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 the SUOX gene 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 cytochrome c . 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 the SUOX gene 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 cytochrome c reduction 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 electrons in cellulo . As result, the patient H143N SO variant retains residual sulphite oxidising activity thus ameliorating iSOD progression.

中文翻译：

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在轻度亚硫酸盐氧化酶缺乏症患者中，血红素缺乏亚硫酸盐氧化酶对氧气和亚硝酸盐的还原作用。

孤立性亚硫酸盐氧化酶缺乏症 (iSOD) 是一种常染色体隐性先天性代谢缺陷，其特征是亚硫酸盐的积累，可导致婴儿早期死亡。亚硫酸盐氧化酶 (SO) 由SUOX基因编码，形成位于线粒体膜间隙的血红素和钼辅因子依赖性酶。在 SO 中，两个辅因子都嵌入两个独立的域中，它们通过灵活的 11 个残基系链连接。亚硫酸盐到硫酸盐的双电子氧化发生在钼活性位点。从那里，电子通过血红素辅因子通过两个分子内电子转移步骤 (IET) 转移到生理电子受体细胞色素c. 以前，我们报道了亚硝酸盐和氧在 Moco 活性位点作为替代电子受体，从而克服了 SO 中的 IET。在这里，我们提供了在具有不寻常的轻度疾病表现的 iSOD 患者中发生这些反应的证据。在该患者中，SUOX基因内的纯合 c.427C>A 突变导致高度保守的 His143 替换为 Asn。受影响的 His143 是 SO 中两个血红素铁配位残基之一。我们证明，H143N SO 变体无法在体内结合血红素，导致 SO 依赖性细胞色素c的消除线粒体减少。我们表明，使得在莫科域的亚硫酸盐氧化为SO His143Asn变体的影响，并且表明，亚硝酸盐和氧气都能够作为亚硫酸盐衍生的电子的电子受体在纤维素的。结果，患者 H143N SO 变体保留了残留的亚硫酸盐氧化活性，从而改善了 iSOD 的进展。