3nks
From Proteopedia
Structure of human protoporphyrinogen IX oxidase
Structural highlights
Disease[PPOX_HUMAN] Porphyria variegata. Defects in PPOX are the cause of variegate porphyria (VP) [MIM:176200]. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. PV is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease.[1] [2] [3] Function[PPOX_HUMAN] Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX. Publication Abstract from PubMedHuman protoporphyrinogen IX oxidase (hPPO), a mitochondrial inner membrane protein, converts protoporphyrinogen IX to protoporphyrin IX in the heme biosynthetic pathway. Mutations in the hPPO gene cause the inherited human disease variegate porphyria (VP). In this study, we report the crystal structure of hPPO in complex with the coenzyme flavin adenine dinucleotide (FAD) and the inhibitor acifluorfen at a resolution of 1.9 A. The structural and biochemical analyses revealed the molecular details of FAD and acifluorfen binding to hPPO as well as the interactions of the substrate with hPPO. Structural analysis and gel chromatography indicated that hPPO is a monomer rather than a homodimer in vitro. The founder-effect mutation R59W in VP patients is most likely caused by a severe electrostatic hindrance in the hydrophilic binding pocket involving the bulky, hydrophobic indolyl ring of the tryptophan. Forty-seven VP-causing mutations were purified by chromatography and kinetically characterized in vitro. The effect of each mutation was demonstrated in the high-resolution crystal structure. Structural insight into human variegate porphyria disease.,Qin X, Tan Y, Wang L, Wang Z, Wang B, Wen X, Yang G, Xi Z, Shen Y FASEB J. 2011 Feb;25(2):653-64. Epub 2010 Nov 3. PMID:21048046[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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