Reduced Ferrochelatase Activity: a Defect Common to Porphyria Variegata and Protoporphyria

Becker, David M.; Viljoen, J. D.; Katz, J.; Kramer, S. D.

doi:10.1111/j.1365-2141.1977.tb00637.x

Cited by 63 publications

(24 citation statements)

References 30 publications

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“…In protoporphyria, protoporphyrin accumulates because of a deficiency in the activity of heme synthase (ferrochelatase), the intramitochondrial enzyme that catalyzes the chelation of ferrous iron to protoporphyrin to form heme. The enzymatic defect has been demonstrated in several tissues from patients with protoporphyria, including liver (1), bone marrow cells (2,3), peripheral blood cells (4,5), and cultured skin fibroblasts (1,6). Deficient heme synthase activity has also been demonstrated in cultured skin fibroblasts from one parent in each of three families in which the children have protoporphyria (7), consistent with the autosomal dominant mode of inheritance that has been postulated for the disease (8).…”

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confidence: 66%

Characterization of Deficient Heme Synthase Activity in Protoporphyria with Cultured Skin Fibroblasts

Bloomer¹

1980

J. Clin. Invest.

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A B S T R A C T Heme synthase (ferrochelatase) activity, as determined by the chelation of ferrous iron to protoporphyrin or deuteroporphyrin, is reduced to 10-25% of normal in tissues of patients with protoporphyria. With cultured skin fibroblasts from seven patients with protoporphyria and six normal individuals, the present studies examined the enzymatic defect.Heme synthase activity in normal and protoporphyria fibroblasts had the same pH optimum, showed similar inhibition by divalent metals, and had the highest specific activity in the mitochondrial-enriched fraction. The ultrastructural features and other biochemical parameters of mitochondria were normal in protoporphyria cells, excluding a general mitochondrial defect. Measurement of the rate of deuteroheme formation at different concentrations of substrate demonstrated a significant reduction in the apparent Km for deuteroporphyrin in detergent-treated sonicates of protoporphyria fibroblasts compared to normal (7.5 ±0.9 gM, mean±SEM, vs. 17.4+1.8), as well as a decrease in the velocity of reaction (mean level was 21% of normal). Studies with intact cells, in which heme synthase activity was estimated indirectly, also indicated that the apparent Km for porphyrin substrate was significantly lower in protoporphyria lines.These data show that heme synthase in protoporphyria fibroblasts has markedly reduced catalytic activity despite an increased affinity for porphyrin substrate. This could be caused by either a change in the enzyme protein, or an alteration of its microenvironment.

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confidence: 66%

Characterization of Deficient Heme Synthase Activity in Protoporphyria with Cultured Skin Fibroblasts

Bloomer¹

1980

J. Clin. Invest.

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“…It is possible for AIP and HC [14], But, in porphyria variegata, the enzymatic defect is still uncertain; an inactive ferrochelatase secondary to an inherited structural gene mutation is perhaps the primary deficiency [1].…”

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confidence: 99%

Urinary Porphyrin Excretion in Various Types of Porphyria

Perrot¹,

Boucherat²,

Gardella³

1980

Dermatology

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A new method of thin-layer chromatography was used for the study of urinary porphyrins in 42 porphyric patients (27 cases of porphyria cutanea tarda (PCT), 5 cases of porphyria variegata, 4 cases of acute intermittent porphyria, 2 cases of hereditary coproporphyria and 4 cases of erythropoietic protoporphyria), 21 of their clinically normal relatives and 5 controls. The results are compared to previously published data and discussed for the diagnosis of the porphyrias. If urinary porphyrin pattern seems sufficiently pathognomonic for PCT, it appears often unable to allow exact diagnosis of the acute porphyrias; faecal studies and sometimes enzymatic determinations are necessary.

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“…Protoporphyrinogen oxidase has been implicated in the genetically inherited disease variegate porphyria (Brenner & Bloomer, 1980), although opinions are divided as to whether protoporphyrinogen oxidase alone, or ferrochelatase and the oxidase, are associated with the disease (Becker et al, 1977;Brenner & Bloomer, 1980;Deybach et al, 1981;Viljoen et al, 1983). Originally it was believed that ferrochelatase was the deficient enzyme (Becker et al, 1977), but later Brenner & Bloomer (1980) and Deybach et al (1981) clearly showed that protoporphyrinogen oxidase activity was decreased in variegate-porphyria patients, whereas ferrochelatase activity was normal.…”

Section: Introductionmentioning

confidence: 96%

Mouse protoporphyrinogen oxidase. Kinetic parameters and demonstration of inhibition by bilirubin

Ferreira

Dailey

1988

Biochemical Journal

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The penultimate step of haem biosynthesis, the oxidation of protoporphyrinogen to protoporphyrin, was examined with purified murine hepatic protoporphyrinogen oxidase (EC 1.3.3.4) in detergent solution. The kinetic parameters for the two-substrate (protoporphyrinogen and oxygen) reaction were determined. The limiting Km for protoporphyrinogen when oxygen is saturating is 6.6 microM, whereas the Km for oxygen with saturating concentrations of protoporphyrinogen is 125 microM. The kcat. for the overall reaction is 447 h-1. The ratio of kcat. to the Km for protoporphyrinogen is approx. 20-fold greater than the kcat./Km,O2 ratio. The ratio of protoporphyrin formed to dioxygen consumed is 1:3. Ubiquinone-6, ubiquinone-10 and dicoumarol stimulate protoporphyrinogen oxidase activity at low concentrations (less than 15 microM), whereas coenzyme Q0 and menadione show no activation at these concentrations. Above 30 microM, all five quinones inhibit the enzyme activity. FAD does not significantly affect the activity of the enzyme. Bilirubin, a product of haem catabolism, is shown to be a competitive inhibitor of the penultimate enzyme of the haem-biosynthetic pathway, protoporphyrinogen oxidase, with a calculated Ki of 25 microM. The terminal enzyme of haem-biosynthetic pathway, namely ferrochelatase, is not inhibited by bilirubin at concentrations over double the Ki value for the oxidase. In contrast with other enzymic systems, the toxicity of bilirubin is not reversed by binding to albumin.

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Reduced Ferrochelatase Activity: a Defect Common to Porphyria Variegata and Protoporphyria

Cited by 63 publications

References 30 publications

Characterization of Deficient Heme Synthase Activity in Protoporphyria with Cultured Skin Fibroblasts

Characterization of Deficient Heme Synthase Activity in Protoporphyria with Cultured Skin Fibroblasts

Urinary Porphyrin Excretion in Various Types of Porphyria

Mouse protoporphyrinogen oxidase. Kinetic parameters and demonstration of inhibition by bilirubin

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