Julian Limburg, Ph.D.
Assistant Professor
Chemistry

Structure and Function
of Bacterial Prolyl-4-Hydroxylase

Dr. Limburg's research is aimed at improving understanding of the mechanism of substrate oxidation by non-heme iron oxygenases and related systems. Particular focus will be on proline hydroxylation by prolyl-4-hydroxylases (P4Hs). P4Hs belong to the 2-oxoglutarate dependent non-heme iron oxygenase family of enzymes.

There are two forms of P4H in humans. The first are collagen-P4Hs that are essential for collagen biosynthesis. Over production of collagen is linked to fibrotic diseases and breast cancer. The second is the hypoxia-inducible factor-P4H (HIF-P4H) that plays a key role in the hypoxic response by oxidation of HIF-alpha.

The project is split into two parts. The first is focused on the isolation and characterization of bacterial forms of P4Hs to understand both the mechanism of proline hydroxylation at the molecular level and the origin of the substrate specificity. These bacterial forms of P4H will serve as models for P4Hs from humans. The second is to develop a protocol for the photolytic generation of the putative Fe(IV)=O species by generating this reactive intermediate in crystals of P4H. Related to the non-heme iron proteins is the antitumor drug iron bleomycin (Fe-BLM). Photolysis will be used to generate fe(IV)=O and Fe(V)=O species in the Fe-BLM system to test some of the mechanisms proposed for DNA cleavage by Fe-BLM.

Dr. Limburg graduated from the COBRE in 2007 when he was awarded an NIH R-01 grant "Mechanism and inhibition of collagen prolyl-4-hydroxylases."

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Copyright © 2008
Center for Biomedical Research Excellence in Protein Structure and Function
Department of Medicinal Chemistry, School of Pharmacy
The University of Kansas

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