期刊
NATURE
卷 566, 期 7745, 页码 548-+出版社
NATURE RESEARCH
DOI: 10.1038/s41586-019-0947-3
关键词
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资金
- National Health and Medical Research Council of Australia (NHMRC) [1020400, 1052616]
- FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) [2012/12663-1]
- FAPESP (CEPID Redoxoma) [2013/07937-8]
- CNPq (Conselho Nacional para o Desenvolvimento Cientifico e Tecnologico) [301307/2013-0]
- PRPUSP (Pro-Reitoria de Pesquisa da Universidade de Sao Paulo, NAP Redoxoma) [2011.1.9352.1.8]
- John Simon Guggenheim Memorial Foundation
- NHMRC [1111632]
- New South Wales Health
- National Health and Medical Research Council of Australia [1111632] Funding Source: NHMRC
- MRC [G1000458, MR/P023150/1, MR/L009684/1, G0700320, MR/P023150/2, MR/K003232/1, MR/R01065X/2, MR/R01065X/1, G0600785] Funding Source: UKRI
Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) 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 O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) 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 G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
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