This project examines enzyme structure and mechanism, in particular those involved in the biosynthesis of tetrapyrroles. This pathway is of fundamental importance to the understanding of the metabolism of hemes, chlorophylls, corrins and bile pigments. 5-Aminolevulinate synthase (ALAS) is the first enzyme involved in the biosynthesis of tetrapyrroles, and the rate-limiting enzyme of the heme biosynthetic pathway in the liver. ALAS is a mitochondrial matrix enzyme and has an absolute requirement for pyridoxal 5-phosphate (PLP) as a cofactor, to become an active enzyme. It is synthesized in the cytosol as a larger precursor protein and imported into the mitochondria, where it is processed to yield the mature ALAS protein. The studies are designed to elucidate the relationship of the structure and function of ALAS and the structure (i.e., the folding state) of ALAS precursor form to its import into the mitochondria. %%% The knowledge obtained from this study is both necessary and fundamental to achieve an understanding of the structure, mechanism, and regulation of the enzymes involved in heme biosynthesis.//
