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Dr. Andrew Gulick has recently determined the structure of the protein Acetyl-CoA Synthetase (ACS) from Salmonella. ACS is an enzyme or biological catalyst that synthesizes acetyl CoA, an important cellular component. This enzyme is being studied for two reasons. First, the structure of ACS provides insight into a family of bacterial and fungal enzymes that are used to make pharmaceutically active molecules. Second, the activity of ACS is regulated by a chemical modification that is also seen in several human proteins, and this modification frequently goes awry in human cancers. Therefore, understanding how ACS activity is controlled may provide a model for this type of regulation in cancer cells.
Certain bacteria and fungi use a family of large proteins known as Non-Ribosomal Peptide Synthetases (NRPSs) to synthesize small molecules that have antibiotic and anticancer activities. These NRPSs are being studied in order to identify how their structures dictate the nature of the final synthesized product and to determine how they might be altered to create new drugs. NRPSs are modular enzymes that contain several distinct portions or domains that perform individual steps in the biosynthetic process (see figure below). By mixing and matching the right domains, it may be possible to realize a long-term goal of creating new multi-domain enzymes that would make novel drugs.
The large size of the NRPS proteins makes them a difficult target for crystallographic studies. Therefore, in addition to studying complete multi-domain enzymes, smaller proteins that are structurally and functionally very similar to the NRPSs are being examined. The ACS structure provides a great deal of insight into the function of the specific NRPS domain that is responsible for binding small chemical building blocks that are used to synthesize antibiotic molecules. This structure suggests that one region of the ACS molecule, shown in light blue in the top figure, undergoes a dramatic rotation that enables this single enzyme molecule to catalyze two separate reactions. This hypothesis is now being tested and applied to the NRPSs in order to engineer the synthesis of new drugs.