尿卟啉原Ⅲ脱羧酶
卟啉
错义突变
突变
生物
遗传学
酶
急性间歇性卟啉症
基因
生物化学
内分泌学
血红素
作者
M. S. Farrag,Ivan Mikula,Eva Richard,Vladimı́r Saudek,Hubert de Verneuil,Pavel Martásek
出处
期刊:Folia Biologica
[First Faculty of Medicine, Charles University]
日期:2015-01-01
卷期号:61 (6): 219-226
被引量:7
标识
DOI:10.14712/fb2015061060219
摘要
Porphyrias are metabolic disorders resulting from mutations in haem biosynthetic pathway genes. Hepatoerythropoietic porphyria (HEP) is a rare type of porphyria caused by the deficiency of the fifth enzyme (uroporphyrinogen decarboxylase, UROD) in this pathway. The defect in the enzymatic activity is due to biallelic mutations in the UROD gene. Currently, 109 UROD mutations are known. The human disease has an early onset, manifesting in infancy or early childhood with red urine, skin photosensitivity in sun-exposed areas, and hypertrichosis. Similar defects and links to photosensitivity and hepatopathy exist in several animal models, including zebrafish and mice. In the present study, we report a new mutation in the UROD gene in Egyptian patients with HEP. We show that the homozygous c.T163A missense mutation leads to a substitution of a conserved phenylalanine (amino acid 55) for isoleucine in the enzyme active site, causing a dramatic decrease in the enzyme activity (19 % of activity of wild-type enzyme). Inspection of the UROD crystal structure shows that Phe-55 contacts the substrate and is located in the loop that connects helices 2 and 3. Phe-55 is strictly conserved in both prokaryotic and eukaryotic UROD. The F55I substitution likely interferes with the enzyme-substrate interaction.
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