Michael Malkowski, PhD

Resident Researcher

Our Goal

Our group works to understand how drugs interact in our bodies with various disease pathologies, including inflammation, cardiovascular disease, and cancer. Our ultimate goal is to provide a foundation for the development of new drugs and repurposing existing ones. We want to see maximum efficacy and minimal risks to people struggling with these diseases.

A Deeper Understanding

The Malkowski Laboratory is focused on understanding the structure and function of integral membrane enzymes involved in the conversion of lipid precursors into potent bioactive signaling molecules. We utilize a myriad of methods and techniques to characterize these enzymes, including X-ray crystallography, electron spin resonance spectroscopy, protein chemistry, biochemistry, molecular biology, cell biology, and kinetics. One key enzyme under current study are the Cyclooxygenases (COX-1 and COX-2). Changes in COX-mediated prostaglandin biosynthesis are associated with various disease pathologies, including inflammation, cardiovascular disease, and cancer. COX-1 and COX-2 are the targets of aspirin, ibuprofen, and other nonsterroidal anti-inflammatory drugs (NSAIDs), and COX-2 selective inhibitors (coxibs) such as Celebrex. These compounds are some of the most heavily utilized drugs in the world, used to decrease acute and chronic inflammation, protect against adverse cardiovascular events, and reduce the risk of developing certain cancers. However, NSAID and coxib use is not without risk. Over 15,000 deaths per year can be ascribed to harmful effects derived from their consumption, the molecular basis of which is unknown.


For a chronological list of publications click here

• Hydroxylase/Desaturase

Zhu, G., Koszelak-Rosenblum, M., Connelly, S.M., Dumont, M.E., and Malkowski, M.G.
The crystal structure of an integral membrane fatty acid alpha-hydroxylase.
J. Biol. Chem. (2015), 290, 29820-29833. PMID: 26515067

• Cyclooxygeanse

Orlando, B.J. and Malkowski, M.G.
Crystal Structure of Rofecoxib Bound to Cyclooxygenase-2.
Acta Cryst. (2016) F72, 772-776.

Orlando, B.J. and Malkowski, M.G.
Substrate-Selective Inhibition of Cyclooxygenase-2 by Fenamic Acid Derivatives is Dependent on Peroxide Tone.
J. Biol. Chem. (2016), 291, 15069-15081. PMID: 27226593

Lucido, M.J., Orlando, B.J., Vecchio, A.J., and Malkowski, M.G.
The Crystal Structure of Aspirin Acetylated Human Cyclooxygenase-2: Insight into the Formation of Products with Reversed Stereochemistry.
Biochemistry (2016), 55, 1226-1238. PMID: 26859324

Orlando, B.J., Borbat, P.P., Georgieva, E., Freed, J.H., and Malkowski, M.G.
Pulsed Dipolar Spectroscopy Reveals that Tyrosyl Radicals are Generated in Both Monomers of the Cyclooxygenase-2 Dimer.
Biochemistry (2015), 54, 7309-7312. PMID: 26636181

Orlando, B.J., Lucido, M.J., and Malkowski, M.G.
The Structure of Ibuprofen Bound to Cyclooxygenase-2.
J. Structural Biol. (2015), 189, 62-66. PMID: 25463020

Orlando, B.J., McDougle, D.R., Lucido, M.J., Eng, E.T., Graham, L.A., Schneider, C., Stokes, D.L., Das, A., and Malkowski, M.G.
Cyclooxygenase-2 Catalysis and Inhibition in Lipid Bilayer Nanodiscs.
Arch. Biochem. Biophys. (2014), 546, 33-40. PMID: 24503478

Vecchio, A.J., Orlando, B.J., Nandagiri, R., and Malkowski, M.G.
Investigating Substrate Promiscuity in Cyclooxygenase-2: The Role of Arg-120 and the Residues Lining the Hydrophobic Groove.
J. Biol. Chem. (2012), 287, 24619-24630. PMID: 22637474

Vecchio, A.J. and Malkowski, M.G.
The Structure of NS-398 Bound to Cyclooxygenase-2.
J. Structural Biol. (2011), 176, 254-258. PMID: 21843643

Vecchio, A.J. and Malkowski, M.G.
The Structural Basis of Endocannabinoid Oxygenation by Cyclooxygenase-2.
J. Biol. Chem. (2011), 286, 20736-20745. PMID: 21489986

Dong, L., Vecchio, A.J., Sharma, N., Jurban, B.J., Malkowski, M.G., and Smith, W.L.
Human Cyclooxygenase-2 is a Sequence Homodimer That Functions as a Conformational Heterodimer.
J. Biol. Chem. (2011), 286, 19035-19046. PMID: 21467029

Vecchio, A.J., Simmons, D.M., and Malkowski, M.G.
The Structural Basis of Fatty Acid Substrate Binding to Cyclooxygenase-2.
J. Biol. Chem. (2010), 285, 22152-22163. PMID: 20463020

Calamini, B., Ratia, K., Malkowski, M.G., Cuendet, M., Pezzuto, J.M., Santarsiero, B.D., and Mesecar, A.D.
Pleiotropic Mechanisms Facilitated by Resveratrol and its Metabolites.
Biochem. J., (2010) 429, 273-282. PMID: 20450491

• Alpha-Dioxygenase

Zhu, G., Koszelak-Rosenblum, M., and Malkowski, M.G.
Crystal Structures of α-Dioxygenase from Oryza sativa: Insights into Substrate Binding and Activation by Hydrogen Peroxide.
Protein Sci. (2013), 22, 1432-1438. PMID: 23934749

Goulah, C.C., Zhu, G., Koszelak-Rosenblum, M. and Malkowski, M.G.
The Crystal Structure of α-Dioxygenase Provides Insight into Diversity in the Cyclooxygenase-Peroxidase Superfamily.
Biochemistry (2013), 52, 1364-1372. PMID: 23373518

Koszelak-Rosenblum, M., Krol, A.C., Simmons, D.M., Goulah, C.C., Wroblewski, L., and Malkowski, M.G.
His-311 and Arg-559 are key residues involved in fatty acid oxygenation in pathogen-inducible oxygenase.
J. Biol. Chem. (2008), 283, 24962-24971. PMID: 18596034

Lloyd, T., Krol, A., Campanaro, D., and Malkowski, M.G.
Purification, Crystallization, and Preliminary X-Ray Diffraction Analysis of Pathogen-Inducible Oxygenase (PIOX) From Oryza sativa.
Acta Cryst. (2006), F62, 365-367.

• Treponema pallidum Membrane Protein Targets

Anand, A., LeDoyt, M., Karanian, C., Luthra, A., Koszelak-Rosenblum, M., Malkowski, M.G., Puthenveetil, R., Vinogradova, O., and Radolf, J.D.
Bipartite Topology of Treponema pallidum Repeat Proteins C/D/ and I: Outer Membrane Insertion, Trimerization, and Porin Function Require a C-Terminal beta-Barrel Domain.
J. Biol. Chem. (2015), 290, 12313-12331. PMID: 25805501

Luthra, A. Zhu, G. Desrosiers, D.C., Eggers, C.H., Mulay, V., Anand, A., Romano, F.B., Caimano, M.J., Heuck, A.P., Malkowski, M.G., and Radolf, J.D.
The Transition from Closed to Open Conformation of Treponema pallidum Outer Membrane-Associated Lipoprotein TP0453 Involves Membrane Sensing and Integration by Two Amphipathic Helices.
J. Biol. Chem. (2011), 286, 41656-41668. PMID: 21965687

• Moraxella catarrhalis Vaccine Targets

Murphy, T.F., Kirkham, C., Johnson, A., Brauer, A.L., Koszelak-Rosenblum, M., and Malkowski, M.G.
Sulfate-binding Protein, CysP, is a Candidate Vaccine Antigen of Moraxella catarrhalis.
Vaccine, (2016) 34, 3855-3861. PMID: 27265455 Role of the Oligopeptide Permease ABC Transporter of Moraxella catarrhalis in Nutrient Acquisition and Persistence in the Respiratory Tract.
Infection and Immunity (2014), 82, 4758-4766. PMID: 25156736

Murphy, T., Brauer, A., Kirkham, C., Johnson, A., Koszelak-Rosenblum, M., and Malkowski, M.G.
Role of the Zinc Uptake ABC Transporter of Moraxella catarrhalis in Persistence in the Respiratory Tract.
Infection and Immunity (2013), 81, 3406-3413. PMID: 23817618

• Miscellaneous Targets

Bauer, W. J., Luthra, A., Zhu, G., Radolf, J. D., Malkowski, M. G., and Caimano, M. J.
Structural characterization and modeling of the Borrelia burgdorferi hybrid histidine kinase Hk1 periplasmic sensor: A system for sensing small molecules associated with tick feeding.
Journal of Structural Biology (2015), 192, 48-58. PMID: 26321039

Pryor, E.E., Horanyi, P.S., Clark, K.M., Fedoriw, N., Connelly, S.M., Koszelak-Rosenblum, M., Zhu, G., Malkowski, M.G., Wiener, M.C., and Dumont, M.E.
Structure of the Integral Membrane Protein CaaX Protease Ste24p.
Science (2013), 339, 1600-1604. PMID: 23539602

• Methods and Tools Development for Structural Biology

Clark, K.M., Fedoriw, N., Robinson, K., Connelly, S.N., Randles, J., Malkowski, M.G., DeTitta, G.T., and Dumont, M.E.
Purification of transmembrane proteins from Saccharomyces cerevisiae for x-ray crystallography.
Protein Expr. Purif. (2010), 71, 207-223. PMID: 20045057

Koszelak-Rosenblum, M., Krol, A., Mozumdar, N., Wunsch, K., Ferrin, A., Cook, E., Veatch, C.K., Nagel, R., Luft, J.R., DeTitta, G.T., and Malkowski, M.G.
Determination and application of empirically derived detergent phase boundaries to effectively crystallize membrane proteins.
Protein Sci. (2009), 18, 1828-1839. PMID: 19554626

Snell, E.H., Lauricella, A.M., Potter, S.A., Luft, J.R., Gulde, S.M., Collins, R.J., Franks, G., Malkowski, M.G., and DeTitta, G.T.
Establishing a training set through the visual analysis of crystallization trials part II: crystal examples.
Acta Cryst. (2008), D64, 1131-1137. PMID: 19020351

Snell, E.H., Luft, J.R., Potter, S.A., Lauricella, A.M., Gulde, S.M., Malkowski, M.G., Said, M.I., Smith, J.L., Veatch, C.K., Collins, R.J., Franks, G., Thayer, M., Cumbaa, C., Jurisica, I., and DeTitta, G.T.
Establishing a training set through the visual analysis of crystallization trials part I: ~150,000 images.
Acta Cryst. (2008), D64, 1123-1130. PMID: 19020350

Malkowski, M.G., Quartley, E., Friedman, A.E., Babulski, J., Kon, Y., Wolfley, J.R., Said, M.I., Luft, J.R., Phizicky, E.M., DeTitta, G.T., and Grayhack, E.J.
Blocking S-adenosylmethionine Synthesis in Yeast Allows Selenomethionine Incorporation and Multiwavelength Anomalous Dispersion Phasing.
Proc. Natl. Acad. Sci., USA. (2007),104, 6678-6683. PMID: 17426150 http://www.ncbi.nlm.nih.gov/pubmed/17426150 

Luft, J.R., Wolfley, J.R., Said, M.I., Nagel, R.M., Lauricella, A.M., Smith, J.L., Thayer, M.H., Veatch, C.K., Snell, E.H., Malkowski, M.G., and DeTitta, G.T.
Efficient Optimization of Crystallization Conditions by Manipulation of Drop Volume Ratios and Temperature.
Protein Sci. (2007), 16, 715-722. PMID: 17327388

• Reviews

Pieper, U., Schlessinger, A., Kloppmann, E., Chang, G.A., Chou, J.J., Dumont, M.E., Fox, B.G., Fromme, P., Hendrickson, W.A., Malkowski, M.G., Rees, D.C., Stokes, D.L., Stowell, M.H.B., Wiener, M.C., Rost, B., Stroud, R.M., Stevens, R.C., and Sali, A.
Coordinating the Impact of Structural Genomics on the Human α-Helical Transmembrane Proteome.
Nat. Struct. Mol. Biol. (2013), 20, 135-138. PMID: 23381628

Fox, B.G., Goulding, C., Malkowski, M.G., Stewart, L., and Deacon, A.
Genes to structure with valuable materials and many scientific questions in between.
Nature Methods (2008), 5, 129-132. PMID: 18235432

Murphy TF, Brauer AL, Johnson A, Wilding GE, Koszelak-Rosenblum M, Malkowski MG.
A Cation-binding Surface Protein as a Vaccine Antigen to Prevent Moraxella catarrhalis Otitis Media and Infections in Chronic Obstructive Pulmonary Disease.
Clin Vaccine Immunol. 2017 Jun 28. pii: CVI.00130-17.