PDBsum entry: 1p1v

Oxidoreductase

PDB id: 1p1v

Contents

Protein chains

146 a.a. *

Ligands

SO4 ×3

Metals

_ZN ×6

Waters ×736

* Residue conservation analysis

PDB id:

1p1v

Name:

Oxidoreductase

Title:

Crystal structure of fals-associated human copper-zinc superoxide dismutase (cuznsod) mutant d125h to 1.4a

Structure:

Superoxide dismutase [cu-zn]. Chain: a, b, c. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: sod1. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.

Biol. unit:

Dimer (from PDB file)

Resolution:

1.40Å R-factor: 0.147 R-free: 0.212

Authors:

J.S.Elam,K.Malek,J.A.Rodriguez,P.A.Doucette,A.B.Taylor, L.J.Hayward,D.E.Cabelli,J.S.Valentine,P.J.Hart

Key ref:

J.S.Elam et al. (2003). An alternative mechanism of bicarbonate-mediated peroxidation by copper-zinc superoxide dismutase: rates enhanced via proposed enzyme-associated peroxycarbonate intermediate. J Biol Chem, 278, 21032-21039. PubMed id: 12649272 DOI: 10.1074/jbc.M300484200

Date:

14-Apr-03 Release date: 26-Aug-03

Protein chains

P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn]

Seq: 154 a.a.

Struc: 146 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.15.1.1 - Superoxide dismutase.
• Reaction: 2 superoxide + 2 H⁺ = O₂ + H₂O₂
• Cofactor: Iron or manganese or (zinc and copper)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (15 terms)
• Biological process: aging (57 terms)
• Biochemical function: antioxidant activity (10 terms)

Added reference

DOI no: 10.1074/jbc.M300484200

J Biol Chem 278:21032-21039 (2003)

PubMed id: 12649272

An alternative mechanism of bicarbonate-mediated peroxidation by copper-zinc superoxide dismutase: rates enhanced via proposed enzyme-associated peroxycarbonate intermediate.

J.S.Elam, K.Malek, J.A.Rodriguez, P.A.Doucette, A.B.Taylor, L.J.Hayward, D.E.Cabelli, J.S.Valentine, P.J.Hart.

ABSTRACT

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.

Selected figure(s)

Figure 2.
FIG. 2. X-ray crystal structure of the copper-binding site of FALS SOD1 mutant D125H. A, the active site of one monomer of D125H is superimposed on 1.4 Å electron density with coefficients 2mF[o] - DF[c] contoured at 1.3 . The histidine copper ligands and zinc ions are labeled. A sulfate anion (green and yellow, all of the oxygen atoms with the exception of the one designated with a red asterisk) is found associated with Arg-143 in the anion-binding site and is bound to the zinc ion through its OX1 atom. Bicarbonate anion (yellow, OX1, OX2, and oxygen labeled with the red asterisk) is modeled based on the position of the sulfate anion (see "Experimental Procedures"). The side chain of Asn-26 (green) comes from a symmetry-related molecule in the crystal lattice and hydrogen bonds simultaneously to the OX2 atom of the oxyanion and to the carbonyl oxygen atom of Gly-141. B, space-filling model of the D125H active site with bound bicarbonate when viewed from the solvent. D125H carbon and oxygen atoms are shown in gray, and nitrogen atoms are shown in blue. The carbon atoms of Arg-143 and Thr-137, residues forming the active site channel constriction, are shown in pink. The positive charge on the guanidinium group of Arg-143 is represented by a (+) symbol. Residues known to be oxidatively damaged in the active site through mass spectrometry analyses (13, 14) are shown in light green. The C 1 position of His-120 is indicated (see "Discussion"). The zinc ion is shown in yellow. The carbonate oxygen atoms are labeled OX2 and OX3 (red), and its carbon atom is shown in black.

Figure 3.
FIG. 3. Proposed mechanism for bicarbonate-mediated peroxidation in SOD1 (see "Discussion"). i, Cu(II) is reduced to Cu(I). ii, bicarbonate binds to the anion-binding site in the manner predicted by the D125H SOD1 crystal structure. iii, reacts with bicarbonate to form peroxycarbonate (iv). v, the oxygen radical species formed [O*] may then oxidize endogenous or exogenous substrates, leaving bicarbonate bound to the anion-binding site (vi). B, the attack of an oxygen radical species on one of the histidine copper ligands in SOD1 leads to the formation of a 2-oxo histidine adduct, leading to cofactor loss and enzyme inactivation.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 21032-21039) copyright 2003.

Figures were selected by the author.