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Delta-aminolevulinic acid synthase 2 expression in combination with iron as modifiers of disease severity in erythropoietic protoporphyria.
Molecular Genetics and Metabolism ( IF 3.8 ) Pub Date : 2019-05-02 , DOI: 10.1016/j.ymgme.2019.04.013
Jasmin Barman-Aksözen 1 , Francois Halloy 2 , Pavithra S Iyer 2 , Daniel Schümperli 2 , Anna Elisabeth Minder 3 , Jonathan Hall 2 , Elisabeth I Minder 3 , Xiaoye Schneider-Yin 1
Affiliation  

Deficiency in ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway, leads to an accumulation of protoporphyrin IX (PPIX) that causes a severely painful phototoxic reaction of the skin in patients with erythropoietic protoporphyria (EPP). Besides phototoxicity of the skin, EPP patients often present with symptoms of iron deficiency in form of a microcytic and hypochromic anemia with low serum iron and ferritin. In addition, elevated aminolevulinic acid synthase 2 (ALAS2) both at the mRNA and protein levels have been observed among EPP patients. ALAS is the first enzyme in the pathway and exists in two isoforms, whereby the isoform 2 (ALAS2) is expressed exclusively in erythropoiesis. The mRNA of ALAS2 contains an iron response element (IRE) at its 5'UTR. When iron is limited, iron response element binding protein 2 (IRP2) binds to the IRE of ALAS2 mRNA and suppresses its translation. In this study, we demonstrated that iron deprivation increased the amount of ALAS2 mRNA as well as the ratio of ALAS2 to FECH mRNAs in cultured erythroleukemic K562 cells. At the protein level, however, iron deprivation in the cell line caused reductions in both enzymes as shown by the Western blot analysis. A comparable increase in the ratio of ALAS2 to FECH mRNAs was also found in EPP patients indicating an imbalance in heme biosynthesis. As iron cannot be completely missing from an organism, we assume that in EPP patients, a certain amount of ALAS2 mRNA is translated despite a partial deficiency of FECH. The increase in ALAS2 enzyme contributes to the accumulation in PPIX in the patients. Targeted inhibition of ALAS2 could therefore be a treatment option for EPP.

中文翻译:

Delta-氨基乙酰丙酸合酶2的表达与铁结合作为促红细胞生成性原卟啉病疾病严重程度的调节剂。

血红素生物合成途径中的最后一种酶-铁螯合酶(FECH)的缺乏导致原卟啉IX(PPIX)的积聚,导致红细胞生成性原卟啉症(EPP)患者的皮肤发生严重的光毒性反应。除了皮肤的光毒性外,EPP患者还经常表现为铁缺乏症,表现为小细胞性贫血和低色素性贫血,血清铁和铁蛋白低。另外,在EPP患者中,在mRNA和蛋白质水平上都观察到了氨基乙酰丙酸合酶2(ALAS2)的升高。ALAS是该途径中的第一个酶,并以两种亚型存在,因此亚型2(ALAS2)仅在红细胞生成中表达。ALAS2的mRNA在其5'UTR处含有铁反应元件(IRE)。当铁有限时,铁反应元件结合蛋白2(IRP2)与ALAS2 mRNA的IRE结合并抑制其翻译。在这项研究中,我们证明了铁剥夺增加了培养的红白血病K562细胞中ALAS2 mRNA的量以及ALAS2与FECH mRNA的比率。然而,在蛋白质水平上,如蛋白质印迹分析所示,细胞系中的铁缺乏导致两种酶的减少。在EPP患者中,还发现ALAS2与FECH mRNA的比例有相当的增加,表明血红素生物合成失衡。由于不能从生物体中完全缺失铁,因此我们假设在EPP患者中,尽管FECH部分缺乏,但仍翻译了一定量的ALAS2 mRNA。ALAS2酶的增加有助于患者中PPIX的积累。
更新日期:2019-11-18
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