Karol Bruzik's homepage

Title: Associate Professor of Medicinal Chemistry Department: Department of Medicinal Chemistry and Pharmacognosy (M/C 781) College: College of Pharmacy
Institution: University of Illinois at Chicago

Description of research

Essential publications

DESCRIPTION OF RESEARCH:
T he main focus of research in my laboratory is chemistry of phospholipid molecules, in particular those containing inositol moiety. These molecules are involved in complex pathways of cellular signal transductions of hormones, neurotransmitters, growth factors and physical stimuli. We have developed a number of synthetic strategies to all naturally ocurring inositol phospholipids and many of their analogs, most notably those bearing phosphorothioate residues instead of the phosphate(s), as well as many naturally ocurring inositol phosphates. We have been using these synthetic analogs to gain insights into the mechanism of the key enzyme of signal transduction, phosphoinositide-specific phospholipase C. There are two goals of this research: (i) to obtain new general insights on the mechanism of phosphoryl transfer in enzymes using the intramolecular nucleophile in transesterification reactions, in particular on the interactions of phosphate and leaving group with enzyme, and the way these interactions affect catalytic functions. (ii) to use mechanistic information on this enzyme coupled with structural information obtained in other laboratories, to design specific inhibitors of this enzyme as potential drugs against cancer and inflammation. In collaboration with biochemical laboratory of Ming-Daw Tsai at the Ohio State University we have used the synthetic analogs modified at a specific substrate position with the site-directed mutants of phospholipase C to obtain a detailed view of the enzyme action. In the most recent study we have obtained strong kinetic evidence for the existence of the novel catalytic triad in the enzyme catalysis comprised of Arg, Asp and His residues. The catalytic triad has a dual function as it participates in both phosphate protonation and in electrophilic assistance to the leaving group. The assembly of this dual-function catalytic triad is governed by enzyme interactions with the leaving group of the substrate. As possible strategies to inhibitor development we have been employing the approach of transition state analog inhibitors. All compounds are obtained using multi-step total organic synthesis.
Another line of research in this Laboratory involves biophysical studies of bilayers of natural phospholipids and of their analogs using high resolution solid-state NMR to study the effect of amphiphile structure on the conformational properties of individual molecules, and the effect of the bilayer phase transition on the conformation and packing of phospholipid head group in the bilayer plane. The goal is to use the obtained information in designing amphiphilic molecules as building blocks for new types of materials, and as molecular devices with pre-programmed properties. Such amphiphiles should be useful in obtaining supramolecular complexes of lipids and proteins, and in studying structure of integral membrane proteins.

ESSENTIAL PUBLICATIONS
1. Identification of a Novel Catalytic Triad with Dual Function in Enzymatic Cleavage of the P-O Bond. R. J. Kubiak, R. J. Hondal, X. Yue, M.-D. Tsai, K. S. Bruzik, J. Am. Chem. Soc. 1999, 121, 488-489.
2. The Mechanism of Phosphatidylinositol-Specific Phospholipase C Revealed by Protein Engineering and Thio-PI Analogs. R. J. Hondal, Z. Zhao, A. V. Kravchuk, S. R. Riddle, K. S. Bruzik and M.-D. Tsai, in Advances in Phosphoinositides, ACS Symp. Ser., Vol. 718, 1998, 109-120.
3. Stereospecific Syntheses of Inositol Phospholipids and Their Phosphorothioate Analogs. R. J. Kubiak, X. Yue and K. S. Bruzik, Advances in Phosphoinositides, ACS Symp. Ser., Vol. 118, 1998, 180-196.
4. Mechanism of Phosphatidylinositol-Specific Phospholipase C: A Unified View of The Mechanism of Catalysis. R. J. Hondal, Z. Zhao, A. V. Kravchuk, H. Liao, S. R. Riddle, K. S. Bruzik and M.-D. Tsai, Biochemistry 1998, 37, 4568-4580.
5. Phosphatidylinositol-Specific Phospholipase C. Elucidation of the Catalytic Mechanism and Comparison with Ribonuclease A. R. J. Hondal, Z. Zhao, S. R. Riddle, K. S. Bruzik, and M.-D. Tsai, J. Am. Chem. Soc. 1997, 119, 9933-9934.
6. Phosphatidylinositol-Specific Phospholipase C as a Target of Rational Drug Design in "Carbohydrates in Drug Design" Nieforth, C. and Witczak, Z., Eds., Marcell Dekker, New York, 1997, pp. 385-431.
7. Synthesis of the Phosphorothioate Analogs of Phosphatidylinositol 3,4,5-Trisphosphate. R. J. Kubiak and K. S. Bruzik, Bioorg.Med. Chem. Lett. 1997, 7, 1231-1234.
8. Synthesis Of Enantiomerically Pure Phosphorothiolate Assay Substrate For Phosphatidylinositol-Specific Phospholipase C. C. Mihai, J. Mataka, S. Riddle, M.-D.Tsai and K. S. Bruzik, Bioorg. Med.Chem. Lett. 1997, 7, 1235-1238.
9. Phosphatidylinositol Phospholipase C: Kinetic and Stereochemical Evidence For an Interaction Between Arginine-69 and the Phosphate Group of Phosphatidylinositol. R. J. Hondal, S. R. Riddle, Kravchuk, A. V., Zhao, Z., K. S. Bruzik, M. -D. Tsai, Biochemistry, 1997, 36, 6633-6642.
10. Synthesis of Inositol Phosphodiesters By Phospholipase C-Catalyzed Transesterification. K. S. Bruzik, G. Zhiwen, S. Riddle and M. -D. Tsai. J.Am.Chem.Soc. 1996, 118, 7679-7688.
11. General Synthesis of Phosphatidylinositol 3-Phosphates, K. S. Bruzik and R. J. Kubiak, Tetrahedron Lett. 1995, 36, 2415-2418.
12. Are D- and L-chiro-Phosphoinositides Substrates of Phosphatidylinositol-Specific Phospholipase C. Bruzik K. S., Hakeem, A. A. and Tsai, M.-D. Biochemistry 1994, 33, 8367-8374.
13. Toward the Mechanism of Phosphoinositide-Specific Phospholipase C. K. S. Bruzik, M.-D. Tsai, (1994) Bioorg. Med. Chem. 2, 49-72.
14. Synthesis of Homochiral Inositol Phosphates From myo-Inositol, K. M. Pietrusiewicz, G. M. Salamonczyk, K. S. Bruzik & W. Wieczorek, Tetrahedron 1992, 48, 5523-42.
15. Efficient and Systematic Syntheses of Enantiomerically Pure and Regiospecifically Protected Myo-Inositols, K. S. Bruzik & M. -D. Tsai, J. Am. Chem. Soc. 1992, 104, 6361-6374.
16. Phospholipids Chiral at Phosphorus. Stereochemical Mechanism For the Formation of Inositol 1-Phosphate Catalyzed by Phosphatidylinositol-Specific Phospholipase C, K. S. Bruzik, A. M. Morocho, D.-Y. Jhon, S. G. Rhee & M.-D. Tsai, Biochemistry 1992, 31, 5183-93.
17. Practical Synthesis of Enantiomerically Pure myo-Inositol Derivatives, K. S. Bruzik, J. Myers & M. -D. Tsai, Tetrahedron Lett. 1992, 1009-1012.
18. Phosphorothioate Analogues of Phosphatidyinositol and Inositol 1,2-Cyclic Phosphate: Application to the Mechanism of Phospholipase C, K. S. Bruzik, G. Lin & M.-D.Tsai, ACS Symp. Ser. 1991, 463, 172-85.
19. The Synthesis of Enantiomeric 1,4,5,6-Tetrabenzyl-myo-Inositols, K. S. Bruzik & G. M. Salamonczyk, Carbohydr. Res. 1989, 195, 67-73.
20. Phospholipid Bilayers Conformational Study of Phospholipids in Crystalline State and Hydrated Bilayers by 13C and 31P CP-MAS NMR. K. S. Bruzik and J. S. Harwood, J. Am. Chem. Soc. 1997, 119, 6629-6637.
21. NMR Study of Conformation of Galactocerebrosides in Bilayers and Solution: Galactose Reorientation During Metastable-Stable Gel Transition, K. S. Bruzik and P.-G. Nyholm, Biochemistry 1997, 36, 566-575.
22. Nuclear Magnetic Resonance Study of Sphingomyelin Bilayers, K. S. Bruzik, B. Sobon & G. M. Salamonczyk, Biochemistry 1990, 29, 4017-21.
23. 13C CP-MAS Study of the Gel Phases of 1,2-Dipalmitoylphosphatidylcholine, K. S. Bruzik, G. M. Salamonczyk & B. Sobon, Biochim. Biophys. Acta 1990, 1023, 143-6.
  Collaborative Research
24. Synthesis of D-1,2-Dideoxy-1,2-difluoro-myo-inositol 3,4,5,6-tetrakisphosphate and Its Enantiomer as Analogues of myo-Inositol 3,4,5,6-Tetrakisphosphate. K. R. H. Solomons, S. Freeman, S. B. Shears, D. J. Nelson, W. Xie, K. S. Bruzik, M. A. Kaetzel, Carbohydr. Res. 1998, 309, 337-343.
25. Regulation of Ca2+ -Dependent Cl- Conductance in a Human Colonic Epithelial Cell Line (T84): Cross-Talk Between Ins(3,4,5,6)P4 and Protein Phosphatases. W. Xie, K. R. H. Solomons, S. Freeman, M. A. Kaetzel, K. S. Bruzik, D. J. Nelson, and S. B. Shears. J. Physiol. 1998, 510, 661-673.
26. Inhibition by Inositol Tetrakis phosphate of Calcium- and Volume-Activated Cl- Currents inn Endothelial Cells. Nilius, B., Prenen, J., Voets, T., Eggermont, J., Bruzik, K. S., Shears, S. B., Droogmans, G.Pfluggers Arch. Europ. J. Physiol. 1998, 435, 637-644.
27. Xie, W., Kaetzel, M., Bruzik, K. S., Dedman, J. R., Shears, S. B., and Nelson, D.J. Inositol 3,4,5,6-Tetrakisphosphate Inhibits Calmodulin-Dependent Protein Kinase II-Activated Chloride Conductance in T84 Colonic Epithelial Cells. J. Biol. Chem. 1996, 271, 14092-14097.
28. Properties of the Inositol 3,4,5,6-Tetrakisphosphate 1-Kinase Purified From the Rat Liver, Z. Tang, K.S. Bruzik and S. B. Shears, J. Biol. Chem. 1997,272, 2285-2290. Ho, M.W.Y., Shears, S.B., Bruzik, K.S., Duszyk, M., French, A. S. Ins(3,4,5,6)P4
29. Specifically Inhibits a Receptor-Mediated Ca2+-Dependent Cl- Current in CCFPAC-1 Cells. Am. J. Physiol. 1997, 41, C1160-C1168.
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