A.B., Princeton University, 1956, High honors in Chemistry;
Ph.D. in Biochemistry, Harvard University, 1959
We study the molecular genetics of nitrogen fixation and cellular differentiation in cyanobacteria as well as genes encoding the enzyme acetyl-CoA carboxylase (ACC) in plants, in apicomplexan parasites and in humans. The cyanobacterium Anabaena grows in filaments of 100 cells or more. When starved for nitrogen, specialized cells called heterocysts differentiate from the photosynthetic vegetative cells at regular intervals along each filament. Heterocysts are anaerobic factories for nitrogen fixation; in them, the nitrogenase enzyme complex is synthesized and the oxygen-evolving photosystem II is turned off. More than 1000 genes are differentially expressed during the irreversible development of heterocysts from vegetative cells. We have sequenced genes for nitrogen fixation, for components of the photosynthetic apparatus and for the sigma and core subunits of RNA polymerase. Among mutants unable to fix nitrogen aerobically are some with altered heterocyst pattern or morphology. We have used complementation to isolate the genes defective in many of these mutants. Some encode proteins that participate in environment-sensing regulatory cascades. The structures of these regulatory proteins are being studied by X-ray diffraction.
Fatty acid synthesis begins in all organisms with the reaction catalyzed by ACC. In chicken, rat, yeast and plants all of the ACC domains reside in a single polypeptide. Yeast cells expressing wheat ACC are sensitive to herbicides that target the enzyme. Yeast expressing chimeras of the cytoplasmic and chloroplast form of the wheat ACC permit determination of the amino acid residues responsible for herbicide binding. We also have yeast strains expressing active ACC from Toxoplasma gondii, Leishmania and Cryptosporidium, suitable for screening for new inhibitors of the parasites. We have also constructed yeast strains expressing active human ACC, which serve in screens for new drugs for obesity, because ACC controls fatty acid oxidation