Catalytic Mechanisms and Biological Roles of Enzymes Involved in Energy Metabolism

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In my research, I learn how enzymes work. An enzyme's job is to speed up a specific reaction, so that the reaction can happen on the time-scale required by a living cell. We study an enzyme by growing crystals of it, similar to crystals of salt in a salt shaker or a diamond. Using our crystals, we are able to get pictures of the enzyme with the molecules it works on. From looking at these pictures, we form ideas of how the enzyme works. We test our ideas by changing the structure of the enzyme and discovering whether it still works. One enzyme we investigate is called succinyl-CoA synthetase. The reaction forming succinyl-CoA uses three molecules: nucleotide triphosphate, succinate and coenzyme A (CoA). From these, the enzyme makes phosphate and nucleotide diphosphate, as well as succinyl-CoA. We would like to discover how the enzyme is able to bind these very different molecules. So far, we have pictures of the enzyme with CoA and with nucleotides. The places on the enzyme where CoA binds and where the nucleotides bind are far apart. Near the CoA, there is a residue of the enzyme that gets phosphorylated during the reaction and this residue is at the tip of a loop of the enzyme. Our idea is that the enzyme swings this loop to shuttle the phosphoryl group between the two binding sites. In this way, the enzyme is able to connect what is happening at one site to what happens at the other. It is able to use two separate binding sites for the molecules it acts on. This may be a general mechanism for enzymes that have to bind three substrates and release three products. Our research will contribute to the basic understanding of enzymes and how they work. Recently, a research group identified patients who suffered from anemia because they had a faulty form of an enzyme that interacts with one form of succinyl-CoA synthetase. Using enzyme that we produced in the lab, we showed that the faulty form of their enzyme could not interact with succinyl-CoA synthetase. Now we are trying to learn how these enzymes interact and why the interaction is important in producing enough heme to prevent anemia.