Area of Interest

 
The focus of our research is on the structure/function relationships of the proteins involved in regulation of glucose metabolism at the molecular level. We have special interests in PFKFB system, because this protein system is a core of control of glucose metabolism and, thus, involved in various metabolic anomaly-related diseases such as cancer, diabetes, and cardiomyopathy. PFKFB proteins are sensitively influenced by abnormal levels of glucose, O2, insulin/glucagon, and oncogenic stress. Chronic exposure to these stresses induces anomalous covalent modifications of PFKFBs and, thus, causes alterations in their catalytic activity, subcellular localization, populations, and interaction with other proteins. Increases in such stress-driven covalent modifications of PFKFB proteins result in severe or irreversible alterations in glucose metabolism, cellular oxidative stress, cell cycle speeds, and new blood vessel formation, leading to ultimate cell death.

Our long term commitment is to understand how those physiological stress influences the PFKFB proteins at the molecular level. For the studies at the molecular level, we mainly use protein X-ray crystallography with assistance from the fields of molecular biology, protein chemistry, and cell biology. We are aimed to address the structural changes induced by allosteric ligand bindings and stress-driven covalent modifications such as methylation, S-glutathionylation, O-GlcNAcylation, and phosphorylation. Together with biological significance assessments, our structural studies are necessary for understanding the structural mechanisms underlying cellular anomalies in diseases.

Additionally, our research also extends to the field of structure-based drug design as well as other computational approaches to facilitate drug discovery. Currently, our research is most focused on studying human PFKFB1 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) for diabetes, PFKFB2 for ischemic myocardium, and PFKFB3 for cancer. Additional efforts are being made to DNA (cytosine-5)-methyltransferase for the reprogramming of somatic cells to stem cells by using drug-like small molecule compounds.  
 
Selected Publications

Cavalier, M., Kim, S.-G, Yim, Y.-S., Neau, D., and Lee, Y.-H. (2012) ‘Molecular basis of the Fructose-2,6-bisphosphatase reaction of PFKFB3: Transition state and the C-terminal function’. Proteins. 80:1143-53.

Cavalier, M., Yim, Y.-S., Asamizu, S., Neau, D., Mahmud, T., and Lee, Y.-H. (2012) ‘Mechanistic Insights into Validoxylamine A 7'-Phosphate Synthesis by VldE Using the Entire Product Complex’ http://dx.plos.org/10.1371/journal.pone.0044934.

Seo, M., Crochet, R.B., and Lee, Y.-H. (2013). Targeting altered metabolism – emerging cancer therapeutic strategy. Chapter 13, In “Cancer Drug Design and Discovery, 2nd Edition” (S. Neidle, Ed.), Elsevier, San Diego.

Seo, M., and Lee, Y.-H. (2014) ‘PFKFB3 regulates oxidative stress homeostasis via its S-glutathionylation in cancer’. J. Mol. Biol. 426: 830-42.

Kim, J.-D., Rim, J.S., Crochet, R.B., Lee, Y.-H., Staszkiewicz, J., Gao, R., and Eilertsen, K.J. (2014). Chemicals facilitating reprogramming: Targeting the SAM binding site to identify novel methyltransferase inhibitors. In “Chemical Biology in Regenerative Medicine: Bridging Stem Cells and Future Therapies”, Chapter 15, Wiley.

Landry, A.P., Wang, Y., Cheng, Z., Crochet, R.B., Lee, Y.-H., and Ding, H. (2016) Flavin nucleotides act as electron shuttles mediating reduction of the [2Fe-2S] clusters in mitochondrial outer membrane protein mitoNEET. Free Radic Biol Med. 102:240-247. 

Crochet, R.B., Kim, J.-D., Lee, H., Yim, Y.-S., Kim, S.-G., Neau, D., and Lee, Y.-H. (2016) ‘Crystal Structure of Heart 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase (PFKFB2) and the Inhibitory Influence of Citrate on Substrate Binding’ Proteins. 85:117-124.

Kim, J.D., Yim, Y.S., Brylinski, M., El-Maghrabi, M.R., and Lee, Y.-H. (2017). ‘Up- vs. Down-Regulation of PFKFB3 Activity: Deactivation by S-Glutathionylation Overrules Activation by N-Methylation’ In preparation.

Yim, Y.S., Kim, J.D., El-Maghrabi, M.R., and Lee, Y.-H. (2017). ‘Up- vs. Down-Regulation of PFKFB3 Activity: Deactivation by S-Glutathionylation Overrules Activation by Phosphorylation at Ser461’ In preparation.