• campus:  a to z index
• map
• directory
• calendar

Search:

John Phillips

Research Associate Professor of Pathology and of Hematology

B.S. University of New Hampshire

Ph.D. Dartmouth College

Research

References

john.phillips@hsc.utah.edu

 

Research

Heme is essential for life; virtually all organisms are either able to make heme or they have developed a mechanism to parasitize it from other organisms.   Heme is a critical component in proteins with diverse functions such as the transport of oxygen (hemoglobin, myoglobin), the production of ATP (cytochromes of the electron transport chain), detoxification reactions in the liver (the cytochrome P450 family of enzymes).   In our laboratory we study the synthesis of heme, the pathway consists of eight enzymes that convert glycine and succinyl-CoA into a tetrapyrrole that eventually accepts an iron atom forming heme.  

In humans defects in heme synthesis are termed the porphyrias.   The most common of the porphyrias is Porphyria Cutanea Tarda (PCT). We have focused on this fifth step in the heme biosynthetic, performed by the enzyme Uroporphyrinoen Decarboxylase (URO-D), using a combination of biochemistry, mouse genetics and structural studies.   There are both environmental and genetic components to the development of PCT.   We have constructed a mouse model of the familial form of PCT.   We have also developed an environmental model of PCT using environmental toxins such as polychlorinated biphenyls (PCB's).   Using these mouse models of PCT we are identifying the changes that occur in the liver that lead to the production of an inhibitor of URO-D.

In collaboration with the structural biochemists here at the University we have made crystallized three of the eight enzymes in the heme biosynthetic pathway.   We are working to identify the mechanisms for these evolutionarily conserved enzymes to explain the molecular details of tetrapyrrole synthesis.   The accompanying figure shows the active site of URO-D with its product, coproporphyrinogen III, bound.   Using this molecular model we have identified how the structure of the substrate adopts a domed configuration to fit appropriately into the active site allowing the tetrapyrrole to act as its own cofactor in this unique decarboxylase.

References