Andrew M. Gulick, Ph.D.
Hauptman-Woodward Institute - Senior Research Scientist
Assistant Professor of Structural Biology, SUNY-Buffalo

EDUCATION
B.S., Biochemistry, Brown University, 1989
Ph.D., Experimental Oncology and Biochemistry
University of Wisconsin-Madison, 1994

Research Interests

Crystallographic studies of non-ribosomal peptide synthetases. Structures of multi-domain enzymes and analysis of enzyme reaction mechanisms. Bacterial Natural Products.

Crystallographic and Functional Studies of Bacterial Enzymes

Proteins can be thought of as molecular machines that carry out a wide variety of functions in the body. Many of these machines speed up chemical reactions, for example breaking down the food we eat or building the important biological molecules that we need. Proteins that perform, or catalyze, these chemical reactions are known as enzymes. Our lab is using multiple biochemical techniques to study a number of different enzymes that play important biological roles. In particular, we are using X-ray crystallography to determine the molecular structure of these enzymes. Additionally, we are using protein engineering to manipulate the protein molecules and explore the impact of these changes on the chemical reactions they perform. These studies allow us to understand the fascinating biochemistry of a living cell.

The studies in our lab focus on important bacterial proteins. Bacteria use novel chemistry to produce many molecules that impact the interactions of bacteria with other bacteria and with other organisms. Some bacteria produce antibiotics and other pharmaceutically active compounds. Other bacteria produce virulence factors that enable them to establish an infection. Blocking the production of a virulence factor may lead to the development of a new antibiotic.

Crystallographic Studies of Non-Ribosomal Peptide Synthetases

We are studying the Non-Ribosomal Peptide Synthetases (NRPSs), a family of enzymes that produce important peptides, molecules that are made by joining together 2-20 building blocks called amino acids. The NRPS peptides sometimes have antibiotic or anticancer activities. Additionally, some NRPS products are used by bacteria to scavenge iron, an essential nutrient for the bacteria.

The NRPS proteins are particularly interesting in that, unlike most biosynthetic processes in which individual enzymes catalyze a single step of a long pathway, the NRPS enzymes are large, multi-domain enzymes that catalyze multiple reactions in an assembly-line fashion. The NRPSs are considered modular enzymes–for each amino acid of the final peptide, the NRPSs contain a complete module that includes all of the steps for the incorporation of a single amino acid. While the peptide is being produced, it remains chemically attached to the NRPS protein through a carrier domain. This carrier domain delivers the peptide intermediates to the other protein domains where the chemistry occurs. Adjacent to the NRPS carrier domain, each module contains an adenylation domain that loads the correct amino acid building block onto the carrier domain. Finally, a condensation domain forms a peptide bond between the building blocks on neighboring carrier domains.

Our experiments are designed to explore the choreography of this modular assembly line. In particular, we have identified a molecular motion within the adenylation domain that we believe is essential to deliver the amino acid substrates to the different domains. We have studied a family of related enzymes that use a similar structure to catalyze a similar chemical reaction. We have used crystallography to determine the structure in multiple conformational states and have used biochemical studies to understand how these two different structures are used to catalyze the chemical reaction.

Studies of Proteins from Pseudomonas aeruginosa.