Bender, Daniel ORCID: 0000-0002-2975-4186, Kaczmarek, Alexander Tobias, Santamaria-Araujo, Jose Angel, Stueve, Burkard, Waltz, Stephan, Bartsch, Deniz, Kurian, Leo, Cirak, Sebahattin and Schwarz, Guenter (2019). Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency. Hum. Mol. Genet., 28 (17). S. 2885 - 2900. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bender, DanielUNSPECIFIEDorcid.org/0000-0002-2975-4186UNSPECIFIED
Kaczmarek, Alexander TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santamaria-Araujo, Jose AngelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stueve, BurkardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waltz, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartsch, DenizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurian, LeoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, GuenterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-142094
DOI: 10.1093/hmg/ddz109
Journal or Publication Title: Hum. Mol. Genet.
Volume: 28
Number: 17
Page Range: S. 2885 - 2900
Date: 2019
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOLYBDENUM COFACTOR DEFICIENCY; INTRAMOLECULAR ELECTRON-TRANSFER; STRUCTURAL INSIGHTS; HPLC METHOD; SAPROPTERIN; MUTATIONS; DOMAIN; G473DMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14209

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