Basic Research:

In our bodies, proteins have many important functions including giving physical strength and structure to our cells, organs, skin, bones, hair, nails and muscle. In addition, antibodies that protect our bodies from infection and enzymes that perform 99.9% of all reactions are proteins.

Proteins are polymers of amino acids. Of the 20 commonly occurring amino acids found in proteins, only three contain sulfur: namely cysteine (Cys) , homocysteine (HCys) and methionine (Met). The sulfur functionality on cysteine and homocysteine are the most reactive groups in comparison to all other amino acids.

Our bodies also produce nitric oxide (NO) and
hydrogen sulfide (H2S) gaseous signaling molecules with many beneficial effects such as vasodilation (or relaxation of blood vessel walls leading to lower blood pressure), neural transmission, immune responses, wound healing, blood vessel growth and proliferation etc. However, elevated levels of NO and H2S are associated with several pathologies including neurodegenerative and cardiovascular diseases, and cancer.

NO when produced at high levels can combine with oxygen to form highly reactive compounds like nitrogen trioxide (N2O3) which can rapidly react with sulfur containing amino acids, peptides and proteins to form S-nitrosothiols (-S-N=O). This process is termed S-nitrosylation.

H2S can also react with oxidized thiols in amino acids, peptides and proteins to form persulfides (-S-S-H). This process is termed S-sulfhydration.

Both
S-nitrosylation and S-sulfhydration can drastically affect protein structure and function eventually leading to a variety of pathologies.

The work in our laboratory is centred around:
1- The development of analytical methods to measure levels of NO(NO
x)and H2S;
2- Picking out the specific amino acids within the proteins that are susceptible to
S-nitrosylation and S-sulfhydration; and
3- Identifying specific
S-nitrosylated- and S-sufhydrated-proteins that are pivotal control points in a given pathology. A good example, of this is our recent work on the cell membrane-resident enzyme neutral sphingomyelinase (NSMase). When normal cells are exposed to stress (such as chemotherapeutic drugs), NSMase is stabilized and activated making more of a compound (creamide) causes the cells to self destruct (apoptosis). However as we recently discovered, cancer cells when stressed inactivate NSMase by S-nitrosylating it thereby avoiding the self destruct-signal and surviving the stress. Currently, we are using our analytical/proteomic methods to identify NSMase’s -S-N=O-susceptible regions with a view of preventing the inactivation of NSMase in cancer cells, thereby rendering them more susceptible to killing by chemotherapeutics.