A Tour of Cu-Zu Superoxide Dismutase


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Cu-Zn Superoxide Dismutase is a metalloenzyme that functions to disproportionate the superoxide ion.

ECu(II) + O2- arrows (1K) ECu(I) + O2

ECu(I) + O2- + 2H+ arrows (1K) ECu(II) + H2O2

-------------------------------------------------------------

2(O2-) + 2H+ arrows (1K) H2O2 + O2

where E represents the enzyme.

The mechanism of this reaction is referred to as a "ping-pong" because of the shuttling back and fourth of copper between its two oxidation states. The role of this enzyme is to protect biological tissue from any superoxide ion.

The polypeptide backbone is mainly composed of β-sheets, which are coloured in red. Two of these polypeptide chains form the dimer in Cu2Zn2-Superoxide Dismutase, which is displayed here. The Cu ion is coloured here in green and the Zn ion is coloured in magenta.

There is a conical channel approximately 4 Å wide at the copper (green) which is exposed to the external environment. Lining this channel are positively charged amino-acid side chain residues. The farthest residue is Lys134, which is approximately 13 Å from Cu. This residue is suspected to attract O2- ions, which diffuse over the protein surface.

Four imidazole side chains from histidine ligands coordinate the Cu(II) ion (green sphere). There is some evidence of a fifth axial water ligand. His44 and His46 are in trans position of the distorted square-planar CuN4 coordination sphere. The tripeptide sequence His44-Ile45-His46 completely blocks access to the copper from one side of the CuN4 plane. The other side is accessible to solvent.

In addition to the cupric ion at the active site there is also a Zn(II) ion (purple sphere). Coordinated to this ion in a tetrahedral fashion are three histidine residues and the carboxylate group from an aspartic acid residue (labeled). The bridging imidazolate in this enzyme had not been encountered in coordination chemistry prior to this structure determination.

The presence of Zn in this enzyme may have three purposes:

  1. In a proposed mechanism, the imidazolate bridge is broken during each catalytic cycle. The histidine rings (His 69, 78) that are coordinated to the Zn, lower the pKa of the bridging imidazole from 14 to approximately 7 to 10. The nitrogen at the Cu end will prefer to bind to a proton rather than Cu(I) (Lippard, pg. 328 Principle of Bioinorganic Chemistry). Reoxidation of Cu(I) to Cu(II) reforms the bridge, with transfer of the proton to peroxide ion, which is released as H2O2. In this mechanism a vacant site on the Cu(I) is created for the purpose of binding a superoxide ion.
  2. Zn(II) also helps create the electric field gradient that attracts O2- into the conical cavity as mentioned previously. O2 and H2O2, the products of the reaction, are neutral molecules and will diffuse out of the active site readily but the O2- anion cannot.
  3. The Zn ion may also stabilize the overall overall structure of this Cu-Zn Superoxide Dismutase. This enzyme is very stable when heated. When the metals are removed from the enzyme, the stability markedly diminishes.

This is the dimer of Cu-Zu Superoxide Dismutase for you to explore further.

The crystal structure of Cu-Zu Superoxide Dismutase was reported by K.Djinovic et al.in J.Mol.Biol. 1992, 225, 791.


Copyright Robert H. Morris, Adrian Lee and Alen Hadzovic, 1998, 2009, 2011