The long-term objective of this research program is to elucidate the structure, mechanism of action and regulation of enzymes involved in fatty acid biosynthesis.  Animal cells have two distinct systems for the biosynthesis of fatty acids; the cytosolic and the mitochondrial fatty acid synthases (FASs).  The long-term goal of the Smith laboratory is the characterization of these two systems and clarification of their respective roles in metabolism.

In the cytosolic FAS, all of the enzymes required to convert malonyl-CoA to long-chain fatty acid are integrated in to a single, multifunctional polypeptide chain of 2500 amino acids.  The amount of FAS present in animal cells is regulated in a tissue specific manner by dietary and hormonal factors.  Recently, this protein has been identified as a target for the development of novel therapeutic agents for the treatment of obesity and cancer.  The Smith laboratory was the first to determine the complete amino acid sequence of an animal FAS, to map the intron-exon organization of the FAS gene and to develop an expression system for the production of recombinant FAS and mutants thereof.  Currently, work is focused on deciphering the structure organization of the whole complex, as well as individual catalytic components, and determining how these components cooperate with each other to form the fatty acid product.

In recent years, analysis of sequence information from the human genome project has revealed that animals most likely contain a second system for fatty acid synthesis; this one located in the mitochondria.  The Smith laboratory is attempting to identify the components of the human mitochondrial FAS system and already has cloned and characterized several of the enzymes involved.  In contrast to the cytosolic FAS, components of the mitochondrial system exist as separate, freestanding proteins that resemble more closely their counterparts in prokaryotes.  Exactly why animals require a second system for fatty acid synthesis, exclusively in the mitochondria, is yet to be established.  The working hypothesis is that the system may provide a key precursor for the production of lipoic acid, which is essential for mitochondrial function, as well as longer chain fatty acids required for the repair of mitochondrial membrane phospholipids.

Dr. Stuart Smith was educated in England, receiving B.Sc and Ph.D degrees in Biochemistry at the University of Birmingham.  He performed postdoctoral studies in Jerusalem before coming to CHORI in 1967.  He was awarded an Established Investigatorship from the American Heart Association in 1973 and in 1980 was awarded a D.Sc degree from the University of Birmingham in recognition for his work in lipid metabolism. He was the recipient of a Career Scientific Achievement Award from CHO in 2000.



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