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John D. Lipscomb

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Title

John D. Lipscomb
Professor

Department:

 

Research Description

We investigate the mechanisms of oxygenases, the enzymes nature uses to catalyze the incorporation of oxygen into biological molecules. Oxygen incorporation reactions are important for a wide variety of reasons, ranging from activation of steroid hormones in humans to the detoxification of compounds in the environment. The oxygenases we study contain a metal which is the key to the chemistry they catalyze. Enzyme mechanisms involve both the chemical reactions occurring at the active site and the regulation of the reaction imposed by the complex protein structure. Consequently, we use many types of biochemical and physical techniques including transient kinetics, site directed mutagenesis, diagnostic substrate reactions, and EPR spectroscopy. This is extended to X-ray crystallography and other spectroscopies through collaborations.

Photograph of Dr. Lipscomb research

Currently, we are studying two large families of oxygenases. The first is typified by methane monooxygenases, the enzyme primarily responsible for preventing the vast amounts of biologically generated methane from reaching the atmosphere. This enzyme splits O2 and incorporates one atom of oxygen into methane to form methanol, while reducing the second atom to water. Another enzyme we have found from this family is essential for the biosynthesis of many important antibiotics and chemotherapy drugs.  The second oxygenase family includes several dioxygenase enzymes that also split O2 but incorporate both atoms into biomolecules. These enzymes are the major means by which the enormous quantities of aromatic compounds that enter the environment annually are reassimilated into the carbon cycle. Recently, we have developed methods to trap reaction cycle intermediates of these enzymes in single crystals for direct structural analysis. Related collaborative projects include studies of the biosynthesis of biofuels, penicillin, fosfomycin, and ethylene (a plant hormone).


Recent Publications

Banerjee, R., Proshlyakov, Y., Lipscomb, J.D., and Proshlyakov, D.A. “Structure of the key species in the enzymatic oxidation of methane to methanol” Nature, 518(7539), 431-434 (2015) PMC:4429310

Makris, T. M., Vu, V. V., Meier, K. K., Komor, A. J., Rivard, B. S., Münck, E., Que, L, Jr., and Lipscomb, J. D. “An Unusual Peroxo Intermediate of the Arylamine Oxygenase of the Chloramphenicol Biosynthetic Pathway”, J. Am. Chem. Soc., 137, 1608-1617 (2015) PMC:4318726

Knoot, C. J., Purpero, Vincent M., Lipscomb, J. D. “Crystal Structures of Alkylperoxo and Anhydride Intermediates in an Intradiol Ring-cleaving Dioxygenase” Proc. Natl. Acad. Sci., 112, 388-393 (2015) PMC:4299229

Lipscomb, J. D. “Life in a Sea of Oxygen” J. Biol. Chem. 289, 15141-15153 (2014) PMC: 4140874

Fielding, A. J., Lipscomb, J. D. and Que, L., Jr. “A Two-electron Shell Game: Intermediates of the Extradiol-cleaving Catechol Dioxygenases” J. Biol. Inorg. Chem., 19, 491-504 (2014) PMC:4039383

Makris, T. M., Knoot, C. J., Wilmot, C. M. and Lipscomb, J. D. “Structure of a Dinuclear Iron Cluster-Containing Beta Hydroxylase Active in Antibiotic Biosynthesis” Biochemistry, 52, 6662-6671 (2013) PMC: 3826434

Aukema, K. G., Makris, T. M., Stoian, S. A., Richman, J. E., Münck, E., Lipscomb, J. D., and Wackett L. P. “Cyanobacterial aldehyde deformylase oxygenation of fatty aldehydes yields n-1 aldehydes and alcohols in addition to fatty alkanes”, ACS Catalysis, 3, 2228–2238 (2013) PMC: 3903409

Banerjee, R., Meier, K. K., Münck, E., and Lipscomb, J. D. “Intermediate P* from Soluble Methane Monooxygenase Contains a Diferrous Cluster” Biochemistry, 52, 4331-4342 (2013) (Highlighted publication) PMC

Kovaleva, E. and Lipscomb, J. D. “Structural Basis for the Role of Tyrosine 257 of Homoprotocatechuate 2,3-Dioxygenase in Substrate and Oxygen Activation” Biochemistry, 51, 8755-8763 (2012) PMC

Mbughuni, M. M., Meier, K. K., Münck, E. and Lipscomb, J. D. “Substrate-Mediated Oxygen Activation by Homoprotocatechuate 2,3-Dioxygenase: Intermediates Formed by a Tyrosine 257 Variant” Biochemistry, 51, 8743-8754 (2012) PMC

Thompson, J. W., Salahudeen, A. A., Chollangi, S., Ruiz, J. C., Brautigam, C. A., Makris, T. M., Lipscomb, J. D., Tomchick, D. R., and Bruick, R. K. “Structural and Molecular Characterization of Iron-sensing Hemerythrin-like Domain within F-box and Leucine-rich Repeat Protein 5 (FBXL5)” J. Biol. Chem. 287, 7357-7365 (2012) (Cover illustration, paper of the year) PMC

Mbughuni, M. M., Chakrabarti, M., Hayden, J. A., Meier, K. K., Dalluge, J. J., Hendrich, M. P., Münck, E., and Lipscomb, J. D. “Oxy-Intermediates of Homoprotocatechuate 2,3-Dioxygenase: Facile Electron Transfer Between Substrates” Biochemistry, 50, 10262-10274 (2011) (Highlighted publication) PMC

Mbughuni, M. M., Chakrabarti, M., Hayden, J. A., Bominaar, E. L., Hendrich, M. P., Münck, E. and Lipscomb, J. D. “Trapping and Spectroscopic Characterization of an FeIII-Superoxo Intermediate from a Non-heme Mononuclear Iron-containing Enzyme” Proc. Natl. Acad. Sci. (U.S.A.), 107,  16788-16793 (2010) PMC

Makris, T. M., Chakrabarti, M., Münck, E. and Lipscomb, J. D. “A Family of Diiron Monooxygenases Catalyzing Amino Acid Beta Hydroxylation in Antibiotic Biosynthesis” Proc. Natl. Acad. Sci. (U.S.A.), 107 15391-15396 (2010) PMC

 

Ph.D., University of Illinois, 1974
Phone Number
(612) 625-6454 Fax:(612) 624-5121
Email Address

lipsc001@umn.edu

Address
5-112 NHH
312 Church St. SE
Minneapolis, MN 55455