Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency.

Autor:	Bender D; Department of Chemistry, Institute for Biochemistry, University of Cologne, 50674 Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne Germany., Kaczmarek AT; Department of Chemistry, Institute for Biochemistry, University of Cologne, 50674 Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne Germany., Santamaria-Araujo JA; Department of Chemistry, Institute for Biochemistry, University of Cologne, 50674 Cologne, Germany., Stueve B; Abteilung für Kinderneurologie, Epileptologie und Sozialpädiatrie, Kliniken Köln, Kinderkrankenhaus, 51058 Cologne, Germany., Waltz S; Abteilung für Kinderneurologie, Epileptologie und Sozialpädiatrie, Kliniken Köln, Kinderkrankenhaus, 51058 Cologne, Germany., Bartsch D; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne Germany., Kurian L; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne Germany., Cirak S; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne Germany.; Klinik für Kinderheilkunde und Jugendmedizin, Uniklinikum Köln, 50937 Cologne, Germany., Schwarz G; Department of Chemistry, Institute for Biochemistry, University of Cologne, 50674 Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne Germany.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2019 Sep 01; Vol. 28 (17), pp. 2885-2899.
DOI:	10.1093/hmg/ddz109
Abstrakt:	Sulfite oxidase (SO) is encoded by the nuclear SUOX gene and catalyzes the final step in cysteine catabolism thereby oxidizing sulfite to sulfate. Oxidation of sulfite is dependent on two cofactors within SO, a heme and the molybdenum cofactor (Moco), the latter forming the catalytic site of sulfite oxidation. SO localizes to the intermembrane space of mitochondria where both-pre-SO processing and cofactor insertion-are essential steps during SO maturation. Isolated SO deficiency (iSOD) is a rare inborn error of metabolism caused by mutations in the SUOX gene that lead to non-functional SO. ISOD is characterized by rapidly progressive neurodegeneration and death in early infancy. We diagnosed an iSOD patient with homozygous mutation of SUOX at c.1084G>A replacing Gly362 to serine. To understand the mechanism of disease, we expressed patient-derived G362S SO in Escherichia coli and surprisingly found full catalytic activity, while in patient fibroblasts no SO activity was detected, suggesting differences between bacterial and human expression. Moco reconstitution of apo-G362S SO was found to be approximately 90-fold reduced in comparison to apo-WT SO in vitro. In line, levels of SO-bound Moco in cells overexpressing G362S SO were significantly reduced compared to cells expressing WT SO providing evidence for compromised maturation of G362S SO in cellulo. Addition of molybdate to culture medium partially rescued impaired Moco binding of G362S SO and restored SO activity in patient fibroblasts. Thus, this study demonstrates the importance of the orchestrated maturation of SO and provides a first case of Moco-responsive iSOD. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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