Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite

J Neurochem. 1997 Nov;69(5):1936-44. doi: 10.1046/j.1471-4159.1997.69051936.x.


Mutations to Cu/Zn superoxide dismutase (SOD) linked to familial amyotrophic lateral sclerosis (ALS) enhance an unknown toxic reaction that leads to the selective degeneration of motor neurons. However, the question of how >50 different missense mutations produce a common toxic phenotype remains perplexing. We found that the zinc affinity of four ALS-associated SOD mutants was decreased up to 30-fold compared to wild-type SOD but that both mutants and wild-type SOD retained copper with similar affinity. Neurofilament-L (NF-L), one of the most abundant proteins in motor neurons, bound multiple zinc atoms with sufficient affinity to potentially remove zinc from both wild-type and mutant SOD while having a lower affinity for copper. The loss of zinc from wild-type SOD approximately doubled its efficiency for catalyzing peroxynitrite-mediated tyrosine nitration, suggesting that one gained function by SOD in ALS may be an indirect consequence of zinc loss. Nitration of protein-bound tyrosines is a permanent modification that can adversely affect protein function. Thus, the toxicity of ALS-associated SOD mutants may be related to enhanced catalysis of protein nitration subsequent to zinc loss. By acting as a high-capacity zinc sink, NF-L could foster the formation of zinc-deficient SOD within motor neurons.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Animals
  • Binding Sites
  • Catalysis
  • Cloning, Molecular
  • Humans
  • Kinetics
  • Liver
  • Metallothionein / metabolism
  • Models, Structural
  • Mutagenesis, Site-Directed
  • Mutation*
  • Nitrates / metabolism
  • Nitrates / pharmacology*
  • Protein Conformation
  • Rabbits
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / isolation & purification
  • Superoxide Dismutase / metabolism*
  • Tyrosine / metabolism
  • Zinc / metabolism*


  • Nitrates
  • Recombinant Proteins
  • peroxynitric acid
  • Tyrosine
  • Metallothionein
  • Superoxide Dismutase
  • Zinc