Research Professor of Hematology and
Adjunct Professor of Bioengineering and Adjunct Associate Professor of Microbiology
B.S. University of New Hampshire
Ph.D. Dartmouth College
John Phillips' Lab Page
John Phillips' PubMed Literature Search
Molecular Biology Program
Porphyrin Biosynthesis, Heme Biosynthesis
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 any of the eight steps involved in heme synthesis are termed the porphyrias. The most common of the porphyrias is Porphyria Cutanea Tarda (PCT) that is due to reduced activity of Uroporphyrinogen Decarboxylase (URO-D). We have primarily focused on this fifth step in the heme biosynthetic, using a combination of biochemistry, mouse genetics and structural studies to understand the molecular basis of the disease. 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). In all cases, the phenotype of PCT (blisters on sun exposed areas of skin, excess porphyrins in urine and excess iron) is due to an inhibitor of the enzyme. 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.
We are one of the six sites that comprise the Porphyria Consortium, funded through the NIH Office of Rare Diseases. Clinical trials for several of the porphyric disorders are currently enrolling patients. We are studying novel therapies for some of the more common porphyric disorders. We are also funded as the Center for Iron and Heme Disorders (CIHD), by NIDDK. (http://cihd.cores.utah.edu/) These resources are used to examine the role of iron in several of the different porphyric diseases.
- Bergonia HA, Franklin MR, Kushner JP, Phillips JD. A method for determining δ-aminolevulinic acid synthase activity in homogenized cells and tissues. Clinical biochemistry. 2015; 48(12):788-95. NIHMS691539 PMID: 25959086, PMC4522353
- Gou EW, Balwani M, Bissell DM, Bloomer JR, Bonkovsky HL, Desnick RJ, Naik H, Phillips JD, Singal AK, Wang B, Keel S, Anderson KE. Pitfalls in Erythrocyte Protoporphyrin Measurement for Diagnosis and Monitoring of Protoporphyrias. Clinical chemistry. 2015; 61(12):1453-6. NIHMS754777 PMID: 26482161, PMC4744648
- Farrell CP, Overbey JR, Naik H, Nance D, McLaren GD, McLaren CE, Zhou L, Desnick RJ, Parker CJ, Phillips JD. The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda. PloS one. 2016; 11(9):e0163322. PMID: 27661980
- Byington CL, Keenan H, Phillips JD, Childs R, Wachs E, Berzins MA, Clark K, Torres MK, Abramson J, Lee V, Clark EB. A Matrix Mentoring Model That Effectively Supports Clinical and Translational Scientists and Increases Inclusion in Biomedical Research: Lessons From the University of Utah. Academic medicine :journal of the Association of American Medical Colleges. 2016; 91(4):497-502. NIHMS731901 PMID: 26650676, PMC4811725
- Kim HJ, Jeong MY, Parnell TJ, Babst M, Phillips JD, Winge DR. The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria. The Journal of biological chemistry. 2016; 291(33):17417-26. PMID: 27317660, PMC5016138
- Yuan X, Rietzschel N, Kwon H, Walter Nuno AB, Hanna DA, Phillips JD, Raven EL, Reddi AR, Hamza I. Regulation of intracellular heme trafficking revealed by subcellular reporters. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113(35):E5144-52. PMID: 27528661, PMC5024633
- Hanson WM, Chen Z, Jackson LK, Attaf M, Sewell AK, Heemstra JM, Phillips JD. Reversible Oligonucleotide Chain Blocking Enables Bead Capture and Amplification of T-Cell Receptor α and β Chain mRNAs. Journal of the American Chemical Society. 2016; 138(35):11073-6. PMID: 27478996 Cover Art
- Piel RB 3rd, Shiferaw MT, Vashisht AA, Marcero JR, Praissman JL, Phillips JD, Wohlschlegel JA, Medlock AE. A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A Partner and Regulator of Ferrochelatase. Biochemistry. 2016; 55(37):5204-17. PMID:27599036
- Farrell CP, Overbey JR, Naik H, Nance D, McLaren GD, McLaren CE, Zhou L, Desnick RJ, Parker CJ, Phillips JD. The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda. PLoS One. 2016 Sep 23;11(9):e0163322. PMID:27661980, PMCID: PMC5035022
- Barton JC, Chen WP, Emond MJ, Phatak PD, Subramaniam VN, Adams PC, Gurrin LC, Anderson GJ, Ramm GA, Powell LW, Allen KJ, Phillips JD, Parker CJ, McLaren GD, McLaren CE. GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes. Blood Cells Mol Dis. 2017 Mar;63:15-20. PMID:27936396
- Yaish HM, Farrell CP, Christensen RD, MacQueen BC, Jackson LK, Trochez-Enciso J, Kaplan J, Ward DM, Salah WK, Phillips JD. Two novel mutations in TMPRSS6 associated with iron-refractory iron deficiency anemia in a mother and child. Blood Cells Mol Dis. 2017 Apr 9;65:38-40. PMID: 28460265