Cytochrome c Oxidase and the Regulation of Oxidative Phosphorylation

Ludwig, Bernd; Bender, Elisabeth; Arnold, Susanne; Hüttemann, Maik; Lee, Icksoo; Kadenbach, Bernhard

doi:10.1002/1439-7633(20010601)2:6<392::aid-cbic392>3.0.co;2-n

Cited by 198 publications

(105 citation statements)

References 133 publications

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“…On the other hand, some of the candidate genes play a crucial role in catabolism like PSAT1, which is catalyzing the second step in the biosynthesis of the amino acid serine (33), which in turn is the crucial carbon source for purine nucleotides, phosphatidylcholine and phosphatidylserine, and other cellular metabolites (33). Another identified gene, COX7A2L, codes for the cytochrome c oxidase subunit VIIA subunit 2L that is involved in energy expenditure (34). Finally, expression of two of the identified genes, S100A2 and SFN, marks a myoepithelial-like breast (cancer) cell type (35).…”

Section: Discussionmentioning

confidence: 99%

Association of DNA Methylation of Phosphoserine Aminotransferase with Response to Endocrine Therapy in Patients with Recurrent Breast Cancer

et al. 2005

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To understand the biological basis of resistance to endocrine therapy is of utmost importance in patients with steroid hormone receptor-positive breast cancer. Not only will this allow us prediction of therapy success, it may also lead to novel therapies for patients resistant to current endocrine therapy. DNA methylation in the promoter regions of genes is a prominent epigenetic gene silencing mechanism that contributes to breast cancer biology. In the current study, we investigated whether promoter DNA methylation could be associated with resistance to endocrine therapy in patients with recurrent breast cancer. Using a microarray-based technology, the promoter DNA methylation status of 117 candidate genes was studied in a cohort of 200 steroid hormone receptor-positive tumors of patients who received the antiestrogen tamoxifen as first-line treatment for recurrent breast cancer. Of the genes analyzed, the promoter DNA methylation status of 10 genes was significantly associated with clinical outcome of tamoxifen therapy. The association of the promoter hypermethylation of the strongest marker, phosphoserine aminotransferase (PSAT1) with favorable clinical outcome was confirmed by an independent quantitative DNA methylation detection method. Furthermore, the extent of DNA methylation of PSAT1 was inversely associated with its expression at the mRNA level. Finally, also at the mRNA level, PSAT1 was a predictor of tamoxifen therapy response. Concluding, our work indicates that promoter hypermethylation and mRNA expression of PSAT1 are indicators of response to tamoxifen-based endocrine therapy in steroid hormone receptor-positive patients with recurrent breast cancer.

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Section: Discussionmentioning

confidence: 99%

Association of DNA Methylation of Phosphoserine Aminotransferase with Response to Endocrine Therapy in Patients with Recurrent Breast Cancer

et al. 2005

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“…Proton transfer from Glu-286 to the D-ring propionate of heme a 3 and from there to the bulk outer aqueous phase is speculated to be a likely path for the pumped proton (e.g. Refs.…”

Section: Relating the Electrogenic Data To Proton Pumping Modelsmentioning

confidence: 99%

“…Cytochrome c oxidase (COX) 1 is the terminal enzyme of the aerobic respiratory chain in mitochondria and in many prokaryotes (1)(2)(3)(4). The enzyme conducts electrons from cytochrome c to O 2 and couples the energetically downhill electron transfer to the uphill electrogenic movement of protons across the membrane from the bacterial cytoplasm (or mitochondrial matrix) to the periplasm (or mitochondrial intermembrane space).…”

mentioning

confidence: 99%

Transmembrane Charge Separation during the Ferryl-oxo → Oxidized Transition in a Nonpumping Mutant of Cytochrome c Oxidase

Siletsky

Pawate

Weiss³

et al. 2004

Journal of Biological Chemistry

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Cytochrome c oxidase (COX) 1 is the terminal enzyme of the aerobic respiratory chain in mitochondria and in many prokaryotes (1-4). The enzyme conducts electrons from cytochrome c to O 2 and couples the energetically downhill electron transfer to the uphill electrogenic movement of protons across the membrane from the bacterial cytoplasm (or mitochondrial matrix) to the periplasm (or mitochondrial intermembrane space).The transmembrane charge separation by COX involves two different mechanisms. Half of the free energy (corresponding to the transmembrane translocation of four elementary electric charges per dioxygen reduced) is conserved by a direct mechanism; the four electrons and four protons required to convert O 2 to water come from opposite sides of the membrane. This direct mechanism was postulated by Mitchell (5, 6) in the original chemiosmotic hypothesis. Charge separation via this mechanism is an intrinsic part of the reaction chemistry and cannot be dissociated from it without re-engineering the proton and/or electron delivery pathways to the active site. Any mutation resulting in inhibition of this electrogenic function would inevitably inhibit electron transfer activity of the enzyme.The other half of the free energy is conserved by virtue of "proton pumping" discovered by Wikström in 1977 (7) and resulting in the transmembrane electrogenic translocation of four more protons per catalytic cycle. This proton pumping occurs by an "indirect" coupling mechanism and is not an obligatory part of the reaction chemistry. In principle, residues constituting the proton pump may be located in a separate part of the protein from the catalytic center, and the coupling can occur by virtue of finely tuned mechano-electrical interactions mediated by minor conformational changes of the protein (cf. Refs. 8 and 9).The indirect coupling of the proton pump has been demonstrated recently by the isolation of cytochrome oxidase mutants that have full catalytic electron transfer activity but that do not pump protons. This was first shown for the N131D mutant of the COX from Paracoccus denitrificans (10), which places an aspartic acid residue near the entrance of the D-channel. This mutant COX has wild type oxidase activity but does not pump protons (10), which is exactly the phenotype expected for cytochrome oxidase in which electron transfer is decoupled from proton translocation at the molecular level. The equivalent mutant of the COX from Rhodobacter sphaeroides, N139D,

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“…1A) that catalyzes the four-electron reduction of O 2 to H 2 O during the terminal step of respiration (25)(26)(27). By translocating protons across the membrane, this process maintains a transmembrane proton gradient, which provides the energy required to phosphorylate ADP to ATP and generates heat in the mitochondria (28,29). A molecule having all of the components of CcO's active site has been synthesized.…”

mentioning

confidence: 99%

Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation

Collman

Ghosh²,

Dey³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

151

142

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Cytochrome c Oxidase and the Regulation of Oxidative Phosphorylation

Cited by 198 publications

References 133 publications

Association of DNA Methylation of Phosphoserine Aminotransferase with Response to Endocrine Therapy in Patients with Recurrent Breast Cancer

Association of DNA Methylation of Phosphoserine Aminotransferase with Response to Endocrine Therapy in Patients with Recurrent Breast Cancer

Transmembrane Charge Separation during the Ferryl-oxo → Oxidized Transition in a Nonpumping Mutant of Cytochrome c Oxidase

Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation

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