2Q71

Uroporphyrinogen Decarboxylase G168R single mutant enzyme in complex with coproporphyrinogen-III

Summary for 2Q71

• Entry DOI: 10.2210/pdb2q71/pdb
• Related: 1RY3 2Q6Z
• Descriptor: Uroporphyrinogen decarboxylase, COPROPORPHYRINOGEN III (3 entities in total)
• Functional Keywords: uroporphyrinogen decarboxylase enzyme urod g168r coproporphyrinogen-iii product complex, lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P06132
• Total number of polymer chains: 1
• Total formula weight: 40523.53

Authors

Phillips, J.D.,Whitby, F.G.,Stadtmueller, B.M.,Edwards, C.Q.,Hill, C.P.,Kushner, J.P. (deposition date: 2007-06-05, release date: 2007-06-19, Last modification date: 2023-08-30)

Primary citation

Phillips, J.D.,Whitby, F.G.,Stadtmueller, B.M.,Edwards, C.Q.,Hill, C.P.,Kushner, J.P.
Two Novel Uropophyrinogen Decarboxylase (URO-D) Mutations Causing Hepatoerythropoietic Porphyria (HEP)
Transl.Res., 149:85-91, 2007

PubMed Abstract: Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria in humans. The disorder is caused by homozygosity or compound heterozygosity for mutations of the uroporphyrinogen decarboxylase (URO-D) gene. Subnormal URO-D activity results in accumulation of uroporphyrin in the liver, which ultimately mediates the photosensitivity that clinically characterizes HEP. Two previously undescribed URO-D mutations found in a 2-year-old Caucasian boy with HEP, a maternal nonsense mutation (Gln71Stop), and a paternal missense mutation (Gly168Arg) are reported here. Recombinant Gly168Arg URO-D retained 65% of wild-type URO-D activity and studies in Epstein-Barr Virus (EBV)-transformed lymphoblasts indicated that protein levels are reduced, suggesting that the mutant protein might be subjected to accelerated turnover. The crystal structure of Gly168Arg was determined both as the apo-enzyme and with the reaction product bound. These studies revealed little distortion of the active site, but a loop containing residues 167-172 was displaced, possibly indicating small changes in the catalytic geometry or in substrate binding or increased accessibility to a cellular proteolytic pathway. A second pregnancy occurred in this family, and in utero genotyping revealed a fetus heterozygous for the maternal nonsense mutation (URO-D genotype WT/Gln71Stop). A healthy infant was born with no clinical evidence of porphyria.

PubMed: 17240319
DOI: 10.1016/j.trsl.2006.08.006

Experimental method

X-RAY DIFFRACTION (1.9 Å)