SUPEROXIDE DISMUTASES: STRUCTURE, FUNCTION, EVOLUTION

Project: Research project

Project Details

Description

Superoxide dismutases are enzymes which catalyze the decomposition of
superoxide, a cytotoxic free radical that is produced in normal oxidative
metabolism and also implicated in the etiology of certain inflammatory
diseases. Three different metalloenzyme forms are known, dismutases
containing manganase, or iron, or both copper and zinc as metal cofactors.
As a superoxide scavenger, Cu-Zn dismutases are used to treat veterinary
inflammations and show promise in clinical trials in humans for managing
rheumatoid arthritis, osteoarthritis, and the side effects of radiation
therapy. Our long-term objectives are to identify the chemical basis of
dismutase structure and catalysis, and to characterize the phylogenetic
distribution and evolutionary relationships among the three forms. These
data are prerequisities for any therapeutic uses of dismutases to be
successful. Our objectives will be pursued on both the protein level,
through determining the amino acid sequences of dismutases representing the
three metalloenzyme forms, and on the DNA level, through isolating and
sequencing the gene for a bacteriocuprein form of dismutase, and using it
to study the distribution of bacteriocuprein in other bacteria and in
primitive eukaryotes. Bacteriocupreins are Cu-Zn dismutases found in
bacteria; all other Cu-Zn dismutases are found in eukaryotes.
Bacteriocupreins have been found in only two species, Photobacterium
leiognathi in 1974 (A.M. Michelson, Paris), and Caulobacter crescentus in
1981 (in my laboratory). Our specific protein structure aims are: (a) to
complete the ongoing amino acid sequence analyses of the Mn dismutase of
chicken liver mitochondria and of the Photobacterium bacteriocuprein, (b)
to perform partial sequence analyses on the Mn dismutase from chimpanzee
liver, the Fe dismutase from E. coli, and the Cu-Zn dismutase of the fish,
Leiognathus nuchalis, in which the P. leiognathi lives as a symbiont. Our
specific aims in characterizing dismutase genes are: (a) to isolate the
gene for bacteriocuprein from C. crescentus and to determine its sequence,
and (b) to use it as a hybridization probe to examine bacteria which lack
expressed bacteriocuprein activity: certain strains of P. leiognathi,
enteric bacteria related to it, bacteria related to Caulobacter, and
Paracoccus denitrificans, for which protein studies have given equivocal
results about the presence of a bacteriocuprein.
StatusFinished
Effective start/end date5/1/8510/31/86

Funding

  • National Institute of General Medical Sciences

ASJC

  • Applied Microbiology and Biotechnology
  • Genetics
  • Structural Biology
  • Biochemistry
  • Microbiology

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