Harderoporphyria: a variant hereditary coproporphyria.

Nordmann, Y; Grandchamp, Bernard; H, de Verneuil; Phung, L. N.; Cartigny, Bernard; Fontaine, Guillaume

doi:10.1172/jci111039

Cited by 86 publications

(40 citation statements)

References 20 publications

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“…Interestingly, R447C mutation also results in diminished activity. Finally, K404E causes harderoporphyria, a disease with symptoms unrelated to HCP (34,(70)(71)(72)(73). This mutation affects the region that separates helices ␣9 and ␣10.…”

Section: Cpo Structure Lacks a Transition Metal Centermentioning

confidence: 99%

Structural basis of hereditary coproporphyria

Lee

Flachsová

Bodnárová

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary coproporphyria is an autosomal dominant disorder resulting from the half-normal activity of coproporphyrinogen oxidase (CPO), a mitochondrial enzyme catalyzing the antepenultimate step in heme biosynthesis. The mechanism by which CPO catalyzes oxidative decarboxylation, in an extraordinary metaland cofactor-independent manner, is poorly understood. Here, we report the crystal structure of human CPO at 1.58-Å resolution. The structure reveals a previously uncharacterized tertiary topology comprising an unusually flat seven-stranded ␤-sheet sandwiched by ␣-helices. In the biologically active dimer (KD ‫؍‬ 5 ؋ 10 ؊7 M), one monomer rotates relative to the second by Ϸ40°to create an intersubunit interface in close proximity to two independent enzymatic sites. The unexpected finding of citrate at the active site allows us to assign Ser-244, His-258, Asn-260, Arg-262, Asp-282, and Arg-332 as residues mediating substrate recognition and decarboxylation. We favor a mechanism in which oxygen serves as the immediate electron acceptor, and a substrate radical or a carbanion with substantial radical character participates in catalysis. Although several mutations in the CPO gene have been described, the molecular basis for how these alterations diminish enzyme activity is unknown. We show that deletion of residues (392-418) encoded by exon six disrupts dimerization. Conversely, harderoporphyria-causing K404E mutation precludes a type I ␤-turn from retaining the substrate for the second decarboxylation cycle. Together, these findings resolve several questions regarding CPO catalysis and provide insights into hereditary coproporphyria.coproporphyrinogen oxidase ͉ oxidative decarboxylation ͉ mitochondria ͉ x-ray crystallography T he terminal three steps of heme biosynthesis occur within the mitochondria (1, 2). First, coproporphyrinogen III is converted to protoporphyrinogen IX in the intermembrane space (3, 4) by coproporphyrinogen oxidase (CPO) (5, 6). Thus, CPO contains an unusually long (110 residues) N-terminal targeting sequence, required for its import into the mitochondria (7,8). The substrate for CPO is generated in the cytosol (9) by uroporphyrinogen decarboxylase, and the precise mechanism by which it enters the mitochondria remains to be elucidated. Second, protoporphyrinogen oxidase mediates the six electron oxidation of protoporphyrinogen to protoporphyrin IX. This enzyme is localized to the cytoplasmic side of the inner mitochondrial membrane. Third, ferrochelatase inserts the ferrous iron to generate heme within the matrix of the mitochondria. Hence, the heme biosynthetic pathway is not only partitioned between mitochondria and cytosol, but the last three enzymes are compartmentalized within the mitochondria.Partial deficiency of CPO leads to hereditary coproporphyria (HCP), an acute hepatic porphyria inherited in an autosomal dominant fashion (10-12). The disease is characterized by abdominal pain, neuropsychiatric symptoms, and͞or cutaneous photosensitivity (13). If diagnosed early, HCP can be treat...

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Section: Cpo Structure Lacks a Transition Metal Centermentioning

confidence: 99%

Structural basis of hereditary coproporphyria

Lee

Flachsová

Bodnárová

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…It is clinically characterized by neurologic dysfunction attacks and occasional photosensitivity. 1 HCP is rare before puberty, 2 and all reported early-onset cases have been in the homozygous [3][4][5][6][7][8] or the compound heterozygous state. 9 Harderoporphyria, a rare erythropoietic variant form of HCP, is characterized by neonatal hyperbilirubinemia and hemolytic anemia, hepatosplenomegaly, and sometimes photosensitivity.…”

Section: Introductionmentioning

confidence: 99%

“…9 Harderoporphyria, a rare erythropoietic variant form of HCP, is characterized by neonatal hyperbilirubinemia and hemolytic anemia, hepatosplenomegaly, and sometimes photosensitivity. [6][7][8][9] To date, 3 families with harderoporphyria have been reported. Molecular analysis indicates that a CPO gene abnormality, K404E, was unique for the disease.…”

Section: Introductionmentioning

confidence: 99%

Neonatal-onset hereditary coproporphyria with male pseudohermaphrodism

Takeuchi

Kondo

Daimon

et al. 2001

Blood

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The appearance of hereditary coproporphyria (HCP) before puberty is very rare, and all reported cases of early-onset HCP have been in the homozygous or the compound heterozygous state. Some have been identified as harderoporphyria, which is a rare erythropoietic variant form of HCP. These conditions can be differentiated by molecular analysis because the gene abnormality responsible for harderoporphyria seems to be unique (K404E IntroductionHereditary coproporphyria (HCP) is a hereditary autosomaldominant disease of heme biosynthesis resulting from a partial deficiency of coproporphyrinogen oxidase (CPO). It is clinically characterized by neurologic dysfunction attacks and occasional photosensitivity. 1 HCP is rare before puberty, 2 and all reported early-onset cases have been in the homozygous 3-8 or the compound heterozygous state. 9 Harderoporphyria, a rare erythropoietic variant form of HCP, is characterized by neonatal hyperbilirubinemia and hemolytic anemia, hepatosplenomegaly, and sometimes photosensitivity. 6-9 To date, 3 families with harderoporphyria have been reported. Molecular analysis indicates that a CPO gene abnormality, K404E, was unique for the disease. 9 Therefore, HCP can be differentially diagnosed from harderoporphyria by both clinical and laboratory examinations and molecular analysis. Here, we describe a first case of neonatal-onset HCP in the heterozygous state with male pseudohermaphrodism. Study design Patient historyThe patient was born at term to healthy, nonconsanguineous Japanese parents with no family history of porphyria. Perinatal history was normal. The amniotic fluid and placenta were yellow, as occurred in a patient with congenital erythropoietic porphyria (CEP). 10 Shortly after birth, the infant was admitted to our hospital for tachypnea and severe jaundice. He displayed icteric skin, petechiae, hypotonia, lethargy, and marked hepatosplenomegaly. Laboratory data showed hypoglycemia (22 mg/dL blood sugar), thrombocytopenia (93 000/L platelets), and anemia (9.4 g/dL erythrocytes) with marked erythroblastosis (26 900/L erythroblasts), similar to what was seen in a patient with CEP. 11 Erythrocyte morphology showed some dacryocytes, leptocytes, and echinocytes. Based on these findings, his anemia was concluded to be hemolytic. Total serum bilirubin level was 14.16 mg/dL (indirect, 6.64 mg/dL). Respiratory distress and hypotonia were improved after intravenous glucose loading for hypoglycemia. Phototherapy was performed for hyperbilirubinemia to avert kernicterus on days 1 and 2. Soon afterward, the patient showed partial edema with vesicles and bulla. After his incubator was wrapped with UV cut-off film, no new skin lesions appeared. The severe hemolytic state, erythroblastosis, and morphologic abnormalities of erythrocyte disappeared, and partial regression of hepatosplenomegaly was observed in a few weeks. In the first week after birth, dark-brown urine was observed. Porphyrins were detected using reverse-phase high-performance liquid-chromatography. 12 He also had ambiguous...

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“…Expression of the cDNA coding for the putative mature human coproporphyrinogen oxidase in Escherichia cofl reulndin a 17-fold increase in coproporphyrinogen activity over endogenous activity. about 10%1o ofnormal, but the molecular basis for the different clinical and biochemical characteristics of these two forms is unknown (15,16).…”

mentioning

confidence: 99%

“…After transformation of E. coli, single colonies were isolated and inserts were sequenced. The assay of CPX in lysates of bacterial cultures was performed as previously described (16).…”

mentioning

confidence: 99%

Molecular cloning, sequencing, and functional expression of a cDNA encoding human coproporphyrinogen oxidase.

Martásek

Camadro

Delfau‐Larue

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Coproporphyrinogen oxidase (EC 1.3.3 To facilitate the characterization of the structure of CPX, to determine the molecular defects in hereditary coproporphyria, and to study the role of CPX in the regulation of the heme biosynthetic pathway, molecular cloning ofa cDNA for human CPX was an important step.To achieve this goal, murine CPX was purified; the aminoterminus of the intact protein and an internal peptide fragment were sequenced; and degenerate oligonucleotides were designed to amplify a specific portion ofthe murine cDNA by using reverse transcription (RT) and the polymerase chain reaction (PCR). By this approach a murine cDNA probe was obtained that was used to isolate a human cDNA. In this communication the primary sequence of human CPXi and

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Harderoporphyria: a variant hereditary coproporphyria.

Cited by 86 publications

References 20 publications

Structural basis of hereditary coproporphyria

Structural basis of hereditary coproporphyria

Neonatal-onset hereditary coproporphyria with male pseudohermaphrodism

Molecular cloning, sequencing, and functional expression of a cDNA encoding human coproporphyrinogen oxidase.

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