Oxidation & reduction of methionine and its relevances in ageing and disease
Our body are made from millions of million cells. Each cell is built by three major chemical components, proteins, lipids and carbohydrates. Among the three components, proteins play vital roles in making up the structure and the functions of the cells.
Methionine, one of 20 common amino acids (& pyrolysine and selenocysteine) that build up a protein molecule, are extremely sensitive to oxidation of its side-chain sulfur to form methionine sulfoxide or methionine sulfone. The oxidation of methionine to methionine sulfoxide is known to occur readily inside living cells under elevated concentrations of reactive oxygen species (ROS). The oxidation of methionine mostly causes the proteins to be non-functional through inactivating the proteins. Evidence has been accumulated that methionine oxidation is accelerated in aged mice and a few dozens of proteins had been identified to has its methionine oxidation directly involves in disease propagation, including thrombosis, atherosclerosis, emphysema and neurodegenerative disorders such as Alzheimer and Parkinson.
Interestingly the oxidized methionine can be reduced to its original form by the cell’s own enzymes, methionine sulfoxide reductases. Here at the Gladyshev Laboratory (and other groups) it has been shown that modulation of methionine sulfoxide reductase (Msrs) affects lifespan in yeast, fruit fly, and mammals.
My current research is aimed at asking several important questions. Approaches involve in this study include protein engineering, mammalian cell culture, molecular imaging, immunology, transgenic mouse model, biophysics methods and computational biology.
Acetohydroxy acid synthase
Proteins in our body are made up of 22 amino acids, which are classified into essential and nonessential amino acids. The term “essential amino acids” refers to the fact that these amino acids is important but can not be synthesized in our body, and thus we have to supply our body with these amino acids via diets. Unlike us humans and animals, plants and microbes are capable of production of essential amino acids, hence, they are a good dietary source those amino acids. Branched-chain amino acids such as Leucine, Isoleucine and Valine are essential amino acids.
Acetohydroxy acid synthase (AHAS) is the common enzyme catalyses the first common step in the biosynthesis of branched-chain amino acids in plants and microbes. It is also known as the target of several classes of potent herbicides, including sulfonylureas, immidazolinone and triazolopyrimidines. My research had been focused on the mechanism of action of AHAS in plant and its inhibition by several herbicides. Using computational modeling and biochemical approaches, I had mapped most of the important residues at the active site and herbicide-binding site of tobacco AHAS. I had also developed a mutant variant insensitive to herbicides without affecting its kinetics properties. This works were conducted at the Enzymology Lab at Chungbuk National University, Korea under the support of Professor Jung-Do Choi. This study has resulted in few publications which can be found at the publication section. Recently evidence has accumulated showing that AHAS could be a potential target to control intracellular disease-causing bacteria, such as tuberculosis. I have put together few data related to this hoping to submit it to a journal.
Rapid & Point-of-Care diagnostics
Rapid & point-of-care diagnostics are playing more and more important role in our life. As the name can tell, it can provide convenient and quick results of the tests. “Point-of care” allows the test to be conducted virtually anywhere while the “rapid” assists us in fast decision makings. I am interested in developing new test KIT and improving the sensitivity of currently available devices through employing nanoparticle conjugates as well as automation. The tests that I am interested in includes “foodborne pathogens”, “mycotoxins”, “infectious diseases”, and “pesticide residues”.
I am trying not to be interest in everything, however I will keep my eyes open for other interesting topics.