Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans
Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans
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DOI：
10.1038/sj.emboj.7600792
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发表时间：
2005-09-21
期刊：
影响因子：
11.4
通讯作者：
Heinz, DW
中科院分区：
文献类型：
--
作者：
Astner, I;Schulze, JO;Heinz, DW
5-氨基乙酰酸合成酶（5-Aminolevulinate synthase， ALAS）是人类、动物、其他非植物真核生物和α -变形菌中血红素生物合成的第一酶和限速酶。它催化甘氨酸和琥珀酰辅酶A （sCoA）以依赖于吡哆醛5'-磷酸（PLP）的方式合成5-氨基乙酰丙酸，这是所有四吡咯的第一个共同前体。x连锁铁母细胞贫血（XLSAs）是一组严重的人类疾病，其特征是红母细胞线粒体中血红素形成不足，是由红系eALAS基因突变引起的，该基因是人类两个ALAS基因之一。本文首次报道了荚膜红杆菌（Rhodobacter capsulatus，简称：ALAS(Rc)）与辅因子PLP结合的二聚体ALAS晶体结构。此外，我们还介绍了ALAS（Rc）与底物甘氨酸或sCoA配合物的结构。荚膜荚膜荚膜荚膜荚膜与人类荚膜荚膜荚膜荚膜的同源性为49%。由此可以绘制出XLSA引起的突变，揭示人类XLSA的分子基础。发现突变会阻碍底物结合，破坏二聚体界面，或妨碍正确折叠。ALAS的结构完成了血红素生物合成酶的结构分析。
5-Aminolevulinate synthase ( ALAS) is the first and rate-limiting enzyme of heme biosynthesis in humans, animals, other non-plant eukaryotes, and alpha-proteobacteria. It catalyzes the synthesis of 5-aminolevulinic acid, the first common precursor of all tetrapyrroles, from glycine and succinyl-coenzyme A (sCoA) in a pyridoxal 5'-phosphate (PLP)-dependent manner. X-linked sideroblastic anemias (XLSAs), a group of severe disorders in humans characterized by inadequate formation of heme in erythroblast mitochondria, are caused by mutations in the gene for erythroid eALAS, one of two human genes for ALAS. We present the first crystal structure of homodimeric ALAS from Rhodobacter capsulatus (ALAS(Rc)) binding its cofactor PLP. We, furthermore, present structures of ALAS(Rc) in complex with the substrates glycine or sCoA. The sequence identity of ALAS from R. capsulatus and human eALAS is 49%. XLSA-causing mutations may thus be mapped, revealing the molecular basis of XLSA in humans. Mutations are found to obstruct substrate binding, disrupt the dimer interface, or hamper the correct folding. The structure of ALAS completes the structural analysis of enzymes in heme biosynthesis.