Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase.
Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase.
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血红素的生物合成依赖于先前未被认识到的铁硫辅助因子在人氨基乙酰丙酸脱水酶中的获得。
DOI：
10.1038/s41467-020-20145-9
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发表时间：
2020-12-09
影响因子：
16.6
通讯作者：
Rouault TA
中科院分区：
文献类型：
--
作者：
Liu G;Sil D;Maio N;Tong WH;Bollinger JM Jr;Krebs C;Rouault TA
血红素生物合成和铁硫簇（ISC）生物合成是两个主要的哺乳动物代谢途径，需要铁。人们早就知道这两种途径相互连接，但先前描述的相互作用并不能完全解释为什么血红素生物合成依赖于完整的ISC生物合成。在这里，我们确定了一个以前未认识到这两个途径之间的连接，通过我们的发现，人氨基乙酰丙酸脱氢酶（ALAD），催化血红素生物合成的第二步，是一个铁-S蛋白。我们发现几个高度保守的半胱氨酸和人ALAD的Ala 306-Phe 307-Arg 308基序是重要的[Fe 4S 4]簇的收购和协调。人ALAD的酶活性在其Fe-S簇损失后大大降低，这导致人细胞中血红素生物合成减少。由于ALAD在血红素生物合成途径中提供了早期Fe-S依赖性检查点，我们的研究结果有助于解释为什么血红素生物合成依赖于完整的ISC生物合成。血红素的生物合成依赖于铁-硫（Fe-S）簇的生物合成，但这些途径之间的分子联系尚未完全了解。在这里，作者表明，血红素生物合成酶ALAD含有一个Fe-S簇，破坏它会降低ALAD活性和人类细胞中的血红素产生。
Heme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we identify a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We find that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [Fe4S4] cluster acquisition and coordination. The enzymatic activity of human ALAD is greatly reduced upon loss of its Fe-S cluster, which results in reduced heme biosynthesis in human cells. As ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway, our findings help explain why heme biosynthesis depends on intact ISC biogenesis. Heme biosynthesis depends on iron-sulfur (Fe-S) cluster biogenesis but the molecular connection between these pathways is not fully understood. Here, the authors show that the heme biosynthesis enzyme ALAD contains an Fe-S cluster, disruption of which reduces ALAD activity and heme production in human cells.
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