For a better experience, click the Compatibility Mode icon above to turn off Compatibility Mode, which is only for viewing older websites.

Marilyn Jorns

Marilyn Jorns, PhD

Professor


Department: Biochemistry & Molecular Biology

Education

  • PhD in Biochemistry - University of Michigan (1970)

Marilyn Jorns, PhD, is a professor in the Department of Biochemistry & Molecular Biology at Drexel University College of Medicine.

Research Interests

Use of structure-based drug design to develop a new class of drugs to treat heart failure, based on modulation of the gasotransmitter hydrogen sulfide; structure and mechanism of membrane-bound oxidoreductases

Research

Cardioprotective effects of hydrogen sulfide in heart failure
Cardioprotective effects of hydrogen sulfide in heart failure

Heart failure is a highly lethal disease affecting more than 6 million Americans. There are presently no effective treatments for heart failure other than heart transplantation, which is limited by the availability of organ donors. Hydrogen sulfide (H2S) is a crucial signaling molecule in the cardiovascular system, where it protects against the development of hypertension and atherosclerosis, the leading causes of heart failure. Patients with heart failure exhibit a pronounced decrease (up to three-fold) in plasma H2S levels that appears to be correlated with the severity of the disease. The finding of reduced H2S levels has been replicated in several experimental rodent models where exogenous administration of H2S is found to protect against the development of heart failure induced by ischemia-reperfusion injury, pressure overload or volume overload. The attractiveness of increasing H2S levels as a novel therapeutic strategy to treat heart failure stems from the ability of this gasotransmitter to activate multiple cardioprotective pathways at the same time.

Crystal of human SQOR and a model of its spatial position in the inner mitochondrial membrane
Crystal of human SQOR and a model of its spatial position in the inner mitochondrial membrane

The steady-state tissue concentration of H2S reflects the difference between high rates of H2S biosynthesis and mitochondrial metabolism. Human sulfide:quinone oxidoreductase (SQOR) is an inner mitochondrial membrane-bound flavoprotein that sits at a key pharmacological intervention point because it catalyzes the first irreversible step in H2S metabolism. SQOR uses coenzyme Q (CoQ) as electron acceptor and glutathione or sulfite as sulfane sulfur in reactions that produce glutathione persulfide (shown) or thiosulfate, respectively. A ~40-fold increase in H2S tissue levels is observed when the mitochondrial metabolism of H2S is completely blocked by a genetic deficiency of a downstream enzyme that catalyzes the third step in the pathway. Slowing H2S metabolism by inhibiting SQOR is, therefore, likely to readily achieve the modest increase (~three-fold) needed to normalize H2S levels in heart failure patients.

We have identified potent inhibitors of human SQOR in hit optimization studies around the most promising scaffolds identified in a high-throughput screening campaign and by structure-based drug design. Biological efficacy studies are in progress.

Publications

"X-ray Structure of Human Sulfide:Quinone Oxidoreductase: Insights into the Mechanism of Mitochondrial Hydrogen Sulfide Oxidation"
MR Jackson, PJ Loll, and MS Jorns
Structure, 27, 794-805 (March 21, 2019)

"Use of Tissue Metabolite Analysis and Enzyme Kinetics to Discriminate Between Alternate Pathways for Hydrogen Sulfide Metabolism"
KDC Augustyn, ML Jackson, and MS Jorns
Biochemistry, 56, 986-996 (2017)

"Role of Human Sulfide:quinone Oxidoreductase in H2S Metabolism"
ML Jackson, SL Melideo, and MS Jorns
Methods Enzymol., 554:255-70 (2015)

"Biosynthesis of a Central Intermediate in Hydrogen Sulfide Metabolism by a Novel Human Sulfurtransferase and its Yeast Ortholog"
SL Melideo, ML Jackson, and MS Jorns
Biochemistry, 53, 4739-4753 (2014)

"Toward Understanding the Mechanism of Oxygen Activation by Flavoprotein Oxidases"
MS Jorns

Handbook of Flavoproteins
(Hille R, Miller SM and Palfey B eds.), De Gruyter, Berlin, pp 195-211 (2013)

"Human Sulfide:quinone Oxidoreductase Catalyzes the First Step in Hydrogen Sulfide Metabolism and Produces a Sulfane Sulfur Metabolite"
ML Jackson, SL Melideo, and MS Jorns
Biochemistry, 51, 6804-6815 (2012)

"Probing Oxygen Activation Sites in Two Flavoprotein Oxidases Using Chloride as an Oxygen Surrogate"
PR Kommoju, Z Chen, RC Bruckner, FS Mathews, and MS Jorns 
Biochemistry, 50, 4949-4962 (2011)

"Pleiotropic Impact of a Single Lysine Mutation on Biosynthesis of and Catalysis by N-Methyltryptophan oxidase"
RC Bruckner, J Winans, and MS Jorns
Biochemistry, 50, 4949-4962 (2011)

"Structural Characterization of the Oxygen Activation Site in Monomeric Sarcosine Oxidase"
MS Jorns, Z Chen, and FS Mathews
Biochemistry, 49, 3631-3639 (2010)

"Factors that Affect Oxygen Activation and Coupling of the Two Redox Cycles in the Aromatization Reaction Catalyzed by NikD, an Unusual Amino Acid Oxidase"
PR Kommoju, RC Bruckner, P Ferreira, CJ Carrell, FS Mathews and MS Jorns
Biochemistry, 48, 9542-9555 (2009)

"Probing the Role of Active Site Residues in NikD, an Unusual Amino Acid Oxidase that Catalyzes an Aromatization Reaction Important in Nikkomycin Biosynthesis"
PR Kommoju, RC Bruckner, P Ferreira and MS Jorns
Biochemistry, 48, 6951-6962 (2009)

"Spectral and Kinetic Characterization of Intermediates in the Aromatization Reaction Catalyzed by NikD, an Unusual Amino Acid Oxidase"
RC Bruckner, and MS Jorns
Biochemistry, 48, 4455-4465 (2009)

"Identification of the Oxygen Activation Site in Monomeric Sarcosine Oxidase: Role of Lys265 in Catalysis"
G Zhao, RC Bruckner, and MS Jorns
Biochemistry, 47, 9124-9135 (2008)

"Covalent Flavinylation of Monomeric Sarcosine Oxidase: Identification of a Residue Essential for Holoenzyme Biosynthesis"
A Hassan-Abdallah, G Zhao and MS Jorns
Biochemistry, 47, 1136-1143 (2008)

"Arginine 49 Is a Bifunctional Residue Important in Catalysis and Biosynthesis of Monomeric Sarcosine Oxidase: A Context-sensitive Model for the Electrostatic Impact of Arginine to Lysine Mutations"
A Hassan-Abdallah, G Zhao, Z Chen, FS Mathews and MS Jorns
Biochemistry, 47, 2913-2922 (2008)

"NikD, an Unusual Amino Acid Oxidase Essential for Nikkomycin Biosynthesis"
CJ Carrell, RC Bruckner, D Venci, G Zhao, MS Jorns and FS Mathews
Structure, 15, 928-941 (2007)

"A Mobile Tryptophan is the Intrinsic Charge Transfer donor in a Flavoenzyme Essential for Nikkomycin Antibiotic Biosynthesis"
RC Bruckner, G Zhao, P Ferreira and MS Jorns
Biochemistry, 46, 819-827 (2007)

"Heterotetrameric Sarcosine Oxidase: Structure of a Diflavin Metalloenzyme at 1.85 Å Resolution"
Z Chen, A Hassan-Abdallah, G Zhao, MS Jorns and FS Mathews
J. Mol. Biol., 360, 1000-1018 (2006)

"Biosynthesis of Covalently Bound Flavin: Isolation and in vitro Flavinylation of the Monomeric Sarcosine Oxidase Apoprotein"
A Hassan-Abdallah, RC Bruckner, GH Zhao and MS Jorns
Biochemistry, 44, 6452-6462 (2005)


Contact Information


Research Office

Department of Biochemistry & Molecular Biology
245 North 15th Street
Mail Stop 497
Philadelphia, PA 19102
Phone: 215.762.7495
Fax: 215.762.4452