James A Imlay
DISRUPTION OF SULFUR METABOLISM BY OXIDATIVE STRESS
Molecular oxygen is a reactive chemical, and its gradual accumulation in the environment must have been a problem for early life forms. For kinetic reasons, much of its toxicity is likely to be mediated by its partially reduced form, superoxide (O2-). In fact, virtually all aerobic organisms synthesize an enzyme (superoxide dismutase) devoted to eliminating O2- from the cell. This implies that O2- is formed somehow during aerobic metabolism, and that, unless scavenged, it will harm the cell. This frames the most fundamental questions about superoxide toxicity: How does O2- arise in the cell? What damage can it do? How do cells repair that damage? And when in nature does O2- stress determine cell fate?
Recent work in Professor Imlay’s laboratory has illuminated the mechanism by which intracellular oxygen is converted into O2-. Molecular oxygen intercepts electrons from a subset of the enzymes and carriers that are involved in redox processes. These reactions depend directly on the concentration of oxygen, which explains why hyperoxia is so toxic to bacteria, animals, and humans.
Once formed, O2- can damage a subset of metalloenzymes, blocking the functions of the pathways to which they belong and releasing iron into the cell cytoplasm. The latter event is significant, since loose iron reacts with hydrogen peroxide to generate hydroxyl radicals, which are DNA-damaging oxidants of the type made by X-rays. The consequent lesions have been postulated to be both an engine of evolutionary change and, in higher organisms, an underlying cause of carcinogenesis and aging.
Yet O2- has additional inhibitory effects on cell growth that have been more difficult to explain. During his Center appointment, Professor Imlay will attempt to identify one aspect of its action, the mechanism by which O2- disrupts sulfur metabolism. This effect is one of the most prominent in oxygen-poisoned cells, and it is observed in both bacteria and eukaryotes, suggesting that a solution determined in one system will also be applicable to the other.