Combining structural genomics and enzymology: completing the picture in metabolic pathways and enzyme active sites

An important goal of structural genomics is to complete the structural anal ysis of all the enzymes in metabolic pathways and to understand the structu ral similarities and differences. A preliminary glimpse of this type of ana lysis was achieved before structural genomics efforts with the glycolytic p athway and efforts are underway for many other pathways, including that of catecholamine metabolism. Structural enzymology necessitates a complete str uctural characterization, even for highly homologous proteins (greater than 80% sequence homology), as every active site has distinct structural featu res and it is these active site differences that distinguish one enzyme fro m another. Short cuts with homology modeling cannot be taken with our curre nt knowledge base. Each enzyme structure in a pathway needs to be determine d, including structures containing bound substrates, cofactors, products an d transition state analogs, in order to obtain a complete structural and fu nctional understanding of pathway-related enzymes.