Washington, March 11 : Researchers at the University of Pittsburgh School of Medicine have achieved a significant success in deciphering the three-dimensional structure of a membrane-bound enzyme that plays a crucial role in glycerol metabolism.
The researchers, claiming to be the first to carry out this work, used X-ray crystallography for the purpose of solving the large enzyme called Sn-glycerol-3-phosphate dehydrogenase (GlpD), which is found in abundance in the cell membranes of almost all organisms, including humans.
Structural biologist Joanne I. Yeh, lead researcher on the project, said that the discovery might lead to important advances against obesity, diabetes and a potential host of other diseases.
"Everybody wants a golden bullet for obesity, and certainly we need better ways of controlling diabetes. I think that glycerol metabolism will be on the forefront of developing treatments for these diseases, and so many others, since it is a pivotal yet underappreciated link among some very important metabolic pathways," said Dr. Yeh, senior author of the study, published in the Proceedings of the National Academy of Sciences.
The researcher said that the new study marks the highest resolution structure of a monotopic membrane protein that scientists have solved to date, and is one of only a handful of structures of this important class of membrane proteins that have been determined.
"These findings and data help to fill an important scientific and technical gap in the structural field and present new information and ideas about how the enzyme works and the importance of the cell membrane in stabilizing the enzyme and in processes related to energy production," said Dr. Yeh.
Dr. Yeh and her colleagues took only three months to decipher the set of 3-D structures of GlpD isolated from E. coli bacteria, thanks to other methodologies they developed in earlier studies.
She said that her team's work could prove helpful in gaining a more complete understanding of how the enzyme functions, details about how GlpD interacts with the membrane, works to catalyse the enzymatic reaction, and links to cellular-energy production.
Talking about the structure of the enzyme, Dr. Yeh said that GlpD is a dimer (a protein with two subunits), which is embedded into and interacts substantially with the lipids that make up the cell membrane. She said that the interaction with the membrane is required to keep the enzyme energetically and functionally stable so that it does not collapse on itself.
The researchers also discovered that the enzyme is made up of two major domains: a soluble extracellular "cap" and a FAD-binding region, whose base is rooted in the membrane. According to them, the location of the enzyme's active site, where the chemical reaction actually occurs, is at this FAD-binding region.
Besides, Dr. Yeh's team discovered a never-before-seen type of protein fold consisting of about 100 amino acids in the "cap" domain of GlpD. They also identified areas where other proteins might bind to regulate the enzyme's activity and transmit chemical signals.
The researchers have already started to use the structural details of GlpD to examine how mutating certain amino acids in the enzyme affects its function and fold, with a view to determining the roles that these specific amino acids play in enzymatic function and regulation of activity.