The Role of Serine 167 in Human Indoleamine 2,3-Dioxygenase: A Comparison with Tryptophan 2,3-Dioxygenase

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• 作者：Nishma Chauhan ; Jaswir Basran ; Igor Efimov ; Dimitri A. Svistunenko ; Harriet E. Seward ; Peter C. E. Moody ; Emma Lloyd Raven
• 刊名：Biochemistry
• 出版年：2008
• 出版时间：April 22, 2008
• 年：2008
• 卷：47
• 期：16
• 页码：4761 - 4769
• 全文大小：880K
• 年卷期：v.47,no.16(April 22, 2008)
• ISSN：1520-4995

文摘

The initial step in the L-kynurenine pathway is oxidation of L-tryptophan to N-formylkynurenine and is catalyzed by one of two heme enzymes, tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO). Here, we address the role of the conserved active site Ser167 residue in human IDO (S167A and S167H variants), which is replaced with a histidine in other mammalian and bacterial TDO enzymes. Our kinetic and spectroscopic data for S167A indicate that this residue is not essential for O₂ or substrate binding, and we propose that hydrogen bond stabilization of the catalytic ferrous−oxy complex involves active site water molecules in IDO. The data for S167H show that the ferrous−oxy complex is dramatically destabilized in this variant, which is similar to the behavior observed in human TDO [Basran et al. (2008) Biochemistry 47, 4752−4760], and that this destabilization essentially destroys catalytic activity. New kinetic data for the wild-type enzyme also identify the ternary [enzyme−O₂−substrate] complex. The data reveal significant differences between the IDO and TDO enzymes, and the implications of these results are discussed in terms of our current understanding of IDO and TDO catalysis.