We are investigating the structural basis of some biological processes by X-ray crystallographic techniques. In the area of chemical carcinogenesis and mutagenesis we are studying the structures of some carcinogenic polycyclic aromatic hydrocarbons, particularly those with bay-region methyl groups, their metabolites and their adducts with portions of DNA. Our major interest is in the conformational distortion that occurs to DNA when a bulky, hydrophobic group, such as a polycyclic aromatic group, forms an adduct with it. We plan to probe which structural features enable the lesion to escape enzymatically-mediated DNA repair. The long term goal is to determine geometrical and electronic factors in carcinogenic molecules that determine their biological activity and to determine what feature of the adduct structure can be correlated with lack of enzymatic repair and with the continuing carcinogenic process. Crystallographic studies of the structures of compounds that modify the carcinogenic process, either enhancing or inhibiting it, are also planned. The studies of enzyme mechanisms involve analyses of the active site structure and attempts to determine the mode of action of the enzyme. Of particular emphasis will be continuing studies of enzymes that catalyze isomerizations, including D-xylose isomerase, for which the mechanism of action proposed by us is controversial and ethanolamine ammonia-lyase, a B 12-utilizing enzyme. We win also continue our studies of the mechanism of action of the B 12 coenzyme itself. Additional enzyme studies include structure analyses of enzymes that catalyze condensations, such as porphobilinogen synthase which is involved in the biochemical construction of pyrroles for corrin or porphyrin manufacture and enzymes that catalyze hydrolysis such as ubiquitin hydrolase, a cysteine protease that removes ubiquitin from ubiquitin-protein conjugates.
| Glusker, Jenny P; Carrell, H L; Kovalevsky, Andrey Y et al. (2010) Using neutron protein crystallography to understand enzyme mechanisms. Acta Crystallogr D Biol Crystallogr 66:1257-61 |
| Kovalevsky, Andrey Y; Hanson, Leif; Fisher, S Zoe et al. (2010) Metal ion roles and the movement of hydrogen during reaction catalyzed by D-xylose isomerase: a joint x-ray and neutron diffraction study. Structure 18:688-99 |
| Kovalevsky, Andrey Y; Katz, Amy K; Carrell, H L et al. (2008) Hydrogen location in stages of an enzyme-catalyzed reaction: time-of-flight neutron structure of D-xylose isomerase with bound D-xylulose. Biochemistry 47:7595-7 |
| Bae, Suyeal; Mah, Heduck; Chaturvedi, Surendrakumar et al. (2007) Synthetic, crystallographic, computational, and biological studies of 1,4-difluorobenzo[c]phenanthrene and its metabolites. J Org Chem 72:7625-33 |
