Three aspects of chemical carcinogenesis will be investigated: the structural effect on DNA of alkylation by a bulky activated carcinogenic polycyclic aromatic hydrocarbon (PAH) and the reason that it escapes enzymatic repair, the roles played by various metal ions in biochemical reactions that control growth and other cellular processes that are affected by cancer, and the types of reactions (particularly isomerizations) that free radicals can undergo readily in a biological setting. Results from these proposed studies will increase our understanding on a molecular scale of a wide range of processes involved in cancer, and will help in the design of chemotherapeutic agents to combat it. Structural studies of PAH-DNA adducts and their interactions with repair enzymes will allow us to identify the specific type of DNA lesion that results in progression of the carcinogenic process. In addition to structural studies, model building will be coupled with energy calculations to study these DNA lesions. Some ab initio molecular orbital studies of reaction pathways in the metabolism of benzene and phenol will also be carried out. In proposed studies of metal ions, their coordination geometry and preferred ligands in biological systems and their effects on the ligands that they bind will be analyzed from structural data retrieved from the Cambridge Crystallographic Database and the Protein Databank. The energetic consequences of deviations from these preferred modes will be determined by ab initio molecular orbital calculations.
The aim i s to derive a series of rules on the different ways a given metal can behave in the environments found in biological systems. Conclusions will be tested in structural studies of enzymes (porphobilinogen synthase and ubiquitin hydrolase) and by studies of the binding of metal ions to D-xylose isomerase, an enzyme with two metal binding sites. Reactions of free radicals, causative agents in some forms of cancer, will be investigated by ab initio molecular orbital calculations to assess energy barriers to various reaction pathways. Initially, the B12-mediated reactions of the enzymes diol dehydrase and ethanolamine-ammonia lysase will be studied together with some structural work, but we will then proceed to other free-radical reactions such as those involving hydroxyl radicals and semiquinones that are relevant to cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA010925-52
Application #
6375557
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Poland, Alan P
Project Start
1976-04-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
52
Fiscal Year
2001
Total Cost
$646,436
Indirect Cost
Name
Institute for Cancer Research
Department
Type
DUNS #
872612445
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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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