WSU CAS

College of Arts and Sciences

Department of Chemistry

Kang, ChulHee

Professor of Chemistry

Professor of School of Chemical Engineering and Bioengineering

Director of Biomolecular Crystallography Center

Address

Fulmer 264
Pullman, WA 99164-4660
(509) 335-1409

email: chkang@wsu.edu
personal page: http://kang7.chem.wsu.edu/~kang

ChulHee Kang

ChulHee Kang

Education

  • BS, MS, Physics & Microbiology Double Major, 1982
    Seoul National University, Seoul, Korea
  • PhD, Biophysics & Chemistry 1987
    University of California, Berkeley, CA
  • Postdoctoral Study, 1988-89
    Lawrence Berkeley National Laboratory, Berkeley, CA
  • Research Fellow, 1989-92
    Massachusetts Institute of Technology, Cambridge, MA

Research

Cardiovascular/Pharmacology/Toxicology Projects

The sarcoplasmic reticulum (SR) plays an essential role in muscle excitation/contraction coupling by regulating the cytosolic free Ca2+ concentration. Functional alterations in this tightly regulated process are directly responsible for most of the cardiac and skeletal complications. The major SR luminal protein, calsequestrin (CASQ), binds Ca2+ ions with high capacity (40-80 mol Ca2+), but moderate affinity (Kd =1mM) over the physiological Ca2+ concentration range and releases it with a high off-rate. Therefore CASQ has been proposed as a Ca2+ buffer inside the SR and/or an allosteric sensor of the fall in SR Ca2+ concentration.

Cardiac CASQ mutations have been identified as the underlying cause of catecholaminergic polymorphic ventricular tachycardia (CPVT2), an arrhythmogenic disorder with a high mortality rate. In addition, defective post-translational modifications of CASQ, have been linked to cardiac pathology.We have been studying the unique mechanism by which CASQ regulates SR Ca2+, and provided a basic insight into its Ca2+-sequestration abilities and the altered behavior of post-translationally modified and/or mutated CASQs.

We have discovered that many pharmaceutical drugs with muscle-related or cardiotoxic side effects, a common side effect seen in many synthetic pharmaceutical drugs, bind to and interfere with the normal functions of CASQ. We predict the potential link between drug-induced cardiac complications and improper CASQ modifications.  Therefore we are trying to determine if there is a correlation between CASQ polymorphism in failed human hearts and pathophysiology with concurrent hypersensitivity to drugs.

In the long run, our study will provide essential insight into how pharmaceutical drugs with notorious muscle-related side effects may be improved in order to mitigate their detrimental impact on patient health due to avid drug binding by CASQ, and help design more effective treatments for hereditary heart diseases such as CPVT.

Bioremediation

Several polychlorophenols, such as 2,4,5-, 2,4,6-trichlorophenol (TCP), and pentachlorophenol (PCP) are primarily introduced into the environment through their use as preservatives in the wood industry, as herbicides in agriculture, and as general biocides in consumer products. They persist in the environment because halogen substitution makes them recalcitrant to microbial degradation.

In the breakdown process of polychlorophenols, the critical step is oxidation at the para-position catalyzed by monooxygenases, because partial or complete dechlorination must occur before ring-cleaving dioxygenases are able to open aromatic rings. The biodegradation of polychlorophenols is considered complete when their constituent carbon skeletons and organic chloride are converted into common metabolic intermediates and the mineral state, respectively.

We will focus on critical monooxygenases and dioxygenases. In the progressive breakdown processes, the quinol or hydroxyquinol rings produced by the above monooxygenases are opened by dioxygenases. Therefore, a comparative investigation of those enzymes will provide a clear understanding of those unique functions.

We have successfully determined the 3D-structure of many participating enzymes allowing us to investigate and compare the unique activities and substrate specificities of the enzymes using site-directed mutagenesis as well as kinetic and thermodynamic characterizations of the enzyme, cofactor and substate interactions. Determination of the 3-D structures will provide insight about their substrate specificity eventually allowing us to rationally design the active sites of enzymes to obtain desired specificities. The systematic structural and biophysical approaches and the designed mutants will offer information not only for the interaction between its unique substrate and active site amino acid residues but the reaction mechanisms.

Cancer Projects

Intensive efforts are taking place to determine the structures of various cancer-associated proteins and types of damaged DNA, including oxidative and UV damaged, and, ultimately, to develop anticancer drugs. Using complex crystal structures and binding studies, the search for new anti-cancer drugs that are free of side effects, are being carried out. We are also investigating key plant enzymes involved in various pathways, which have important and direct connections with human health such as chemoprotection against various cancers, lowering blood cholesterol levels, and as antifungal/antiviral agents, biocides, antifeedants, and antioxidants. These studies will be used to develop treatments for various cancers.

Publications

  • Hayes RP, Green AR, Nissen MS, Lewis KM, Xun L, Kang C. (2013) Structural characterization of 2,6-dichloro-p-hydroquinone 1,2-dioxygenase (PcpA) from Sphingobium chlorophenolicum, a new type of aromatic ring-cleavage enzyme. Mol Microbiol 88, 523-536.
  • Walker AM, Hayes RP, Youn B, Vermerris W, Sattler SE and Kang C (2013) Elucidation of the structure and reaction mechanism of Sorghum bicolor hydroxycinnamoyltransferase and its structural relationship to other CoA-dependent transferases and reductases. Plant Physiology 162, 640-651.
  • Hayes RP, Lewis KM, Xun L and Kang C (2013) Catalytic mechanism of 5-chlorohydroxyhydroquinone dehydrochlorinase from the YCII superfamily of largely unknown function. J Biol. Chem. 288, 28447-28456.
  • Sanchez EJ, Hayes RP, Barr JT, Lewis KM, Webb BN, SubramanianAK, Nissen MS, Jones JP, Shelden EA, Sorg BA, Fill M, Schenk JO and Kang C (2013) Potential Role of cardiac calsequestrin in the lethal arrhythmic effects of cocaine. Drug and Alcohol Dependence 133, 344–351.
  • Green, AR, Nissen MS, Kumar, GNM, Knowles NR and Kang C (2013) Characterization of Solanum tuberosum Multicystatin and the Significance of Core Domains. Plant Cell (25, 5043-5052.
  • Kang C, Hayes R, Sanchez EJ, Webb BN, Li Q, Hooper T, Nissen MS & Xun L. (2012) Furfural reduction mechanism of a zinc-dependent dehydrogenase from Cupriavidus necator JMP134. J. Molecular Microbiology 83, 85-95 doi: 10.1111/j.1365-2958.2011.07914.x
  • Sanchez EJ, Lewis KM, Munske GR, Nissen MS & Kang C. (2012) Glycosylation of Skeletal calsequestrin, Implications for its function. J Biol. Chem. 287, 3042-3050.
  • Sanchez EJ*, Lewis KM*, Danna BR, Kang C. (2012) High-Capacity Ca2+-binding of human skeletal calsequestrin J Biol. Chem. 287, 11592-11601. doi: jbc.M111.335075.
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