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Singlet molecular oxygen (.sup.1O.sub.2) has well-established roles in photosynthetic plants, bacteria and fungi.sup.1-3, but not in mammals. Chemically generated .sup.1O.sub.2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine.sup.4, whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1.sup.5. Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure.sup.6. However, whether indoleamine 2,3-dioxygenase 1 forms .sup.1O.sub.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 .sup.1O.sub.2. We observed that in the presence of hydrogen peroxide, the enzyme generates .sup.1O.sub.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 .sup.1O.sub.2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. Singlet molecular oxygen, produced by indoleamine 2,3-dioxygenase 1 activity, gives rise to a signalling molecule that regulates arterial relaxation under inflammatory conditions., Author(s): Christopher P. Stanley [sup.1] , Ghassan J. Maghzal [sup.1] [sup.2] , Anita Ayer [sup.1] [sup.2] , Jihan Talib [sup.1] [sup.2] , Andrew M. Giltrap [sup.3] , Sudhir Shengule [sup.1] [...]

We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess. diabetes | mitochondria | superoxide doi/ 10.1073/pnas.0902380106

The studies related to the oxidation of methionine and N-terminal methionine residues by biologically relevant reactive halogen species and neutrophils during infection and inflammation are reported. The results obtained suggested that reactive halogen species wouldl produce dehydromethionine and form azasulfonium cations on the N-termini of peptides and proteins during inflammatory events.

Chroni→c granulomatous disease (CGD) is an inherited disorder of phagocyte function, caused by a genetic defect in NADPH oxidase (NOX2), leading to an impaired ability of leukocytes to produce superoxide [...]