Jung-Ja Kim, Ph.D.

Professor

Dr. Kim received her Ph.D. in Physical Chemistry at Cornell University in 1969. Her postdoctoral study at Massachusetts Institute of Technology involved the structure determination of transfer RNA. After a brief interruption of her career, she joined the faculty of the Medical College of Wisconsin in 1978.

Contact Information

jjkim@mcw.edu
Phone: (414) 955-8479
Fax: (414) 456-6510

Research Interests

Our research interest is to study the structure-function relationship of biologically interesting molecules by using X-ray diffraction methods, one of the most powerful techniques to date to study macromolecular structure. Currently our studies are focused on the following projects:

Acyl-CoA Dehydrogenases and Related Enzymes

Ribbon structure of MCAD monomer with C8-CoA complex

Acyl-CoA Dehydrogenases are a family of enzymes that are involved in both the first oxidative step in the metabolism of fatty acids and in the catabolism of some amino acids. Electron transfer from the primary dehydrogenase to the main mitochondrial respiratory chain is catalyzed, in sequence, by electron transfer flavoprotein (ETF) and the membrane-associated ETF-ubiquinone oxidoreductase (ETF-QO). The crystal structures of several acyl-CoA dehydrogenases including medium chain acyl-CoA dehydrogenase, short chain acyl-CoA dehydrogenase, and isovaleryl-CoA dehydrogenase have been determined in our laboratory. These structures reveal their catalytic mechanism as well as the structural basis for the substrate specificity. Currently we are extending these studies to site-specific mutants, inhibitor/substrate complexes, and to other members of the dehydrogenase family.

We have recently obtained high resolution structures of human ETF and a bacterial ETF. These, together with those of various acyl-CoA dehydrogenases, have enabled us to study the molecular basis of electron transfer between the dehydrogenases and ETF and of flavoprotein-flavoprotein interactions, in general. We have recently crystallized the membrane associated protein, ETF-QO and its complete structure determination is in progress.

NADPH-Cytochrome P450 Oxidoreductase

Ribbon diagram of NADPH-Cytochrome P450 Oxidoreductase

NADPH-Cytochrome P450 Reductase exists in every tissue in which cytochrome P450-mediated reactions occur of both endogenous substrates, including steroids, fatty acids, and prostaglandins, and exogenous compounds such as therapeutic drugs, environmental toxicants, and carcinogens. We have recently solved the three dimensional structure of the rat liver reductase. The structure shows how the two flavins (FMN and FAD) are communicating with each other and provides insights into not only the interaction of the reductase with its physiological electron partner, cytochrome P450, but also the mechanism of electron transfer and its regulation in other FMN- and FAD-containing enzymes, including nitric oxide synthase isozymes. We are extending our studies to interactions between cytochromes P450 and the reductase, as well as to other related enzymes.

Structure/Function studies of 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. Currently, we are exending our studies to the larger of the two receptors, the insulin-like growth factor II/cation-independent MPR (IGF-II/CI-MPR).

Selected Publications

“Structural Basis for Substrate Fatty-Acyl Chain specificity: Crystal Structure of Human Very Long Chain Acyl-CoA Dehydrogenase” McAndrew RP, Wang Y., Mohsen AW, He M., Vockley, J  and Kim, JJP J Biol Chem. 283:9435-9443 (2008).

“Structural Insights into the Mechanism of pH-dependent Ligand Binding and Release by the Cation-dependent Mannose 6-Phosphate Receptor” Olson, L.J. Hindsgaul, O. Dahms, N.M. and Kim, J.J.P. J Biol Chem. 283: 10124-10134 (2008).
 
“The Biochemical and Structural Basis for Feedback Inhibition of Mevalonate Kinase and Isoprenoid Metabolism” Fu, Z., Voynova, NE., Herdendorf, T., Miziorko, HM., and Kim, JJP Biochemistry 47: 3715-3724 (2008).

“Botulinum neurotoxin/B - host receptor recognition: it takes two receptors to tango” Baldwin, M., Kim, J.J.P., and Barbieri J News and Views in Nature Struct. Mol. Biol. 14:9-10 (2007).

“Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool” Zhang, J., Frerman, F., and Kim, J.-J.P  Proc. Natl. Acad. Sci., USA, 103: 16212-16217 (2006).
  
“Recruitment of governing elements for electron transfer in the nitric oxide synthase family” Jáchymová M, Martásek P, Panda S, Roman LJ, Panda M, Shea TM, Ishimura Y, Kim, J.-J. P , Masters BS  Proc Natl Acad Sci USA. 102:15833-15838 (2005).

“Acyl-CoA dehydrogenases and Acyl-CoA oxidases: Structural basis for mechanistic similarities and differences.”  Kim, J.-J.P. and Miura, R. Minireview, Eur J. Biochem., 271:483-493 (2004).

 “Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions." Fu, Z., Wang, M., Paschke, R., Rao, K.S., Frerman, F.E., Kim, J.-J.P.  Biochemistry 43:9674-9684 (2004).

"Structure of uPAR, plasminogen, and sugar-binding sites of the 300 kDa mannose 6-phosphate receptor" Olson, L. J., Yammani, R. D., Dahms, N. M. & Kim, J. J.  Embo J. 23:2019-2028 (2004).
     
“The Crystal Structure and Reaction Mechanism of E. coli 2,4-Dienoyl-CoA Reductase.”  Hubbard, P.A., Liang, X., Schulz, H., and Kim, J.-J.P. J. Biol. Chem. 278:37553-37560 (2003).
 
“Twists and Turns of CD-MPR: Ligand- Bound vs. Ligand-Free Recptor” Olson, L.J.,  Zhang J., Dahms, N.M., and Kim, J.-J. P. J. Biol. Chem. 277:10156-10161  (2002).

“The Structure of a Binary Complex between a Mammalian Mevalonate Kinase and ATP: Insights into the Reaction Mechanism and Human Inherited Disease”  Fu Z, Wang M, Potter D, Miziorko HM, and Kim J-JP J. Biol. Chem. 277:18134-18142 (2002).

"Burning fat: the structural basis of fatty acid beta-oxidation" Kim, J. J. & Battaile, K. P.  Curr Opin Struct Biol. 12:721-728 (2002).

"Molecular basis of lysosomal enzyme recognition: three-dimensional structure of the cation-dependent mannose 6-phosphate receptor" Roberts, D. L., Weix, D. J., Dahms, N. M. & Kim, J. J.  Cell 93:639-648 (1998).

"Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes" Wang, M., Roberts, D. L., Paschke, R., Shea, T. M., Masters, B. S. & Kim, J. J. Proc Natl Acad Sci USA 94:8411-8416 (1997).

"Three-dimensional structure of human electron transfer flavoprotein to 2.1-A resolution"  Roberts, D. L., Frerman, F. E. & Kim, J. J.  Proc Natl Acad Sci USA 93:14355-14360 (1996).