1p1v: Difference between revisions
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==Overview== | ==Overview== | ||
Hydrogen peroxide can interact with the active site of copper-zinc | Hydrogen peroxide can interact with the active site of copper-zinc superoxide dismutase (SOD1) to generate a powerful oxidant. This oxidant can either damage amino acid residues at the active site, inactivating the enzyme (the self-oxidative pathway), or oxidize substrates exogenous to the active site, preventing inactivation (the external oxidative pathway). It is well established that the presence of bicarbonate anion dramatically enhances the rate of oxidation of exogenous substrates. Here, we show that bicarbonate also substantially enhances the rate of self-inactivation of human wild type SOD1. Together, these observations suggest that the strong oxidant formed by hydrogen peroxide and SOD1 in the presence of bicarbonate arises from a pathway mechanistically distinct from that producing the oxidant in its absence. Self-inactivation rates are further enhanced in a mutant SOD1 protein (L38V) linked to the fatal neurodegenerative disorder, familial amyotrophic lateral sclerosis. The 1.4 A resolution crystal structure of pathogenic SOD1 mutant D125H reveals the mode of oxyanion binding in the active site channel and implies that phosphate anion attenuates the bicarbonate effect by competing for binding to this site. The orientation of the enzyme-associated oxyanion suggests that both the self-oxidative and external oxidative pathways can proceed through an enzyme-associated peroxycarbonate intermediate. | ||
==Disease== | ==Disease== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Superoxide dismutase]] | [[Category: Superoxide dismutase]] | ||
[[Category: Cabelli, D | [[Category: Cabelli, D E.]] | ||
[[Category: Doucette, P | [[Category: Doucette, P A.]] | ||
[[Category: Elam, J | [[Category: Elam, J S.]] | ||
[[Category: Hart, P | [[Category: Hart, P J.]] | ||
[[Category: Hayward, L | [[Category: Hayward, L J.]] | ||
[[Category: Malek, K.]] | [[Category: Malek, K.]] | ||
[[Category: Rodriguez, J | [[Category: Rodriguez, J A.]] | ||
[[Category: Taylor, A | [[Category: Taylor, A B.]] | ||
[[Category: Valentine, J | [[Category: Valentine, J S.]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
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[[Category: cuznsod peroxidation mechanism]] | [[Category: cuznsod peroxidation mechanism]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:24:09 2008'' | ||
Revision as of 15:24, 21 February 2008
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Crystal Structure of FALS-associated human Copper-Zinc Superoxide Dismutase (CuZnSOD) Mutant D125H to 1.4A
OverviewOverview
Hydrogen peroxide can interact with the active site of copper-zinc superoxide dismutase (SOD1) to generate a powerful oxidant. This oxidant can either damage amino acid residues at the active site, inactivating the enzyme (the self-oxidative pathway), or oxidize substrates exogenous to the active site, preventing inactivation (the external oxidative pathway). It is well established that the presence of bicarbonate anion dramatically enhances the rate of oxidation of exogenous substrates. Here, we show that bicarbonate also substantially enhances the rate of self-inactivation of human wild type SOD1. Together, these observations suggest that the strong oxidant formed by hydrogen peroxide and SOD1 in the presence of bicarbonate arises from a pathway mechanistically distinct from that producing the oxidant in its absence. Self-inactivation rates are further enhanced in a mutant SOD1 protein (L38V) linked to the fatal neurodegenerative disorder, familial amyotrophic lateral sclerosis. The 1.4 A resolution crystal structure of pathogenic SOD1 mutant D125H reveals the mode of oxyanion binding in the active site channel and implies that phosphate anion attenuates the bicarbonate effect by competing for binding to this site. The orientation of the enzyme-associated oxyanion suggests that both the self-oxidative and external oxidative pathways can proceed through an enzyme-associated peroxycarbonate intermediate.
DiseaseDisease
Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]
About this StructureAbout this Structure
1P1V is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Superoxide dismutase, with EC number 1.15.1.1 Full crystallographic information is available from OCA.
ReferenceReference
An alternative mechanism of bicarbonate-mediated peroxidation by copper-zinc superoxide dismutase: rates enhanced via proposed enzyme-associated peroxycarbonate intermediate., Elam JS, Malek K, Rodriguez JA, Doucette PA, Taylor AB, Hayward LJ, Cabelli DE, Valentine JS, Hart PJ, J Biol Chem. 2003 Jun 6;278(23):21032-9. Epub 2003 Mar 20. PMID:12649272
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