Daniel Dowling Email & Phone Number

Boston, Massachusetts, United States

100 Morrissey Blvd, Boston Ma 02125

Cambirdge, Ma

While in the lab of Professor Catherine Drennan, my research has focused on two main projects involving natural product biosynthesis. I have gained excellent training in anaerobic techniques that are necessary when working with enzymes containing oxygen-sensitive cofactors, such as iron-sulfur clusters. My first area of research involves the formation of azoline moieties within nonribosomal peptide synthetases (NRPSs). My work has led to the first crystal structure of a cyclization domain of an NRPS, which provides a huge step forward in being able to biochemically characterize this enzyme family.The second area of focus is a collaboration with the lab of Professor Vahe Bandarian at the University of Arizona. I am studying two enzymes in the bacterial biosynthetic pathway of the modified tRNA base queuosine. The first is a radical S-adenosylmethionine (rSAM) enzyme responsible for a complex free radical transformation, and the second involves the use of cofactors cobalamin and two iron-sulfur clusters to catalyze an epoxide ring opening and subsequent dehydration. These structures have provided considerable insight into the rSAM and cobalamin-dependent enzyme families.

Philadelphia, Pa

My graduate studies focused on the structural studies of two related metallohydrolases, human HDAC8 and a malarial arginase. Structures of inhibited HDAC8 were used to develop inhibition experiments and enzymology assays of generated site-specific variants to detail residues critical for binding substrate and inhibitors. These results characterized the importance of an aspartate amino acid within an outer loop of the protein that engages in a critical substrate binding interaction. Additionally, the active site metal ion was probed by solving crystal structures with different divalent metal ions bound, and these structures confirmed that different metal ions, such as Co(II) and Fe(II), bind similarly to Zn(II) within the active site of HDAC8.Arginase is responsible for the hydrolysis of the amino acid L-arginine to L-ornithine and urea. Interestingly, arginase activity lowers the arginine substrate pool for nitric oxide synthase in the immune response; therefore, parasitic arginase enzymes may be involved in aiding in evasion of the host immune response. Studies of the malarial arginase, from Plasmodium falciparum, revealed a key difference between the enzyme active site of human and malarial arginase enzymes. This modification is predicted to be the primary reason for a significant loss in binding affinities of known human arginase inhibitors to the malarial enzyme, supporting the possibility of generating parasite-specific compounds.

Doctor Of Philosophy (Ph.D.), Structural Chemical Biology

Bachelor Of Arts (B.A.), Chemistry And Music