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A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda.

ABSTRACT: Porphyria cutanea tarda (PCT), the most common form of porphyria in humans, is due to reduced activity of uroporphyrinogen decarboxylase (URO-D) in the liver. Previous studies have demonstrated that protein levels of URO-D do not change when catalytic activity is reduced, suggesting that an inhibitor of URO-D is generated in hepatocytes. Here, we describe the identification and characterization of an inhibitor of URO-D in liver cytosolic extracts from two murine models of PCT: wild-type mice treated with iron, delta-aminolevulinic acid, and polychlorinated biphenyls; and mice with one null allele of Uro-d and two null alleles of the hemochromatosis gene (Uro-d(+/-), Hfe(-/-)) that develop PCT with no treatments. In both models, we identified an inhibitor of recombinant human URO-D (rhURO-D). The inhibitor was characterized by solid-phase extraction, chromatography, UV-visible spectroscopy, and mass spectroscopy and proved to be uroporphomethene, a compound in which one bridge carbon in the uroporphyrinogen macrocycle is oxidized. We synthesized uroporphomethene by photooxidation of enzymatically generated uroporphyrinogen I or III. Both uroporphomethenes inhibited rhURO-D, but the III isomer porphomethene was a more potent inhibitor. Finally, we detected an inhibitor of rhURO-D in cytosolic extracts of liver biopsy samples of patients with PCT. These studies define the mechanism underlying clinical expression of the PCT phenotype, namely oxidation of uroporphyrinogen to uroporphomethene, a competitive inhibitor of URO-D. The oxidation reaction is iron-dependent.

SUBMITTER: Phillips JD

PROVIDER: S-EPMC1820519 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Modified uroporphyrinogen decarboxylase activity in a yeast mutant which mimics porphyria cutanea tarda.

Project description:The isolation of a new mutant Sm1 strain of yeast, Saccharomyces cerevisiae, is described: this strain was partially defective in haem formation and accumulated large amounts of Zn-porphyrins. Genetic analysis showed that the porphyrin accumulation was under the control of a single nuclear recessive mutation. Biochemical analysis showed that the main porphyrins accumulated in the cells were uroporphyrin and heptacarboxyporphyrin, mostly of the isomer-III type. The excreted porphyrins comprised mainly dehydroisocoproporphyrin. Analysis of uroporphyrinogen decarboxylase activity in the cell-free extract revealed a 70-80% decrease of activity in the mutant and showed that the relative rates of the different decarboxylation steps were modified with the mutant enzyme. A 2-3-fold increase in 5-aminolaevulinate synthase activity was measured in the mutant. The biochemical characteristics of the Sm1 mutant are very similar to those described for porphyria cutanea tarda.

| S-EPMC1153354 | biostudies-other

Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives.

Project description:Porphyria cutanea tarda (PCT) arises from decreased hepatic activity of uroporphyrinogen decarboxylase (UROD). Both genetic and environmental factors interplay in the precipitation of clinically overt PCT, but these factors may vary between different geographic areas. Decreased activity of UROD in erythrocytes was used to identify patients with UROD mutations among a group of 130 Spanish PCT patients. Nineteen patients (14.6%) were found to harbor a mutation in the UROD gene. Eight mutations were novel: M1I, 5del10, A22V, D79N, F84I, Q116X, T141I and Y182C. Five others were previously described: F46L, V134Q, R142Q, P150L and E218G. The new missense mutations and P150L were expressed in Escherichia coli. D79N and P150L resulted in proteins that were localized to inclusion bodies. The other mutations produced recombinant proteins that were purified and showed reduced activity (range: 2.3-73.2% of wild type). These single amino acid changes were predicted to produce complex structural alterations and/or reduced stability of the enzyme. Screening of relatives of the probands showed that 37.5% of mutation carriers demonstrated increased urinary porphyrins. This study emphasizes the role of UROD mutations as a strong risk factor for PCT even in areas where environmental factors (hepatitis C virus) have been shown to be highly associated with the disease.

| S-EPMC3804340 | biostudies-literature

Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles.

Project description:Familial porphyria cutanea tarda (f-PCT) results from the half-normal activity of uroporphyrinogen decarboxylase (URO-D). Heterozygotes for this autosomal dominant trait are predisposed to photosensitive cutaneous lesions by various ecogenic factors, including iron overload and alcohol abuse. The 3.6-kb URO-D gene was completely sequenced, and a long-range PCR method was developed to amplify the entire gene for mutation analysis. Four missense mutations (M165R, L195F, N304K, and R332H), a microinsertion (g10insA), a deletion (g645Delta1053), and a novel exonic splicing defect (E314E) were identified. Expression of the L195F, N304K, and R332H polypeptides revealed significant residual activity, whereas reverse transcription-PCR and sequencing demonstrated that the E314E lesion caused abnormal splicing and exon 9 skipping. Haplotyping indicated that three of the four families with the g10insA mutation were unrelated, indicating that these microinsertions resulted from independent mutational events. Screening of nine f-PCT probands revealed that 44% were heterozygous or homozygous for the common hemochromatosis mutations, which suggests that iron overload may predispose to clinical expression. However, there was no clear correlation between f-PCT disease severity and the URO-D and/or hemochromatosis genotypes. These studies doubled the number of known f-PCT mutations, demonstrated that marked genetic heterogeneity underlies f-PCT, and permitted presymptomatic molecular diagnosis and counseling in these families to enable family members to avoid disease-precipitating factors.

| S-EPMC1377546 | biostudies-other

Down-regulation of hepcidin in porphyria cutanea tarda.

Project description:Hepatic siderosis is common in patients with porphyria cutanea tarda (PCT). Mutations in the hereditary hemochromatosis (hh) gene (HFE) explain the siderosis in approximately 20% patients, suggesting that the remaining occurrences result from additional genetic and environmental factors. Two genes known to modify iron loading in hh are hepcidin (HAMP) and hemojuvelin (HJV). To determine if mutations in or expression of these genes influenced iron overload in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes with marked hepatic iron overload. We also compared hepatic expression of these and other iron-related genes in a group of patients with PCT and hh. Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE C282Y homozygotes. No exonic polymorphisms were identified. Sequencing of HAMP revealed exonic polymorphisms in 2 patients with PCT: heterozygosity for a G-->A transition (G71D substitution) in one and heterozygosity for an A-->G transition (K83R substitution) in the other. Hepatic HAMP expression in patients with PCT was significantly reduced, regardless of HFE genotype, when compared with patients with hh but without PCT with comparable iron overload. These data indicate that the hepatic siderosis associated with PCT likely results from dysregulated HAMP.

| S-EPMC2597139 | biostudies-literature

When Simple Phlebotomy Is the Cure: Porphyria Cutanea Tarda.

Project description: Not available

| S-EPMC9551155 | biostudies-literature

Novel UROD mutation for porphyria cutanea tarda, type 2: a case report.

Project description:Porphyria cutanea tarda (PCT) is usually caused by acquired defects in uroporphyrinogen decarboxylase (UROD) activity in the liver. This more common form of PCT is called type 1 PCT. Major known risk factors for PCT include iron overload, such as occurs due to mutations in HFE, associated with classical hereditary hemochromatosis, chronic hepatitis C infection, heavy alcohol use, tobacco use, and estrogen therapy. In addition, in about 25% of patients with PCT, namely, those with PCT type 2, an inherited partial defect in UROD activity is found. In such persons, this partial defect, which is found in all cells, including hepatocytes, red blood cells, and others, contributes to the development of biochemically and clinically active disease. Herein we describe salient features of a man in his eighth decade of life with onset of clinical PCT. Among risk factors were heavy alcohol and tobacco use. Genetic testing revealed a novel mutation in one of his alleles of the UROD gene, namely, c.224 G>C; p. Arg 75 Pro, and enzymatic testing revealed that red blood cell UROD activity was decreased by 50%. This mutation in the UROD gene is predicted to have a major effect on protein structure and function, confirmed by the 50% decrease in activity of the enzyme. The previously undescribed mutation in UROD, found in this man, namely, c.224 G>C; p. Arg 75 Pro is pathogenic.

| S-EPMC11292069 | biostudies-literature

CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda.

Project description:Porphyria cutanea tarda (PCT) is a cutaneous porphyria with sporadic (type 1) and familial (type 2) subtypes, both resulting from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. Environmental and genetic factors are involved in the development of PCT, and genetic variants in the cytochrome P450 (CYP ) genes, CYP1A1 and CYP1A2, have been implicated. We investigated the association between PCT and variants in CYP1A1, CYP1A2 and CYP2E1, and the glutathione-S-transferase (GST ) genes, GSTM1 and GSTT1. PCT diagnosis was based on urinary or plasma porphyrin profiles. Patients were classified as type 1 or 2 PCT based on UROD mutation analysis. The CYP1A2*1F promoter A allele frequency was significantly higher (P < 0.022) and the A/A genotype frequency marginally higher in PCT patients overall (P < 0.057), with the A/A genotype significantly more common in type 1 PCT (P < 0.043). The presence of the wild-type GSTM1 allele also was associated significantly with PCT (P < 0.019). Neither hemochromatosis (HFE) mutations, tobacco smoking, hepatitis C and HIV infection, ethanol consumption, nor estrogen use were associated with these allelic variants. Age at onset was significantly lower in type 2 PCT patients (P < 0.001), as observed previously. Thus, positive associations between PCT and the CYP1A2*1F promoter A allele and A/A genotype and the wild-type GSTM1 allele indicates that these functional hepatic biotransformation enzymes are risk factors for the development of this disease.

| S-EPMC3060985 | biostudies-literature

Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene.

Project description:BackgroundHepatoerythropoietic porphyria (HEP) is a rare form of porphyria that results from a deficiency of uroporphyrinogen decarboxylase (UROD). The disease is caused by homoallelism or heteroallelism for mutations in the UROD gene.ObjectiveTo study a 19-year-old woman from Equatorial Guinea, one of the few cases of HEP of African descent and to characterize a new mutation causing HEP.MethodsExcretion of porphyrins and residual UROD activity in erythrocytes were measured and compared with those of other patients with HEP. The UROD gene of the proband was sequenced and a new mutation identified. The recombinant UROD protein was purified and assayed for enzymatic activity. The change of amino acid mapped to the UROD protein and the functional consequences were predicted.ResultsThe patient presented a novel homozygous G170D missense mutation. Porphyrin excretion showed an atypical pattern in stool with a high pentaporphyrin III to isocoproporphyrin ratio. Erythrocyte UROD activity was 42% of normal and higher than the activity found in patients with HEP with a G281E mutation. The recombinant UROD protein showed a relative activity of 17% and 60% of wild-type to uroporphyrinogen I and III respectively. Molecular modelling showed that glycine 170 is located on the dimer interface of UROD, in a loop containing residues 167-172 that are critical for optimal enzymatic activity and that the carboxyl side chain from aspartic acid is predicted to cause negative interactions between the protein and the substrate.ConclusionsThe results emphasize the complex relationship between the genetic defects and the biochemical phenotype in homozygous porphyria.

| S-EPMC3818800 | biostudies-literature

Porphyria cutanea tarda increases risk of hepatocellular carcinoma and premature death: a nationwide cohort study.

Project description:BackgroundPorphyria cutanea tarda (PCT) is a skin disorder originating from a deficit of the liver enzyme uroporphyrinogen decarboxylase. PCT may be a risk factor for hepatocellular carcinoma (HCC) and other cancers, but the evidence is unclear. We aimed to investigate cancer and premature mortality risk in persons with PCT.MethodsThe cohort study consisted of all Norwegian residents from 18 years between 2000 and 2016 (n = 5.4 million). 612 persons with PCT, and all cancer diagnoses and causes of death were identified through record linkage between national registries. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were adjusted for age, sex, education and calendar years. We additionally compared persons with PCT to persons with a history of chronic alcohol abuse (n = 30,468).ResultsPersons with PCT were more likely to be diagnosed with HCC [adjusted HR (aHR) = 19.7, CI = 8.8-44.0) and gallbladder and biliary tract cancer (aHR = 6.8, CI = 2.2-21.0) than the reference population. A moderate increased risk for HCC (aHR = 3.1, CI = 1.2-7.7) and gallbladder and biliary tract cancer (aHR = 4.0, CI = 1.1-14.4) remained when compared to persons with a history of chronic alcohol abuse. Additionally, compared to the reference population, persons with PCT had an increased risk of premature death (aHR = 1.5, CI = 1.2-1.7), due to the following causes of death: malignant neoplasms (aHR = 1.4, CI = 1.0-1.9), diseases of the liver (HR = 5.5, CI = 2.5-12.2), and drug and alcohol overdose (HR = 9.9, CI = 4.7-20.8).ConclusionsPersons with PCT had an increased risk of HCC and cancer of the gallbladder and biliary tract, as well as premature death. Although most of our findings can likely be explained by common lifestyle risk factors, something inherent in PCT may contribute to the development of HCC.

| S-EPMC6448269 | biostudies-literature

Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C.

Project description:Background and aimsChronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT.MethodsBetween September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine.ResultsAll 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT.ConclusionsLedipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment.Trial registrationClinicalTrials.gov NCT03118674.

| S-EPMC9945827 | biostudies-literature

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