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Cytochrome C, Cytochrome B5 and Electron Transfer

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Cytochrome C, Cytochrome B5 and Electron Transfer Cytochrome c, cytochrome b5: electron transfer and new functions 1 Iron Protoporphyrin IX, heme b Heme a Prosthetic group Heme a is a form of heme found A flat and planar structure. In cytochromes a and a3. -. Itself Toxic O2 , H2O2 are formed. Insoluble 2 Covalent bonds Cytochrome c is a major player in membrane associated electron transport systems in bacteria and mitochondria. 3 Myoglobin, Hemoglobin His E7 Distal side Heme iron His F8 Proximal side Myoglobin has a strong affinity for oxygen Heme is located in the hydrophobic site. when it is in the lungs, and where the pressure is around 100 torr. When it reaches Heme Fe interacts with His. the tissues, where it's around 20 torr, the Coordination bond affinity for oxygen is still quite high. This makes myoglobin less efficient of an oxygen Propionates of heme interact with Arg. transporter than hemoglobin, which loses it's Ionic bond affinity for oxygen as the pressure goes down and releases the oxygen into the tissues. Heme is easily dissociated from the protein. Myoglobin's strong affinity for oxygen means that it keeps the oxygen binded to itself His (E7) is the oxygen binding site. instead of releasing it into the tissues. 4 Sickle cell anemia & malaria resistance In sickle cell hemoglobin (HbS) glutamic acid in position 6 (in beta chain) is mutated to valine. This change allows the deoxygenated form of the hemoglobin to stick to itself. 5 Figure 1. HO-1 Protects against Severe Malaria Using a mouse model for cerebral malaria, Ferreira et al. (2011) suggest a biochemical basis for the link between sickle cell disease and severe malaria. The figure shows a molecular pathway that may explain why carriers of the sickle cell trait, who are heterozygous for the mutation that causes the disease (HbS), may have more resistance to severe malaria symptoms. Mice harboring the human HbS allele have elevated levels of free heme in the blood. Free heme is toxic and can cause oxidative damage, but its effects are suppressed by the upregulation of heme oxygenase-1 (HO-1), which converts heme into the antioxidant molecules carbon monoxide (CO) and biliverdin and releases iron to bind to ferritin H chain (FtH). HO-1 expression is regulated by Nrf2. In individuals with the sickle cell trait, the elevated levels of carbon monoxide prior to infection may inhibit pathogenic CD8+ T cell immune responses and also prevent Cell 145, 335 (2011). oxidative tissue damage during severe malaria. 6 - - External axial ligands: O2, CO, NO, CN , H2O, OH Distal side O2 O2 NO OH- Fe(III) Fe(II) Fe(II) Fe(II) Fe(II) His Cys His His Internal axial ligands from protein: His, Cys Proximal side 6-coordinated 5-coordinated Ligand field - - Strong: O2, CO, NO – heme Fe(II), OH , CN - heme Fe(III) Low spin complex - 3- Weak: vacant, H2O – heme Fe(II), H2O, F , N - heme Fe(III) High spin complex 7 Iron Protoporphyrin IX, heme b Heme a Prosthetic group Heme a is a form of heme found A flat and planar structure. In cytochromes a and a3. -. Itself Toxic O2 , H2O2 are formed. Insoluble 8 6-coordinate low-spin Cytochrome c has two axial ligands to the heme iron complex. Cytochrome c does not have the vacant pocket to receive O2 or CO. 9 Cytochrome c has no O (CO, NO) binding pocket, different from myoglobin and hemoglobin. 2 Nat. Chem. Biol. 1, 223 (2005). Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B- cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidation during apoptosis. The oxidation is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of 10 reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation. - - External axial ligands: O2, CO, NO, CN , H2O, OH Distal side O2 Met NO OH- Fe(III) Fe(II) Fe(II) Fe(II) Fe(II) His His His His Internal axial ligands from protei: His, Cys Proximal side 6-coordinated 5-coordinated Ligand field - - Strong: O2, CO, NO – heme Fe(II), OH , CN - heme Fe(III) Low spin complex - 3- Weak: vacant, H2O – heme Fe(II), H2O, F , N - heme Fe(III) High spin complex 11 Complex I Complex III Complex IV The red line traces the path of electrons released from a molecule called NADH. The electrons pass through three different membrane complexes called complex I, complex III, and complex IV. At each step, protons are pumped across the membrane. In complex IV (not complex III! Upper is wrong!) the electrons are passed to oxygen (O2) to make water. This final step is why you need oxygen to live. 12 Complex III 13 Ubiquinone and the Proton Pump Ubiquinone is a lipid soluble cofactor that accepts and donates electrons in oxidation- reduction reactions. These are reactions in which electrons are transferred from one molecule (oxidation) and accepted by another (reduction). Quinones play a role in pumping proteins across a membrane in order to create a proton gradient that's used to make ATP. Note that when two electrons are taken up, two protons (H+) are added to neutralize the negative charge. In the reverse reaction (ubiquinol to ubiquinone: bottom to top) two protons are released when the electrons are given up. 14 Complex III 15 Cytochrome c plays a key part in electron transport associated with aerobic cellular respiration. Cytochrome c is a small heme protein which is associated with the inner membrane of the mitochondria. In the electron transport process it transfers electrons between Complex III and Complex IV. 16 Cytochrome c oxidase or Complex IV is a large transmembrane protein complex Found in bacteria and mitochondria. 2+ + 4 Fe -cytochrome c + 8 H in + O2 3+ 2 + 4 Fe -cytochrome c + 2 H O + 4 H out 17 Subunits I and II of Complex IV excluding all other subunits. 18 Complex IV Two electrons are passed from two cytochrome c's, through the CuA and cytochrome a sites to the cytochrome a3- CuB binuclear center, reducing the metals to the Fe+2 form and Cu+1. The hydroxide ligand is protonated and lost as water, creating a void between the metals that is filled by O2. The oxygen is rapidly reduced, with two electrons +2 coming from the Fe cytochrome a3, which is converted to the ferryl +4 oxo form (Fe =O). The oxygen atom close to CuB picks up one electron from Cu+1, and a second electron and a proton from the hydroxyl of Tyr(244), which becomes a tyrosyl radical: The ....... 19 A cytochrome complex plays a key part in electron transport associated with the membranes of the thylakoids in the process of photosynthesis. It accepts electrons from Photosystem II through plastoquinone and contributes to proton transport across the membrane. 20 Cytochrome c has no O (CO, NO) binding pocket, different from myoglobin and hemoglobin. 2 Nat. Chem. Biol. 1, 223 (2005). Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B- cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidation during apoptosis. The oxidation is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of 21 reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation. Apoptosis – the programmed death of a cell 22 Nature Rev. Immu. 2, 527 (2002) Schematic diagram of death receptor (DR) and mitochondrial pathways for the induction of apoptosis. Apoptosis can be induced by DR ligation (for example, FAS–FASL) or by the disruption of mitochondrial integrity, such as occurs after DNA damage by cytotoxic agents or UV irradiation. DR-induced caspase activation is suppressed by FLIP, which interferes with caspase-8 activation. Induction of the DR pathway, which results in the activation of caspase-8, might lead directly to the activation of caspase-3, without requiring mitochondrial damage, or it might proceed though BID, resulting in the loss of mitochondrial transmembrane potential and the release of cytochrome c into the cytoplasm. Cytochrome c, in the presence of APAF1 and ATP, activates caspase-9, which results in the activation of caspase-3. The anti- apoptotic molecules Bcl-2 and Bcl-XL protect against the loss of mitochondrial transmembrane potential that is induced by pro-apoptotic molecules, such as BAX and BAK.
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