3978-11-8Relevant articles and documents
Photooxidation of tryptophan: O2(1Δ(g)) versus electron-transfer pathway
Wessels,Foote,Ford,Rodgers
, p. 96 - 102 (1997)
Tris (2,2'-bipyridyl)ruthenium(II)chloride hexahydrate (Ru[bpy]32+) free in solution and adsorbed onto antimony-doped SnO2 colloidal particles was used as a photosensitizer for a comparison of the O2(1/sup
Directed Evolution of a Tryptophan 2,3-Dioxygenase for the Diastereoselective Monooxygenation of Tryptophans
Bai, Wen-Ju,Jiang, Shengsheng,Li, Qiuchun,Lu, Chen,Wang, Xiqing,Wei, Yanxin,Zhang, Yanyan
, p. 3043 - 3047 (2020/02/04)
Herein, we report an engineered enzyme that can monooxygenate unprotected tryptophan into the corresponding 3a-hydroxyhexahydropyrrolo[2,3-b]indole-2-carboxylic acid (HPIC) in a single, scalable step with excellent turnover number and diastereoselectivity. Taking advantage of directed evolution, we analyzed the stepwise oxygen-insertion mechanism of tryptophan 2,3-dioxygenases, and transformed tryptophan 2,3-dioxygenase from Xanthomonas campestris into a monooxygenase for oxidative cyclization of tryptophans. It was revealed that residue F51 is vital in determining the product ratio of HPIC to N′-formylkynurenine. Our reactions and purification procedures use no organic solvents, resulting in an eco-friendly method to prepare HPICs for further applications.
Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
Stanley, Christopher P.,Maghzal, Ghassan J.,Ayer, Anita,Talib, Jihan,Giltrap, Andrew M.,Shengule, Sudhir,Wolhuter, Kathryn,Wang, Yutang,Chadha, Preet,Suarna, Cacang,Prysyazhna, Oleksandra,Scotcher, Jenna,Dunn, Louise L.,Prado, Fernanda M.,Nguyen, Nghi,Odiba, Jephthah O.,Baell, Jonathan B.,Stasch, Johannes-Peter,Yamamoto, Yorihiro,Di Mascio, Paolo,Eaton, Philip,Payne, Richard J.,Stocker, Roland
, p. 548 - 552 (2019/03/06)
Singlet molecular oxygen (1O2) has well-established roles in photosynthetic plants, bacteria and fungi1–3, but not in mammals. Chemically generated 1O2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine4, whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 15. Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure6. However, whether indoleamine 2,3-dioxygenase 1 forms 1O2 and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of 1O2. We observed that in the presence of hydrogen peroxide, the enzyme generates 1O2 and that this is associated with the stereoselective oxidation of l-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1α. Our findings demonstrate a pathophysiological role for 1O2 in mammals through formation of an amino?acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
Nitrobenzofurazan derivatives of N′-hydroxyamidines as potent inhibitors of indoleamine-2,3-dioxygenase 1
Paul, Saurav,Roy, Ashalata,Deka, Suman Jyoti,Panda, Subhankar,Trivedi, Vishal,Manna, Debasis
, p. 364 - 375 (2016/06/13)
Tryptophan metabolism through the kynurenine pathway is considered as a crucial mechanism in immune tolerance. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism in the immune system and it is also considered as an important therapeutic target for the treatment of cancer and other diseases that are linked with kynurenine pathway. In this study, a series of nitrobenzofurazan derivatives of N′-hydroxybenzimidamides (1) and N′-hydroxy-2-phenylacetimidamides (2) were synthesized and their inhibitory activities against human IDO1 enzyme were tested using in-vitro and cellular enzyme activity assay. The optimization leads to the identification of potent compounds, 1d, 2i and 2k (IC50 = 39-80 nM), which are either competitive or uncompetitive inhibitors of IDO1 enzyme. These compounds also showed IDO1 inhibition potencies in the nanomolar range (IC50 = 50-71 nM) in MDA-MB-231 cells with no/negligible amount of cytotoxicity. The stronger selectivity of the potent compounds for IDO1 enzyme over tryptophan 2,3-dioxygenase (TDO) enzyme (312-1593-fold) also makes them very attractive for further immunotherapeutic applications.
