structure of the complete enzyme and the coupling mechanism are not yet known. The membrane domain of Escherichia coli complex I consists of seven different subunits with total molecular mass of 258 kDa. It is significantly more stable than the whole enzyme, which allowed us to obtain well-ordered two-dimensional crystals of the domain, belonging to the space group p22(1)2(1). Comparison of the projection map of negatively stained crystals with previously published low-resolution structures indicated that the characteristic curved shape of the membrane domain is remarkably well conserved between bacterial and mitochondrial enzymes, helping us to interpret projection maps in the context of the intact complex. Two pronounced stain-excluding densities at the distal end of the membrane domain are likely to represent the two large antiporter-like subunits NuoL and NuoM. Cryo-electron microscopy on frozen-hydrated crystals allowed us to calculate a projection map at 8 A resolution. About 60 transmembrane alpha-helices, both perpendicular to the membrane plane and tilted, are present within one membrane domain, which is consistent with secondary structure predictions. A possible binding site and access channel for quinone are found at the interface with the peripheral arm. Tentative assignment of individual subunits to the features of the map has been made. The location of subunits NuoL and NuoM at substantial distance from the peripheral arm, which contains all the redox centres of the complex, indicates that conformational changes are likely to play a role in the mechanism of coupling between electron transfer and proton pumping.
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PMID:Projection structure of the membrane domain of Escherichia coli respiratory complex I at 8 A resolution. 1715 74

The role for mitochondrial electron transport chain (ETC) in neurogenic hypertension is unidentified. We evaluated the hypothesis that feedforward depression of mitochondrial ETC functions by superoxide anion (O(2)(.-)) and hydrogen peroxide (H(2)O(2)) in rostral ventrolateral medulla (RVLM), a brain stem site that maintains sympathetic vasomotor tone and contributes to oxidative stress and neural mechanism of hypertension. Compared with normotensive Wistar-Kyoto rats, spontaneously hypertensive rats exhibited mitochondrial ETC dysfunctions in RVLM in the forms of depressed complex I or III activity and reduced electron coupling capacity between complexes I and III or II and III. Microinjection of coenzyme Q(10) into RVLM of spontaneously hypertensive rats reversed the depressed ETC activity and augmented O(2)(.-) production and hypertensive phenotypes. This mobile electron carrier also antagonized the elevated H(2)O(2) in RVLM and vasopressor responses to complex I (rotenone) or III (antimycin A) inhibitor in Wistar-Kyoto or prehypertensive rats. Intracerebroventricular infusion of angiotensin II promoted mitochondrial ETC dysfunctions in Wistar-Kyoto rats, and coenzyme Q(10) or gene knockdown of the p22(phox) subunit of NADPH oxidase antagonized the resultant elevation of H(2)O(2) in RVLM. Overexpression of superoxide dismutase or catalase in RVLM of spontaneously hypertensive rats by gene transfer reversed mitochondrial dysfunctions and blunted the augmented O(2)(.-) and H(2)O(2) in RVLM. We conclude that O(2)(.-)- and H(2)O(2)-dependent feedforward impairment of mitochondrial ETC complexes because of predisposed downregulation of superoxide dismutase or catalase and a cross-talk between NADPH oxidase-derived O(2)(.-) and ETC enzymes contribute to chronic oxidative stress in the RVLM of spontaneously hypertensive rats, leading to augmented sympathetic vasomotor tone and hypertension.
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PMID:Oxidative impairment of mitochondrial electron transport chain complexes in rostral ventrolateral medulla contributes to neurogenic hypertension. 1911 41