Michael G. Malkowski PhD

Michael Malkowski

Michael G. Malkowski
PhD

Professor and Chair

Department of Structural Biology

Jacobs School of Medicine & Biomedical Sciences


Specialty/Research Focus

Metalloenzymes; Protein Function and Structure

Contact Information
Department of Structural Biology
Jacobs School of Medicine And Biomedical Sciences
955 Main Street
Buffalo, New York 14203-1121
Phone: 716-829-3698
mgm22@buffalo.edu



Professional Summary:

The major focus of my research program is to apply structural biology approaches to investigate structure-function relationships of proteins with significant medical relevance. We utilize a myriad of biophysical and biochemical technologies for our investigations. In general, X-ray crystallography is the main method used to elucidate the three-dimensional architecture of the protein. We then wed structure with function by carrying out functional and biophysical characterizations of the protein in conjunction with site-directed mutagenesis. Insights derived from these studies help us understand: how changes in protein sequence and structure are revealed at the biochemical, cellular, and organismal level; how drug compounds and small molecules modulate enzyme activity; and how the interplay between structure and function impacts fundamental biomedical processes that underlie healthy and diseased states.

A long-standing research interest within my laboratory has been on the characterization of enzymes that derivatize the acyl chains of lipid substrates. The resulting products play important structural roles in the stabilization and fluidity of biological membranes and serve as precursors in the production of bioactive lipids. Altered production of these lipid messengers results in the dysregulation of physiological processes that contribute to the pathogenesis of diabetes, obesity, leukodystrophies, inflammation, and many cancers. Current targets include the membrane-associated cyclooxygenase and fatty acid dioxygenase enzymes, as well as integral membrane fatty acid hydroxylase and desaturase enzymes.

We have also recently initiated collaborative studies to examine the structure-function relationships of novel virulence factors in Treponema denticola, one of the major virulent pathogens associated with chronic periodontitis. These pathogens have evolved complex mechanisms to evade host immune defenses, which allow them to thrive in the oral cavity. Our current focus is on the structural characterization of the cysteine protease TDE0362.

Education and Training:

  • PhD, Biochemistry, Wayne State University (1997)
  • BS, Chemistry, University of Detroit, Magna Cum Laude (1991)

Employment:

  • Professor, Structural Biology, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo (2014-present)
  • Principal Research Scientist, Hauptman-Woodward Medical Research Institute (2012–2017)
  • Research Assistant Professor, Structural Biology, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo (2002–2014)
  • Senior Research Scientist, Hauptman-Woodward Medical Research Institute (2007–2012)
  • Research Scientist, Hauptman-Woodward Medical Research Institute (2001–2007)
  • NIH Postdoctoral Fellow, Biochemistry, Michigan State University (1997–2001)

Awards and Honors:

  • Eicosanoid Research Foundation Young Investigator Award (2011)
  • Arthritis Investigator Award, Arthritis Foundation (2005)
  • NRSA Individual Postdoctoral Fellowship, National Institutes of Health (1999)
  • NIH Predoctoral Training Fellowship, Wayne State University (1993)
  • Merck Index Award, Outstanding Chemistry Student, University of Detroit (1991)
  • Presidential Scholarship, University of Detroit, Detroit, MI (1987)

Research Expertise:

  • Cyclooxygenase Catalysis and Inhibition: One of the most important groups of lipid second messengers is the eicosanoid class, derived from the oxygenation of arachidonic acid by the cyclooxygenase enzymes (COX-1 and COX-2). COX-1 and COX-2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors. My laboratory is a leader within the field in utilizing X-ray crystallographic methods coupled with mutagenesis, functional and biophysical characterizations to understand the mechanistic basis of substrate and inhibitor binding in COX-1 and COX-2, as well as substrate selective oxygenation, inhibition, and allosteric regulation in COX-2.
  • Membrane Proteins: My lab has technical expertise in the expression, detergent solubilization, and purification of membrane-associated and integral membrane proteins for subsequent functional, biophysical, and structural characterization.
  • Protein Production: My lab has technical expertise in the expression of prokaryotic and eukaryotic proteins in bacterial, yeast, and insect cell expression hosts. We also have expertise in the purification of proteins using various modes of column chromatography.
  • X-Ray Crystallography: My lab has technical expertise in all aspects of protein structure determination using X-ray crystallographic methods, including high-throughput crystallization screening and optimization, diffraction data collection, phasing (MIR and MAD), refinement, and model building.

UB 2020 Strategic Strengths:

  • Molecular Recognition in Biological Systems and Bioinformatics

Grants and Sponsored Research:

  • April 2019–March 2024
    Exploring New Virulence Factors of the Oral Spirochete Treponema denticola
    National Institutes of Health
    Role: Co-Principal Investigator
  • September 2017–August 2020
    Community Crystallization Resource for Biological Macromolecules
    National Institutes of Health/NIGMS
    Role: Principal Investigator
  • August 2015–July 2019
    Structure and Dynamics of Cyclooxygenase Catalysis and Inhibition
    NIH/NIGMS
    Role: Principal Investigator
  • April 2013–March 2017
    Characterization of Treponema pallidum Rare Outer Membrane Proteins
    National Institutes of Health/NIAID
    Role: Co-Investigator
  • July 2010–June 2015
    Multi-Level Optimization of Membrane Proteins for Crystallography
    NIGMS
    Role: Principal Investigator
  • September 2011–May 2015
    Catalysis by Prostaglandin Endoperoxide H Synthases
    NIGMS
    Role: Co-Investigator
  • January 2008–December 2012
    T. pallidum Membrane Immunogènes and Anti-Oxidant Defense
    National Institutes of Health/NIAID
    Role: Co-Investigator
  • February 2007–January 2012
    Structure Biology of Oxylipin Biosynthesis
    NIH/NIGMS
    Role: Principal Investigator

Journal Articles:

See all (46 more)

Professional Memberships:

  • American Crystallographic Association (2020–present)
  • American Society for Biochemistry and Molecular Biology (2009–present)

Presentations:

  • "Reexamining Aspirin and Celebrex Interactions with Cyclooxygenase-2: Identification of a New Hotspot for Inhibition" Protein Science Group Seminar Series, Department of Structural Biology, University of Buffalo (2020)
  • "Time-Dependent Inhibition of Cyclooxygenase-2 by Aspirin and Celebrex: The Role of Arg-513 and Leu-531" Bioactive Lipids in Cancer, Inflammation and Related Diseases 16th International Conference (2019)
  • "Cyclooxygenase Catalysis and Inhibition: New Insights and New Directions" Seminar Series, Department of Chemistry, University of Buffalo (2016)
  • "New Insights into Cyclooxygenase Catalysis and Inhibition" Seminar Series; University of Connecticut; Department of Molecular Biology and Biochemistry (2016)
  • "New Perspectives in Cyclooxygenase Structure, Function, and Dynamics" Seminar Series; SUNY at Buffalo; Department of Oral Biology (2014)
  • "Investigating Cyclooxygenase-2 Catalysis and Inhibition in a Lipid Bilayer" Bioactive Lipids in Cancer, Inflammation, and Related Disease 13th International Conference; Eicosanoid Research Foundation (2013)
  • "Monotopic Membrane Enzymes: Structural Features that Govern Catalysis at the Membrane Interface" Advanced Photon Source User's Meeting; Argonne National Laboratory (2013)
  • "Do Plants Have COX? Structural Studies of a Cyclooxygenase-like alpha-dioxygenase from Arabidopsis" Seminar Series, Hospital for Sick Kids, Department of Molecular and Structural Function, University of Toronto (2012)
  • "Flexibility Drives Substrate Promiscuity in Cyclooxygenase-2" CHESS User's Meeting; Cornell University (2012)
  • "Insights into the Oxygenation of Substrates by COX-2" Seminar Series, Department of Chemistry, SUNY-IT (2012)
  • "Molecular Features that Govern the Oxygenation of Substrates by COX-2" 14th Winter Eicosanoid Conference, Baltimore, MD (2012)
  • "The Structure of alpha-Dioxygenase: a Case Study in the Use of Detergent Phase Boundaries to Crystallize Membrane Proteins" Seminar Series, Department of Biochemistry, Michigan State University (2011)
  • "The Who, What, and Why of Structural Biology" Seminar Series, Department of Chemistry, University of Detroit-Mercy (2011)
  • "Substrate Binding to Cyclooxygenase-2: Insight into Specificity and Catalysis" Bioactive Lipids in Cancer, Inflammation, and related Diseases 12th International Conference; Eicosanoid Research Foundation (2011)
  • "High-Throughput Crystallization Screening for the Structural Biology Community" American Crystallographic Association Annual Meeting; New Orleans, LA (2011)
  • "Structural Studies of Fatty Acid Oxygenation by Membrane Bound Enzymes" The Institute for Molecular Diversity and Drug Design 13th Annual Symposium; University of Louisville (2011)
  • "Using Experimentally Derived Detergent Phase Boundaries to Facilitate Crystallization of Membrane Proteins" 13th International Conference on the Crystallization of Biomolecules, Trinity College, Dublin, Ireland (2010)
  • "Multi-Level Optimization of Membrane Proteins" PSI:Biology Kickoff Meeting; National Institutes of Health; National Institute for General Medical Sciences (2010)
  • "Just a Phase? Using Experimentally-derived Detergent Phase Boundaries to Facilitate Crystallization of Membrane Proteins" 40th Mid-Atlantic Crystallography Meeting, Johns Hopkins University (2010)
  • "Using Experimentally-Derived Detergent Phase Boundaries to Facilitate Crystallization of Membrane Proteins" Seminar Series, GlaxoSmithKline (2010)
  • "Then and Now: Structural Biology of Cyclooxygenase-2" Seminar Series, Institute of Chemical Biology, Vanderbilt University (2010)
  • "CHTSB: Technology Development Highlights" Protein Structure Initiative Annual Meeting; National Institutes of Health; National Institute of General Medical Sciences (2009)
  • "Molecular Determinants Governing Oxylipin Biosynthesis in Fatty Acid Oxygenases" Seminar Series, Department of Chemistry, Johns Hopkins University (2009)
  • "Recent Advances in Membrane Protein Crystallization: Determination and Application of Empirically-Derived Detergent Phase Boundaries for Crystallization" 2009 SSRL/LCLS User's Meeting; Stanford University (2009)
  • "Molecular Determinants Governing Fatty Acid Oxygenation in alpha-dioxygenases" Regulatory Oxylipins: an International Symposium, Lausanne, Switzerland (2009)
  • "Technology Development Efforts at the Center for High-Throughput Structural Biology" Protein Structure Initiative Annual Meeting; National Institutes of Health; National Institute of General Medical Sciences (2008)
  • "Using Detergent Phase Boundaries to Crystallize Membrane Proteins" Protein Structure Initiative 7th Bottlenecks Workshop; National Institutes of Health; National Institute of General Medical Sciences (2008)
  • "Technology Developments at the CHTSB" Protein Structure Initiative Annual Meeting; National Institues of Health; National Institute of General Medical Sciences (2007)
  • "The Utilization of Detergent Phase Boundary Information for Crystallizing Membrane Proteins" 65th Annual Pittsburgh Diffraction Conference; Pittsburgh Diffraction Society, Buffalo, NY (2007)
  • "The Center for High-Throughput Structural Biology: Show Me the Bottlenecks" Protein Structure Initiative's 6th Bottlenecks Workshop; National Institutes of Health; National Institute of General Medical Sciences (2007)
  • "Oxylipin Biosynthesis in Pathogen-Inducible Oxygenase" Biophysics and Structural Biology Retreat; University of Rochester (2007)
  • "Novel Oxygenations of Arachidonic Acid by Cyclooxygenases" Segal Osteoarthritis Symposium, Arthritis Foundation, Northwestern University, Evanston, IL (2006)
  • "Technology Development at the Center for High-Throughput Structural Biology" Protein Structure Initiative Annual Meeting; National Institues of Health; National Institute of General Medical Sciences (2006)
  • "The Center for High-Throughput Structural Biology" Protein Structure Initiative's 5th Bottlenecks Workshop; National Institutes of Health; National Institute of General Medical Sciences (2006)
  • "Novel Oxygenations of Polyunsaturated Fatty Acids" Upstate New York Structural Biology Day; University of Rochester (2003)
  • "Fatty Acid Interactions with Cyclooxygenases" Seminar Series, Department of Molecular and Cellular Biophysics, Rosewll Park Cancer Institute (2001)
  • "Fatty Acid Substrate Interactions with Cyclooxygenases" 10th Buffalo-Hamilton-Toronto Crystallography Meeting, McMaster University, Hamilton, Ontario (2001)
  • "Fatty Acid Substrate Interactions with Cyclooxygenases" 4th International Workshop on COX-2, San Juan, Puerto Rico (2001)
See all (28 more)

Service Activities:

  • NIH ZRG1 F04B-T (20); Reviewer (2020)
  • Ad Hoc Committee on Promotions to Academic (Tenurial) Ranks (2020–2023)
  • NIH ZRG1 BCMB-G (02); Reviewer (2020)
  • Decanal Academic Grievance Committee; Chair (2019–2020)
  • NIH ZRG1 BCMB-G; Study Section Chair (2019)
  • NIH ZRG1 BCMB-G; Study Section Chair (2019)
  • JSMBS Research Strategic Plan Steering Committee; Member (2017–2018)
  • Israeli Science Foundation; Ad Hoc Reviewer (2017)
  • NIH ZRG1 BCMD-T (01) I; Panel Member (2016)
  • BioXFEL Faculty Search Committee; Committee Member (2016–present)
  • ZRG1 BCMB-D (02) M;; Ad Hoc Reviewer (2016)
  • NIH Molecular Structure and Function B; Ad Hoc Reviewer (2015)
  • PPBS Admissions Commitee; Committee Member (2015–2021)
  • NIH ZGM1 CBB-0 (EM); Panel Member (2015)
  • Chair, Department of Structural Biology; Chair (2014–2021)
  • PPBS Steering Committee Department of Structural Biology representative; Committee Member (2013–2014)
  • NIH ZRG1 BCMB-D (0); Panel Member (2013)
  • US-Israeli Binational Science Foundation; Ad hoc Reviewer (2012)
  • NCI Intramural Program, Laboratory of Cell Biology; Site Visit Review Team Member (2011)
  • Jeffress Memorial Trust; Ad Hoc Reviewer (2010)
  • NIGMS Pathway to Independence grants (K99-R00); Stage 1 Reviewer (2010)
  • National Science Foundation; Ad hoc Reviewer (2010)
  • Israeli Science Foundation; Ad hoc Reviewer (2010)
  • NIH Challenge Grants; Reviewer (2009)
  • IGPBS Admissions Assessment Committee Department of Structural Biology representative; Committee Member (2008)
  • Arthritis Foundation, Molecular Immunology Study Section; Reviewer (2008)
  • IGPBS Steering Committee Department of Structural Biology representative; Committee Member (2001–2009)
  • IGPBS Admissions Committee Department of Structural Biology representative; Committee Member (2001–2003)

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Contact Information

Department of Structural Biology
Jacobs School of Medicine And Biomedical Sciences
955 Main Street
Buffalo, New York 14203-1121
Phone: 716-829-3698
mgm22@buffalo.edu