Shelagh Ferguson-Miller Research Interests
Electron transfer
coupled to proton translocation is the basic mechanism of energy
generation in most living organisms, but the molecular mechanism is not
understood. A key enzyme in all eukaryotic and most prokaryotic electron
transfer systems is cytochrome c oxidase, 
which accepts electrons
derived from food and donates them to oxygen, generating a pH and
electrical gradient to drive ATP synthesis.
We are studying mammalian,
plant and bacterial cytochrome c oxidases which differ in peptide
composition but carry out the same reactions using the same metal centers
to catalyze the process. Each of these enzymes offers different advantages
for investigating the molecular mechanism of energy transduction by a
variety of approaches, including kinetic analysis, chemical modification,
physical/spectral techniques, genetic engineering and crystallography. To
understand the molecular basis of electron transfer and coupled proton
translocation, mutants have been prepared in highly conserved residues
predicted to be metal ligands or proton ligands. Extensive spectral and
biochemical analysis has led to a model of the active site and proposed
pathways for proton translocation, which are confirmed by recent high
resolution crystal structures for both prokaryotic and eukaryotic enzymes.
On-going work involves the design of site-directed mutants to further test
these models and efforts to crystallize the oxidase from Rhodobacter
sphaeroides and its mutant forms. The goal is to elucidate how the
oxygen chemistry drives a proton pump, how the process is regulated to
balance fat storage and heat generation, and how aging and disease are
associated with loss of efficiency of energy production.