Grant: Operating Grant

Bacteria, plants and animals require molybdenum as an essential nutrient. It is found in trace amounts in food, is taken up by our cells, and is incorporated into enzymes critical for human health. For it to be incorporated into enzymes, it must be combined with a complicated chemical compound to form what is called molybdenum cofactor. There are two critical molybdenum enzymes that impact human health: these are sulfite oxidase and xanthine oxidase. Sulfite oxidase is required for normal brain development and children born with a genetic defect in this enzyme are gravely ill and die soon after birth. In some patients, the defect has been traced to an inability to make molybdenum cofactor, and it has recently been demonstrated that treatment is possible by injecting them with molybdenum cofactor isolated from bacteria. Xanthine oxidase is another molybdenum enzyme that degrades certain chemicals called purines in our body. If this enzyme does not function correctly we develop gout, a painful disease caused by crystal formation of purines in our joints. We and others discovered that many species of bacteria, including many that cause bacterial infections, use molybdenum enzymes to convert the nutrients they subsist on into more usable forms of energy, allowing them to grow and multiply. Thus understanding molybdenum enzymes has important implications for fighting bacterial infections. Why have some enzymes evolved to require molybdenum? How is the molybdenum-containing cofactor made in cells? How is it incorporated into enzymes? What does the cofactor do in enzymes, that is, how does it work? As there is great similarity between molybdenum-containing enzymes from bacteria to humans, we use bacterial enzymes for our research as they are easier to isolate and modify by genetic manipulation. In our research we address these questions by conducting sophisticated experiments using cutting edge techniques.