Jung-Ja Kim, PhD

Dr. Kim received her PhD in Physical Chemistry from Cornell University, where she was a Fulbright Scholar. She conducted her postdoctoral study at Massachusetts Institute of Technology, where she was part of the research team under Dr. Alexander Rich that determined the first structure of transfer RNA. She joined the faculty of the Medical College of Wisconsin in 1978 and went on to establish the Structural Biology Research at MCW by setting up an X-ray Crystallographic Facility. Dr. Kim is a fellow of the American Association for the Advancement of Science (AAAS).

Our research interest is to study the structure-function relationship of biologically interesting molecules (enzymes, nucleic acids, receptors, etc.) using X-ray diffraction methods in combination with biochemical and computational methods. Our studies are focused on the following projects:

1. Enzymes involved in fatty acid metabolism - Acyl-CoA dehydrogenases and related enzymes
   
   β-Oxidation of fatty acids is the principal energy-yielding process in the liver, heart, kidney, and muscle.  It is carried out by a series of enzymes that successively and repetitively cleave acetyl-CoA fragments from fatty acyl-CoA molecules, until the fatty acyl-CoA is completely degraded.  The rate of oxidation can be altered by diet (such as in starvation), physiological status (such as in pregnancy), and disease (such as in diabetes).  The initial reaction in each cycle of fatty acid β-oxidation is the dehydrogenation of an acyl-CoA thioester to the corresponding trans-2,3-enoyl-CoA. This reaction is catalyzed by a family of closely related flavoenzymes, acyl-CoA dehydrogenases (ACADs), that exhibit distinct but overlapping chain length specificities for acyl-CoA thioesters.
   
   Electron transfer from the dehydrogenases to the main mitochondrial respiratory chain is catalyzed, in sequence, by electron transfer flavoprotein (ETF) and the membrane-bound ETF-ubiquinone oxidoreductase (ETF-QO), an iron-sulfur flavoprotein. We have determined the structures of several acyl-CoA dehydrogenases, including medium chain acyl-CoA dehydrogenase (MCAD, the most abundant ACAD), human ETF, and ETF-QO. These structures have enabled us to study the molecular basis of electron transfer between the dehydrogenases and ETF and between ETF and ETF-QO, and flavoprotein-flavoprotein interactions in general.
   
   MCAD deficiency is the most common among all fatty acid metabolism disorders. It is manifested by fasting intolerance, hypoglycemic coma, failure of ketogenesis, and dicarboxylic aciduria, and has been implicated in sudden infant death syndrome.
   
   
2. NADPH-cytochrome P450 reductase (CYPOR)
   
   NADPH-cytochrome P450 oxidoreductase (CYPOR) is a microsomal diflavin protein that shuttles electrons from NADPH → FAD → FMN to members of the ubiquitous cytochrome P450 superfamily.  In humans, the cytochromes P450 (cyt P450) are one of the most important families of proteins involved in the biosynthesis and degradation of a vast number of endogenous compounds and the detoxification and biodegradation of most foreign compounds. We have determined the structure of human CYPOR. CYPOR undergoes a large conformational change in the course of electron transfer from FAD to FMN and from FMN to cyt P450, its physiological redox partner.  Furthermore, as CYPOR is the prototype of the diflavin enzyme family that utilizes pyridine nucleotides, our findings can be applied to the mechanism of electron transfer in other members of the family, including NOS isozymes and methionine synthase reductase.
   
   NADPH-cytochrome P450 reductase dancing with cytochrome P450 Movie
   
   
3. Mannose 6-Phosphate Receptors (MPRs)
   
   MPRs are responsible for the targeting of lysosomal acid hydrolases to lysosomes. In collaboration with Dr. Nancy Dahms, we have been studying the structure/function relationships of these receptors. We have solved the structures of the cation-dependent MPR (CD-MPR) with and without mannose 6-phosphate ligand and complexes with high mannose oligosaccharides. We are extending our studies to the larger of the two receptors, the insulin-like growth factor II/cation-independent MPR (IGF-II/CI-MPR).