Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan:: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase
Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan:: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase
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DOI：
10.1042/bj20042075
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发表时间：
2005-05-15
影响因子：
4.1
通讯作者：
Boutin, JA
中科院分区：
文献类型：
--
作者：
Ferry, G;Ubeaud, C;Boutin, JA
褪黑素的分解代谢，无论是自然发生的还是被摄取的，都通过两条途径发生：类似于70%的褪黑素可以通过结合(硫代和葡萄糖醛酸结合)来解释，类似于30%的通过氧化来解释。通常认为，干扰素诱导的吲哚胺2，3-双加氧酶(EC 1.13.11.42)氧化色氨酸，也是氧化5-羟色胺(5-羟色胺)及其衍生物褪黑素的原因。利用在大肠杆菌中表达的重组酶，我们在本工作中证明了吲哚胺2，3-双加氧酶确实能裂解色氨酸，但在相同的条件下，它不能裂解另外两种吲哚胺。相比之下，髓过氧化物酶(EC 1.11.1.7)能够裂解褪黑素的吲哚部分。然而，当使用过氧化物酶测定的条件下-以H_2O_2为共底物-吲哚胺2，3-双加氧酶能够将褪黑素裂解成其主要代谢物-犬尿氨酸衍生物。本工作证明，在过氧化氢存在下，褪黑素的氧化代谢是由于髓过氧化物酶和吲哚胺2，3-双加氧酶(效价较低)的活性，因为这两种酶对褪黑素的K-m值都在微摩尔范围内。在这种条件下，几种吲哚化合物可以被两种酶切割，如色胺和5-羟色胺。此外，褪黑素的代谢产生了犬尿氨酸衍生物，其药理作用仍有待研究，并可能放大褪黑素的作用机制。
The catabolism of melatonin, whether naturally occurring or ingested, takes place via two pathways: similar to 70% can be accounted for by conjugation (sulpho- and glucurono-conjugation), and similar to 30% by oxidation. It is commonly thought that the interferon-induced enzyme indoleamine 2,3-dioxygenase (EC 1.13.11.42), which oxidizes tryptophan, is also responsible for the oxidation of 5-hydroxytryptamine (serotonin) and its derivative, melatonin. Using the recombinant enzyme expressed in Escherichia coli, we show in the present work that indoleamine 2,3-dioxygenase indeed cleaves tryptophan; however, under the same conditions, it is incapable of cleaving the two other indoleamines. By contrast, myeloperoxidase (EC 1.11.1.7) is capable of cleaving the indole moiety of melatonin. However, when using the peroxidase conditions of assay-with H2O2 as co-substrate-indoleamine 2,3-di-oxygenase is able to cleave melatonin into its main metabolite, a kynurenine derivative. The present work establishes that the oxidative metabolism of melatonin is due, in the presence of H2O2, to the activities of both myeloperoxidase and indoleamine 2,3-dioxygenase (with lower potency), since both enzymes have K-m values for melatonin in the micromolar range. Under these conditions, several indolic compounds can be cleaved by both enzymes, such as tryptamine and 5-hydroxytryptamine. Furthermore, melatonin metabolism results in a kynurenine derivative, the pharmacological action of which remains to be studied, and could amplify the mechanisms of action of melatonin.