MECHANISM OF FLAVOPROTEIN REDUCTASES

Project: Research project

Project Details

Description

DESCRIPTION (adapted from applicant's abstract): This competing continuation
application proposes the extension of mechanistic and structural analyses of
flavoenzymes that function in key physiological and protective roles in
microorganisms. Typical examples of flavoprotein disulfide reductases that
serve this function include the sequence-related alkylhydroperoxide reductase,
NADH peroxidase, glutathione reductase and the trypanosomal ortholog,
trypanothione reductase, found uniquely in parasitic protozoans. With the
determination of the genome sequence of the human pathogenic bacterium,
Mycobacterium tuberculosis, the identification of putative flavin-containing
enzymes using advanced sequence searching methods has become possible. Using
these methods, a number of genes have been identified which are likely to
encode flavoproteins. The subsequent cloning of these genes, and the expression
and purification of the gene products has confirmed putative assignments based
on primary sequence considerations.

One example of the application of this method includes the identification of
the flavin-containing disulfide reductase that catalyzes the reduction of the
oxidized form of mycothiol; a recently discovered, structurally unique thiol
present at high concentrations in mycobacteria and a limited number of
additional bacterial species. It is likely that this enzyme is responsible for
maintaining a reducing intracellular environment, and may contribute to the
ability of the bacterium to survive the hostile oxidizing environment
encountered in the macrophage phagolysosomal compartment. Two other
sequence-related flavoenzymes have been identified, and the principal
investigator will attempt to define the physiological function of these two
proteins, determine their chemical mechanism and attempt to determine their
three-dimensional structure. The principal investigator proposes that these
latter enzymes play key roles in the oxidative stress management, survival of
the organism and propagation of the infection. The experiments described are
designed to assess these roles, and if found to be correct, could ultimately
lead to the development of specific inhibitors with chemotherapeutic utility.
StatusFinished
Effective start/end date1/1/901/31/06

ASJC

  • Physiology
  • Catalysis
  • Microbiology

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