Drexel University College of Medicine - Department of Biochemistry Faculty
Marilyn S. Jorns, Ph.D.
Professor of Biochemistry
Telephone: (215) 762-7495
Ph.D. (1970) Biochemistry, University of Michigan
Flavin-containing enzymes participate in an extraordinary range of reactions fromsimpleelectron transfer to complex energy transduction systems like regulation of biological clocks. From a physiological and biomedical standpoint, oxidation of amino acids and other amines are among the most important reactions catalyzed by flavoenzymes. Amine-oxidizing flavoenzymes play a key role in the biosynthesis of biologically significant nonribosomal peptides like nikkomycin antibiotics (nikD), are major drug targets in treating various neurological disorders (monoamine oxidase, pipecolate oxidase), are used in clinical diagnostics (sarcosine oxidase), and are defective in various hereditary diseases like sarcosinemia (sarcosine dehydrogenase). Our current research is focused on the recently recognized monomeric sarcosine oxidase (MSOX) superfamily, a group of amine-oxidizing flavoenzymes that all contain covalently bound flavin. Members of the MSOX superfamily include monomeric and heterotetrameric bacterial sarcosine oxidases, nikD, pipecolate oxidase, sarcosine dehydrogenase, monoamine oxidase and others. Two ongoing projects in the laboratory illustrate our approaches:
Monomeric Sarcosine Oxidase (MSOX) is widely used in the clinical evaluation of renal function. The crystal structure of MSOX and its complexes with various inhibitors has been determined at high resolution (1.3 - 2.0 Angstrom) in collaboration with Dr. Scott Mathews. Structural studies on enzyme-substrate complexes are in progress. Despite considerable attention, the molecular mechanism of amine oxidation is still a matter of dispute and has evoked several contrasting proposals. MSOX constitutes one of the most experimentally accessible systems in which to further examine the mechanism of these reactions. Additional studies focus on the biosynthesis of the covalent flavin linkage (found in all members of the MSOX superfamily) and the role of the covalent linkage in catalysis.
NikD catalyzes a key step in the biosynthesis of nikkomycins, peptidyl nucleoside antibiotics that act as potent anti-fungal agents against several important human pathogens. Diffraction quality crystals of nikD have been obtained. Structural studies are in progress and will serve to identify active site residues. We plan to define and kinetically characterize the reaction(s) catalyzed by nikD with its proposed physiological substrate. Our results currently suggest that nikD may be a novel trifunctional enzyme that catalyzes both oxidation and isomerization reactions.
Selected Recent Publications
Bruckner, R.C., Zhao,G., Venci,D. and Jorns, M.S. (2004) Nikkomycin Biosynthesis: Formation of a 4-electron product during turnover of nikD with its physiological substrate, Biochemistry 43, 9160-9167.
Khanna, P. and Jorns, M.S. (2003) Tautomeric rearrangement of a dihydroflavin bound to monomeric sarcosine oxidase or N-methyltryptophan oxidase. Biochemistry 42, 864-869.
Venci, D., Zhao, G. and Jorns, M.S. (2002) Molecular characterization of nikD, a new flavoenzyme important in the biosynthesis of nikkomycin antibiotics. Biochemistry 41, 15795-15802.
Zhao, G., Song, H., Chen, Z., Mathews, F.S. and Jorns, M. S. (2002) Monomeric sarcosine oxidase: role of histidine 269 in catalysis. Biochemistry 41, 9751-9764.
Eschenbrenner, M., Chlumsky, L.J., Khanna, P., Strasser, F. and Jorns, M.S. (2001) Organization of the multiple coenzymes and subunits and role of the covalent flavin link in the complex heterotetrameric sarcosine oxidase. Biochemistry 40, 5352-5367.
Khanna, P. and Jorns, M.S. (2001) Characterization of the FAD-containing N-methyltryptophan oxidase from Escherichia coli. Biochemistry 40, 1441-1450.
Wagner, M.A., Trickey, P., Chen, Z., Mathews, F.S., and Jorns, M.S. (2000) Monomeric sarcosine oxidase: 1. Flavin reactivity and active site binding determinants. Biochemistry 39, 8813-8824.
Zhao, G., Qu, J., Davis, F.A., and Jorns, M.S. (2000) Inactivation of monomeric sarcosine oxidase by reaction with N(cyclopropyl)glycine. Biochemistry 39, 14341-14347.
Eschenbrenner, M. and Jorns, M.S. (1999) Cloning and mapping of the cDNA for human sarcosine dehydrogenase, a flavoenzyme defective in patients with sarcosinemia. Genomics 59, 300-308.
Trickey, P., Wagner, M.A., Jorns, M.S., and Mathews, F.S. (1999) Monomeric sarcosine oxidase: Structure of a covalently-flavinylated secondary amine oxidizing enzyme. Structure 7, 331-345.