Hydrogen sulfide (H2S) is the newest member of a small family of gaseous, biological signaling molecules, termed gasotransmitters. H2S is the only gasotransmitter that is enzymatically metabolized. H2S signaling is involved in numerous cellular processes and plays an especially important role in the cardiovascular system. Despite its multiple life-supporting properties, H2S is a Janus-faced molecule that can exhibit toxic effects at higher concentrations. For example, a genetic defect in the mitochondrial metabolism of H2S is the cause of ethylmalonic encephalopathy (EE), a devastating, invariably fatal disorder of infancy that is characterized by extremely high (toxic) levels of the gasotransmitter and impaired metabolism of short-chain fatty acids. On the other hand, clinical data and animal model studies provide compelling evidence for a functional association between abnormally low levels of H2S and cardiovascular disease. The long-term goals of this project are to elucidate the pathways for and the possible regulation of the mitochondrial metabolism of H2S, to apply this knowledge to treat EE and other defects in H2S metabolism. Sulfide:quinone oxidoreductase (SQOR) is an integral membrane protein that catalyzes the first irreversible step in H2S metabolism and, as such, sits at a key potential regulatory point. We will elucidate the catalytic mechanism of this important enzyme and investigate its possible regulation by posttranslational modification. Our recent identification of the physiological acceptor of the sulfane sulfur (S0) produced in the SQOR reaction has necessitated a major revision of previously proposed pathways for H2S metabolism. To address important gaps in the current knowledge, we will characterize two postulated enzymes in the new model for H2S metabolism and evaluate the biological function of each enzyme in cells. Our discoveries in H2S metabolism allow us to design novel therapeutic strategies to treat EE and also suggest how a defect in H2S metabolism can interfere with fatty acid metabolism. This work will be conducted in close collaboration with basic and clinical scientists with expertise in mitochondrial disease, medicinal chemistry, drug discovery, cell biology, and structural biology.

Public Health Relevance

Hydrogen sulfide, the newest member of a small family of gaseous, biological signaling molecules, plays a vital role in numerous physiological processes and is especially important in the cardiovascular system. This project will evaluate a novel therapy for the treatment of ethylmalonic encephalopathy, an invariably fatal disorder of hydrogen sulfide metabolism, and will seek to discover the functional link between aberrant hydrogen sulfide metabolism and deficits in fatty acid metabolism observed in ethylmalonic encephalopathy and ulcerative colitis patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM107389-01
Application #
8560708
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Anderson, Vernon
Project Start
2013-09-15
Project End
2017-07-31
Budget Start
2013-09-15
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$290,917
Indirect Cost
$100,917
Name
Drexel University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Melideo, Scott L; Jackson, Michael R; Jorns, Marilyn Schuman (2014) Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog. Biochemistry 53:4739-53