Annotated Bibliography

Barbaro, M., Kotajarvi, M., Harper, P. & Floderus, Y. Partial protoporphyrinogen oxidase (PPOX) gene deletions, due to different Alu-mediated mechanisms, identified by MLPA analysis in patients with variegate porphyria. Orphanet J Rare Dis 8, 13 (2013). DOI: 10.1186/1750-1172-8-13

  • This paper shows how MLPA (Multiplex Ligation-dependent Probe Amplification) can be used for comprehensive genetic diagnostics in patients with variegate porphyria (VP). Due to similarities between the porphyrias, more accurate testing is important to develop.

Bhagavan, N. V. & Ha, C.-E. in Essentials of Medical Biochemistry Chapter 27 “Iron and Heme Metabolism” 369–382 (Academic Press, 2011). at <http://www.sciencedirect.com/science/article/pii/B9780120954612000278>. ISBN: 978-0-12-095461-2

  • This chapter provides an overview of iron and heme metabolism, how they are interconnected, and the diseases that arise when these processes malfunction, one of which is variegate porphyria.

Bishop, A. C. & Chen, V. L. Brought to life: targeted activation of enzyme function with small molecules. J Chem Biol 2, 1–9 (2009). DOI: 10.1007/s12154-008-0012-4

  • This review summarizes the ways in which small molecules have been used to activate enzymes as opposed to inhibiting them.

Chen, B. C. & Griffey, R. T. A Case Report of Porphyria Variegata Management in the Emergency Department. The Journal of Emergency Medicine 43, e235–e238 (2012). DOI: 10.1016/j.jemermed.2010.02.028

  • Provides information about a case of variegate porphyria and how the patient was treated in the emergency room. Gives insight into how the disease is currently handled in the clinic.

Davids, L. M., Corrigall, A. V. & Meissner, P. N. Mitochondrial targeting of human protoporphyrinogen oxidase. Cell Biol. Int. 30, 416–426 (2006). DOI: 10.1016/j.cellbi.2006.02.001

  • This paper proposes a mechanism by which protophorphyrinogen oxidase (PPOX) targets the mitochondrial membrane, its typical location in the cell. In addition, they examine three VP-causing mutations and determine if they interfere with this process.

Dooley, K. A. et al. montalcino, A zebrafish model for variegate porphyria. Experimental Hematology 36, 1132–1142 (2008). DOI: 10.1016/j.exphem.2008.04.008

  • Establishes a zebrafish model of variegate porphyria, providing further insight into the disease and a practical means to study it more and potentially develop new forms of treatment.

Du Plessis, N. et al. Functional analysis of the 5’ regulatory region of the 5-aminolevulinate synthase (ALAS1) gene in response to estrogen. Cell. Mol. Biol. (Noisy-le-grand) 55, 20–30 (2009). DOI: 10.1170/T848

  • Examines the rate-determining step in heme biosynthesis, which is catalyzed by 5-aminolevulinate synthase. Sequenced several patients with variegate porphyria and found mutations in the 5’ regulatory region of 5-aminolevulinate synthase DNA that either increased or decreased the rate of transcription.

Felitsyn, N., McLeod, C., Shroads, A. L., Stacpoole, P. W. & Notterpek, L. The heme precursor delta-aminolevulinate blocks peripheral myelin formation. J Neurochem 106, 2068–2079 (2008). DOI: 10.1111/j.1471-4159.2008.05552.x

  • This article studies the impact of aminolevulinate on the ability of neurons to produce myelin, and the oxidative damage of proteins and lipids that can be induced by this molecule as well.

Ferrer, M. D. et al. Antioxidants restore protoporphyrinogen oxidase in variegate porphyria patients. Eur. J. Clin. Invest. 43, 668-678 (2013). DOI: 10.1111/eci.12091

  • Demonstrates that patients with variegate porphyria are in a state of oxidative stress and that treatment with vitamins E and C can restore PPOX, superoxide dismutase, and glutathione peroxidase activity.

Ferrer, M. D. et al. Enzyme antioxidant defences and oxidative damage in red blood cells of variegate porphyria patients. Redox Report 14, 69–74 (2009). DOI: 10.1179/135100009X392502

  • Provides evidence for the state of oxidative stress in the erythrocytes of individuals with variegate porphyria. Discusses the specific activity of key enzymes such as catalase and superoxide dismutase involved in redox balance.

Ferrer, M. D. et al. Impaired lymphocyte mitochondrial antioxidant defences in variegate porphyria are accompanied by more inducible reactive oxygen species production and DNA damage. British Journal of Haematology 149, 759–767 (2010). DOI: 10.1111/j.1365-2141.2010.08149.x

  • Reveals that lymphocytes from women with variegate porphyria (VP) exhibit impaired expression of mitochondrial antioxidant defenses. Shows that patients with VP are under oxidative stress and that treating this disease should take this biological state into account.

Ferrer, M. D. et al. Variegate porphyria induces plasma and neutrophil oxidative stress: effects of dietary supplementation with vitamins E and C. Br. J. Nutr. 103, 69–76 (2010). DOI: 10.1017/S0007114509991413

  • Talks about the state of oxidative stress in women within blood plasma and how treatment with vitamins E and C reduced oxidative damage and enhanced the activities of enzymes involved in redox balance in the body.

Handschin, C. et al. Nutritional Regulation of Hepatic Heme Biosynthesis and Porphyria through PGC-1α. Cell 122, 505–515 (2005). DOI: 10.1016/j.cell.2005.06.040

  • Relates the induction of porphyric attacks by fasting to glucagon activation of ALAS-1 transcription. Explains how glucose and insulin are effective in treating attack as they reduce ALAS-1 transcription and hence lowers the rate of heme biosynthesis.

Hift, R. J., Peters, T. J. & Meissner, P. N. A review of the clinical presentation, natural history and inheritance of variegate porphyria: its implausibility as the source of the ‘Royal Malady’. J Clin Pathol 65, 200–205 (2012). DOI: 10.1136/jclinpath-2011-200276

  • Provides an argument for why King George III did not likely suffer from variegate porphyria. Also provides useful statistics on the prevalence of the disease in different areas of the world.

Hift, R. J., Todd, G., Meissner, P. N. & Kirsch, R. E. Administration of oral activated charcoal in variegate porphyria results in a paradoxical clinical and biochemical deterioration. British Journal of Dermatology 149, 1266–1269 (2003). DOI: 10.1111/j.1365-2133.2003.05548.x

  • Indicates that the hypothesis of treating variegate porphyria with sorbents, which would theoretically bind the heme metabolites and flush them out of the body, is faulty as administration of charcoal worsened the condition.

Koch, M. et al. Crystal structure of protoporphyrinogen IX oxidase: a key enzyme in haem and chlorophyll biosynthesis. EMBO J 23, 1720–1728 (2004). DOI: 10.1038/sj.emboj.7600189

  • Provides a crystal structure of protophorphyrinogen IX oxidase (PPO), the enzyme mutated in variegate porphyria, with a resolution of 2.9 angstroms. Data reveals PPO complexes with ferrochelatase, the enzyme that inserts the iron into protporphoryin IX to make heme, to form a channel through which the pathway intermediates travel.

Meyer, U., Schuurmans, M. & Lindberg, R. Acute Porphyrias: Pathogenesis of Neurological Manifestations. Seminars in Liver Disease 18, 43–52 (1998). DOI: 10.1055/s-2007-1007139

  • Provides three possible mechanisms for the pathogenesis of acute porphyria symptoms: aminolevulinate binding of GABA receptors, heme deficiency in neurons, and alterations to tyrptophan synthesis.

Mydlík, M. & Derzsiová, K. Vitamin B6 and Oxalic Acid in Clinical Nephrology. Journal of Renal Nutrition 20, S95–S102 (2010). DOI: 10.1053/j.jrn.2010.06.009

  • Studies the levels of vitamin B6, used to make pyridoxal-5-phosphate, and oxalic acid, a produce of amino acid metabolism, in patients contracted with various diseases. Shows that in variegate porphyria, vitamin B6 is deficient while oxalic acid is elevated.

Qin, X. et al. Structural insight into human variegate porphyria disease. FASEB J 25, 653–664 (2011). DOI: 10.1096/fj.10-170811

  • Studies the crystal structure of human protoporphyrinogen IX oxidase with a resolution of 1.9 angstroms; used to reveal details of FAD binding. Also examined the crystal structures of several VP-causing mutants and discussed how the mutations impact the enzyme’s activity.

Rhee, H.-W. et al. Proteomic Mapping of Mitochondria in Living Cells via Spatially Restricted Enzymatic Tagging. Science 339, 1328–1331 (2013). DOI: 10.1126/science.1230593

  • Uses proteomics to analyze map the location of enzymes in mitochondria of living cells. Found that PPOX actually faces the mitochondrial matrix as opposed to the intermembrane space.

Sassa, S. Modern diagnosis and management of the porphyrias. British Journal of Haematology 135, 281–292 (2006). DOI: 10.1111/j.1365-2141.2006.06289.x

  • Provides an overview of all the porphyrias, including their identification and treatment in the clinic. Gives details of how heme metabolites are toxic to the body and elicit the symptoms characteristic of this group of diseases.

Siegesmund, M., van Tuyll van Serooskerken, A.-M., Poblete-Gutiérrez, P. & Frank, J. The acute hepatic porphyrias: Current status and future challenges. Best Practice & Research Clinical Gastroenterology 24, 593–605 (2010). DOI: 10.1016/j.bpg.2010.08.010

  • Details treatment routes currently available for porphyrias and challenges for developing new options for handling these conditions.

Singal, A. K. & Anderson, K. E. in GeneReviews(®) (Pagon, R. A. et al.) (University of Washington, Seattle, 1993). at <http://www.ncbi.nlm.nih.gov/books/NBK121283/>. PMID: 23409300

  • Gives information on the history of variegate porphyria, information about its metabolic context, and current treatments available.

Tokola, O., Mustajoki, P. & Himberg, J. J. Haem arginate improves hepatic oxidative metabolism in variegate porphyria. Br J Clin Pharmacol 26, 753–757 (1988). DOI: 10.1111/j.1365-2125.1988.tb05315.x

  • Demonstrates that treatment with haem arginate in the clinic helps alleviate acute attacks of variegate porphyria by restoring hepatic oxidative metabolism.

Wang, B. et al. Quantitative Structural Insight into Human Variegate Porphyria Disease. J. Biol. Chem. 288, 11731–11740 (2013). DOI: 10.1074/jbc.M113.459768

  • Studies the crystal structure of human protophoryinogen oxidase with a resolution of 2.8 angstroms. They applied site-directed mutagenesis to study the alterations on the conformation of the enzyme and the resulting impact on catalysis.

Williams, D. M., Wang, D. & Cole, P. A. Chemical Rescue of a Mutant Protein-tyrosine Kinase. J. Biol. Chem. 275, 38127–38130 (2000). DOI: 10.1074/jbc.C000606200

  • Demonstrates the capability of small molecules, namely imidazole, to activate mutant enzymes and restore catalytic activity,

Wolff, F., Gulbis, B. & Cotton, F. Spectrophotometric quantification of total urinary porphyrins as a screening test for porphyrias: Threshold value revisited. Clinical Biochemistry 46, 1825–1829 (2013). DOI: 10.1016/j.clinbiochem.2013.08.021

  • Provides a method for more accurately screening heme metabolites in urine as a means of diagnosing porphyrias.

Zachariae, H. & Cramers, M. Porphyria variegata treated with cyproterone acetate and ethinyl estradiol. Dermatologica 166, 272–274 (1983). DOI: 10.1159/000249885

  • Presents a case study in which a woman with variegate porphyria was treated with an oral contraceptive to alleviate menstrual cramps. The drug also ended up alleviating her symptoms of variegate porphyria.