Universität zu Köln

Bender, Daniel, Kaczmarek, Alexander T., Kuester, Sabina, Burlina, Alberto B. and Schwarz, Guenter ORCID: 0000-0002-2118-9338 (2020). Oxygen and nitrite reduction by heme-deficient sulphite oxidase in a patient with mild sulphite oxidase deficiency. J. Inherit. Metab. Dis., 43 (4). S. 748 - 758. HOBOKEN: WILEY. ISSN 1573-2665

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Abstract

Isolated sulphite oxidase deficiency (iSOD) is an autosomal recessive inborn error in metabolism characterised by accumulation of sulphite, which leads to death in early infancy. Sulphite oxidase (SO) is encoded by theSUOXgene and forms a heme- and molybdenum-cofactor-dependent enzyme localised in the intermembrane space of mitochondria. Within SO, both cofactors are embedded in two separated domains, which are linked via a flexible 11 residue tether. The two-electron oxidation of sulphite to sulphate occurs at the molybdenum active site. From there, electrons are transferred via two intramolecular electron transfer steps (IETs) via the heme cofactor and to the physiologic electron acceptor cytochromec. Previously, we reported nitrite and oxygen to serve as alternative electron acceptors at the Moco active site, thereby overcoming IET within SO. Here, we present evidence for these reactions to occur in an iSOD patient with an unusual mild disease representation. In the patient, a homozygous c.427C>A mutation within theSUOXgene leads to replacement of the highly conserved His143 to Asn. The affected His143 is one of two heme-iron-coordinating residues within SO. We demonstrate, that the H143N SO variant fails to bind heme in vivo leading to the elimination of SO-dependent cytochromecreduction in mitochondria. We show, that sulphite oxidation at the Moco domain is unaffected in His143Asn SO variant and demonstrate that nitrite and oxygen are able to serve as electron acceptors for sulphite-derived electronsin cellulo. As result, the patient H143N SO variant retains residual sulphite oxidising activity thus ameliorating iSOD progression.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bender, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaczmarek, Alexander T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuester, Sabina UNSPECIFIED UNSPECIFIED UNSPECIFIED Burlina, Alberto B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-327671
DOI:	10.1002/jimd.12216
Journal or Publication Title:	J. Inherit. Metab. Dis.
Volume:	43
Number:	4
Page Range:	S. 748 - 758
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1573-2665
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOLYBDENUM COFACTOR DEFICIENCY; ELECTRON-TRANSFER; MITOCHONDRIA; MECHANISM; ISCHEMIA; INJURY; PROTECTION Multiple languages Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/32767