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Research Article Free access | 10.1172/JCI109675

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

Joseph R. Bloomer

Howard Hughes Medical Institute Laboratory, Yale University School of Medicine, New Haven, Connecticut 06510

Find articles by Bloomer, J. in: JCI | PubMed | Google Scholar

Published February 1, 1980 - More info

Published in Volume 65, Issue 2 on February 1, 1980
J Clin Invest. 1980;65(2):321–328. https://doi.org/10.1172/JCI109675.
© 1980 The American Society for Clinical Investigation
Published February 1, 1980 - Version history
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Abstract

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 μM, 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 micro-environment.

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