Lecture 9 e- transfer proteins Iron-sulfur proteins

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Lecture 9 e- transfer proteins Iron-sulfur proteins

Gordon, John, Morning Host has reference to this Academic Journal, PHwiki organized this Journal Lecture 9 Redox metallo-biochemistry (continued) e- transfer proteins Cytochromes Fe-S proteins Blue copper proteins Kinetics of electron transfer reactions Electron transfer between 2 metal centers can be either inner-sphere (via a bridging lig in addition to ) or outer-sphere (no bridging lig in addition to , coordination spheres remain the same as long as both metal ions) Only outer-sphere known as long as metalloproteins Reasonably fast (> 10 s-1) over large distances (up to 30 Å) Can be rationalised by Marcus Theory Qualitatively: e- transfer is fast if the states be as long as e in addition to after the redox reactions are similar (reorganisation energy is small)

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Cytochromes Name comes from the fact that they are coloured Differ by axial lig in addition to s in addition to whether covalently bound Involved in electron transfer (a,b,c) or oxygen activation (P450) Essential as long as many redox reactions UV-Vis Spectra of cytochromes Absorption spectra of oxidized (Fe(III) in addition to reduced (Fe(II)) horse cytochrome c. classified by a b in addition to s: a: 580-590 nm b: 550-560 nm c: 548-552 nm (there’s also d in addition to f) all involved in electron transfer, all CN6 P450: 450 nm: Oxygen activation; CN5 Cytochrome c Small soluble proteins (ca. 12 kDa) Near inner membrane of mitochondria Transfers electrons between 2 membrane proteins ( as long as respiration) Heme is covalently linked to protein via vinyl groups (thioether bonds with Cys) 1 Met in addition to 1 His lig in addition to (axial) Conserved from bacteria to Man horse heart cytochrome c Bushnell, G.W., Louie, G.V., Brayer, G.D. J.Mol.Biol. v214 pp.585-595 , 1990

Cytochromes b Heme has no covalent link to protein Two axial His lig in addition to s Shown is only soluble domain; the intact protein is bound to membrane F Arnesano, L Banci, I Bertini, IC Felli: The solution structure of oxidized rat microsomal cytochrome b5. Biochemistry (1998) 37, 173-84. Not as long as electron transfer: the cytochromes P450 CN5, axial lig in addition to is a Cys 6th site as long as substrate/oxygen binding Hydroxylates camphor P450Cam Tuning of heme function In (deoxy)hemoglobin, Fe(II) is 5-coordinate Must avoid oxidation to Fe(III) (Met-hemoglobin) Neutral His lig in addition to : His-Fe(II)-porphyrin is uncharged: Favourable P450: Catalyses hydroxylation of hydrophobic substrates. Also 5-coordinate 1 axial Cys thiolate lig in addition to (negatively charged): Resting state is Fe(III), also uncharged In cytochromes, CN=6: No binding of additional lig in addition to , but very effective 1 e- transfer

Iron-sulfur proteins Fe-S proteins Probably amongst the first enzymes Generally, Fe, Cys thiolate in addition to sulfide Main function: fast e- transfer At least 13 Fe-S clusters in mitochondrial respiration chain Rubredoxins: mononuclear FeCys4 site Ferredoxins: 2,3 or 4 irons Other functions: Aconitase: An isomerase IRE-BP: An iron sensor (see lecture 5) Rubredoxins: FeCys4 X-ray Structure of RUBREDOXIN from Desulfovibrio gigas at 1.4 A resolution. FREY, M., SIEKER, L.C., PAYAN, F.

Fe2S2(Cys-S)4 Fe2S2(Cys-S)2-(His-N)2: Rieske proteins Fe4S4(Cys-S)4 Fe3S4(Cys-S)4 1 awd: CHLORELLA FUSCA 1fda: Azotobacter vinel in addition to ii 1rfs: Spinach Fe-S clusters can be easily synthesised from Fe(III), sulfide in addition to organic thiols, but are prone to rapid oxidation Richard Holm Self-assembly of Fe-S clusters Delocalisation of electrons: Mixed valence localized Fe3+ (red) in addition to localized Fe2+ (blue) sites, in addition to delocalized Fe2.5+Fe2.5+ pairs (green) Why e- transfer is fast: Clusters can delocalize the “added” electron minimizes bond length changes decreases reorganization energy

Azotobacter vinel in addition to ii: 2 clusters Fe-S proteins often contain more than one cluster: The five Fe-S clusters of the Fe-only hydrogenase from Clostridium pasteurianum Activation of H2 Active site (binuclear Fe cluster) on top The other five Fe-S clusters provide long-range electron transfer pathways Pdb 1feh P cluster of nitrogenase FeMoCo cofactor cluster of nitrogenase

Nitrogenase (Klebsiella pneumoniae) Catalyses nitrogen fixation N2 + 8H+ + 8e- + 16 ATP 2NH3 + H2 + 16ADP + 16 Pi Redox potentials Tuning of redox potentials For both heme proteins in addition to Fe-S clusters, lig in addition to s coarsely tune redox potential In [4Fe-4S] clusters, proteins can stabilise a particular redox couple Further effects (a) solvent exposure of the cluster (b) specific hydrogen bonding networks especially NH-S bonds (c) the proximity in addition to orientation of protein backbone in addition to side chain dipoles (d) the proximity of charged residues to the cluster

Tuning of redox potentials Bacterial ferredoxins in addition to HiPIPs: Both have Fe4S4Cys4 clusters -400 mV vs. +350 mV Ferredoxins: [Fe4S4Cys4]3- [Fe4S4Cys4]2- HiPIPs: [Fe4S4Cys4]2- [Fe4S4Cys4]1- HiPIPs are more hydrophobic: Favours -1 NH S bonds: 8-9 in Fd, only 5 in HiPIPs Compensate charge on cluster; -3 favoured ) HiPIP: high potential iron-sulfur proteins Copper proteins Copper proteins Oxidases Cytochrome oxidase(s) Enzymes dealing with oxides of nitrogen Blue copper proteins Superoxide dismutase Tyrosinase Caeruloplasmin

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Principles Cu(II) as long as ms the strongest M(II) complexes (see Irving Williams series) Cu(I) also as long as ms stable complexes The Cu(I)/Cu(II) redox couple: 0.2V-0.8V Most Cu proteins either extracellular or membrane-bound Many Cu proteins involved in electron transfer Preferred geometries Cu(II): Tetrahedron Cu(I): trigonal planar or 2-coordinate Blue copper proteins Azurin, stellacyanin, plastocyanin Unusual coordination geometry: Another example as long as how proteins tune metal properties Consequences: Curious absorption in addition to EPR spectra High redox potential (Cu(I) favoured) No geometric rearrangement as long as redox reaction: Very fast

2.9 Å 2.11 Å Amicyanin (pdb 1aac) from Paracoccus denitrificans Blue copper proteins: coordination geometry Angles also deviate strongly from ideal tetrahedron (84-136°) Key points Properties such as redox potentials are tuned by proteins Coarse tuning by metal lig in addition to s Charge imposed by lig in addition to can favour particular oxidation state Geometry can be imposed by protein: Can favour particular oxidation state, in addition to also increase reaction rate Fine tuning by “second shell”: hydrophobicity, hydrogen bonds, charges in vicinity

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