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Characterization of a patient-derived variant of GPX4 for precision therapy
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2021-12-20 , DOI: 10.1038/s41589-021-00915-2
Hengrui Liu 1 , Farhad Forouhar 2 , Tobias Seibt 3 , Russell Saneto 4, 5 , Kristen Wigby 6, 7 , Jennifer Friedman 6, 7, 8, 9 , Xin Xia 10 , Mikhail S Shchepinov 11 , Sanath Kumar Ramesh 12 , Marcus Conrad 13, 14 , Brent R Stockwell 1, 2, 10, 15
Affiliation  

Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.



中文翻译:

用于精确治疗的患者衍生 GPX4 变体的表征

谷胱甘肽过氧化物酶 4 (GPX4) 作为哺乳动物中唯一能够在细胞环境中减少酯化磷脂氢过氧化物的酶,可保护细胞免于铁死亡。我们在GPX4中发现了一个纯合点突变基因,导致 R152H 编码突变,在三名 Sedaghatian 型脊柱骨骺发育不良患者中。使用该变体的基于结构的分析和细胞模型(包括患者成纤维细胞),我们发现错义变体破坏了一个关键环的稳定性,从而破坏了活性位点并导致酶功能的大量丧失。我们还发现 GPX4 的 R152H 变体不易降解,揭示了 GPX4 蛋白的降解机制。确定了克服 R152H GPX4 活性受损的概念验证治疗方法,包括补充硒、选择性抗氧化剂和氘代多不饱和脂肪酸。除了揭示调查罕见遗传疾病的一般方法外,

更新日期:2021-12-20
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