Canadian Research Chair in Bioinorganic Chemistry
B.A. (Reed College, 1978)
M. Phil. (University of Auckland, 1984)
Ph.D. (University of Auckland, 1989)
PDF (Freiberg, Germany, 1988-1989)
PDF (Stanford University, 1989-1991)
Professor (University of Wyoming, 1991-2002)
- Chemical Biology
Broadly stated our research is one aspect of an area termed chemical biology; it is a part of the general endeavor to learn new chemistry from biology. To this end we take a problem oriented approach and will use any technique, inventing them if need be, to solve problems at the interface of these disciplines. Overall the two main interests in our lab concern unique aspects of the biochemistry in the malaria parasite, and the amazingly diverse chemical biology of nitric oxide. To answer questions relating to these problems we use a combination of structural, synthetic, mechanistic, and theoretical approaches. This research and all of our lab's work is highly interdisciplinary and we collaborate with a diverse group of scientists.
Biological Chemistry of Malaria: The rising human toll of malaria is startling; there are an estimated 200 million new malaria cases annually, and of these some 2.6 million fatalities will result, most amongst children under ten years of age. In addition to these grim statistics, there are many individuals with recurring infections and their attendant side effects of anemia and immune complications. Given this background it is of considerable urgency to find replacements for the once very effect antimalarial family of quinolines, such as quinine or chloroquine, 1. Chloroquine resistant strains of malaria are now widespread; unfortunately no new replacement is undergoing phase III, or IV trials. New drugs are needed to treat this common disease, and it is alarming that our biochemical understanding of the quinoline drug target remains poorly developed. It is known that the quinoline antimalarials inhibit heme detoxification in young trophozoites, and that resistant strains transport the drug out of the digestive vacuole, where aggregative heme detoxification rapidly and specifically produces the crystalline heme derivative term malaria pigment, b-hematin, or hemozoin.
We have recently determined the structure of malaria pigment by powder diffraction, shown below. The structure is surprising in that rather than being a coordination polymer, as widely held, it is a hydrogen bonded chain of dimers. The insoluble microcrystalline habit is as fine thin needles, and we are currently trying to index these crystals to determine the surface structures at the small fast growing facet. The impetus for this effort is from autoradiographs of malarial trophozoites treated with tritiated chloroquine where the chloroquine label clearly adheres to the small faces of the growing crystallites of malaria pigment. We hypothesize that the quinoline drug target is this surface where hemes released from the degradation of the red blood cell's hemoglobin is aggregated. Chemical Biology of Nitric Oxide: The recognition that a small diffusible paramagnetic gas can act as intercellular signaling agent continues to challenge accepted ideas of how cells communicate with one another. In addition to not requiring a membrane receptor, NO freely diffuses through membranes and tissues until it finds either a receptor or a sink. It remains one of the ironies of this area that we now understand the biosynthesis of this signaling agent in exquisite detail, but considerable debate lingers over its targets, sinks, and fate. Among our research interests are the nature of these sinks, for example metal complexes react rapidly and directly with NO to give high affinity nitrosyl adducts, and thus the heme site in sGC is the best characterized target. But the diffusion controlled reaction of NO with superoxide to give peroxynitrite is also an important sink, as well as the direct oxygenation of NO with dioxygen, or its reaction with oxyheme proteins. We are currently very interested in the biological consequences of the diffusion gradients created by these sinks, and we are actively developing new probes and donors to both generate biologically relevant NO gradients, and to detect them in situ.