SEMINAR: Cytochrome P450: Nature's Versatile Catalyst – University of Copenhagen

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27 February 2013

SEMINAR: Cytochrome P450: Nature's Versatile Catalyst

Professor Stephen G. Sligar

Swanlund Endowed Chair
University of Illinois Urbana-Champaign

Thursday 7th March
10:00-11:00

H117-3 Thorvaldsensvej 40

The superfamily of cytochromes P450 forms a large class of heme monooxygenases with more than 18,000 enzymes being represented in organisms from all biological kingdoms. Despite impressive variability in size, sequence, location and function, all cytochromes P450 from various organisms display a similar tertiary structure.  In humans, these enzymes carry out two classes of metabolic processes.  First is the catabolism of all xenobiotics, including therapeutic drugs and environmental toxins.  In addition, they play a central role in the biosynthesis of signaling molecules such as steroid hormones and prostaglandins.  As such, the cytochrome P450s represent an critical target for the treatment of cancer, inflammation and other important human diseases.   Determining the detailed bioinorganic mechanism of cytochrome P450 catalysis has occupied chemists, biochemists and pharmacologists for six decades.  Much of the early structural and functional knowledge was gleaned from the study of bacterial systems that are soluble proteins.  Yet most of the identified P450s are associated with membranes and many of these offer unique and fundamental questions of substrate recognition, ligand binding, electron transfer, oxygen activation and substrate functionalization.  The study of membrane-associated metalloproteins has been greatly aided by our discovery that the amphipathic P450 and redox partners could be readily self-assembled into a phospholipid bilayer nanoparticle that provides a native bilayer environment, thus preserving native activity, yet is soluble in aqueous solution.  We have used this Nanodisc technology to provide detailed spectroscopic and catalytic characterization of the critical heme-oxygen intermediates in P450 oxygenase catalysis.   In my lecture I will provide a historic overview of metalloprotein oxygenases and describes our recent findings regarding the mechanisms of this enzyme superfamily.