Abnormal sulphur oxidation in systemic lupus erythematosus

“…Intracellular cys concentration is limiting in glutathione synthesis, therefore the activity of CDO directly competes with cellular redox buffering under conditions of low cys availability and oxidative stress [6]. Abnormal cys metabolism has been observed in patients suffering from a variety of neurological diseases [5, 7, 8], suggesting a correlation between impaired sulfur metabolism, oxidative stress, and neurodegenerative disease [9, 10]. Consequently, enzymes involved in sulfur-oxidation and transfer are increasingly being recognized as potential drug targets for development of antimicrobials, therapies for cancer and inflammatory disease [11–14].…”

Section: Introductionmentioning

confidence: 99%

Thiol dioxygenase turnover yields benzothiazole products from 2-mercaptoaniline and O2-dependent oxidation of primary alcohols

Morrow

Sardar

Thapa

et al. 2017

Archives of Biochemistry and Biophysics

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Thiol dioxygenases are non-heme mononuclear iron enzymes that catalyze the O2-dependent oxidation of free thiols (-SH) to produce the corresponding sulfinic acid (-SO2−). Previous chemical rescue studies identified a putative FeIII-O2•− intermediate that precedes substrate oxidation in Mus musculus cysteine dioxygenase (Mm CDO). Given that a similar reactive intermediate has been identified in the extradiol dioxygenase 2, 3-HCPD, it is conceivable that these enzymes share other mechanistic features with regard to substrate oxidation. To explore this possibility, enzymatic reactions with Mm CDO (as well as the bacterial 3-mercaptopropionic acid dioxygenase, Av MDO) were performed using a substrate analogue (2-mercaptoaniline, 2ma). This aromatic thiol closely approximates the catecholic substrate of homoprotocatechuate of 2, 3-HPCD while maintaining the 2-carbon thiol-amine separation preferred by Mm CDO. Remarkably, both enzymes exhibit 2ma-gated O2-consumption; however, none of the expected products for thiol dioxygenase or intra/extradiol dioxygenase reactions were observed. Instead, benzothiazoles are produced by the condensation of 2ma with aldehydes formed by an off-pathway oxidation of primary alcohols added to aqueous reactions to solubilize the substrate. The observed oxidation of 1°-alcohols in 2ma-reactions is consistent with the formation of a high-valent intermediate similar to what has been reported for cytochrome P450 and mononuclear iron model complexes.

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“…Elevated cysteine levels were reported previously in relation to several neurodegenerative diseases, including the well known Parkinson and Alzheimer diseases (12)(13)(14), and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (15,16). CDO is considered to be involved in these diseases due to its function in regulating free cysteine levels.…”

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confidence: 99%

An Insight into the Mechanism of Human Cysteine Dioxygenase

Ye¹,

Wu²,

Wei³

et al. 2007

Journal of Biological Chemistry

167

131

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Cysteine dioxygenase is a non-heme mononuclear iron metalloenzyme that catalyzes the oxidation of cysteine to cysteine sulfinic acid with addition of molecular dioxygen. This irreversible oxidative catabolism of cysteine initiates several important metabolic pathways related to diverse sulfurate compounds. Cysteine dioxygenase is therefore very important for maintaining the proper hepatic concentration of intracellular free cysteine. Mechanisms for mouse and rat cysteine dioxygenases have recently been reported based on their crystal structures in the absence of substrates, although there is still a lack of direct evidence. Here we report the first crystal structure of human cysteine dioxygenase in complex with its substrate L-cysteine to 2.7 Å , together with enzymatic activity and metal content assays of several single point mutants. Our results provide an insight into a new mechanism of cysteine thiol dioxygenation catalyzed by cysteine dioxygenase, which is tightly associated with a thioether-bonded tyrosine-cysteine cofactor involving Tyr-157 and Cys-93. This cross-linked protein-derived cofactor plays several key roles different from those in galactose oxidase. This report provides a new potential target for therapy of diseases related to human cysteine dioxygenase, including neurodegenerative and autoimmune diseases.Cysteine dioxygenase (CDO, 2 EC 1.13.11.20) is a non-heme mononuclear iron metalloenzyme that catalyzes the irreversible oxidation of cysteine to cysteine sulfinic acid (CSA) with addition of molecular oxygen (1) (Structure 1). This oxidative catabolism of cysteine initiates several important metabolic pathways related to pyruvate and several sulfurate compounds, including sulfate, hypotaurine, and taurine. CDO is expressed at appreciable levels in the brain, kidney, and lung, with extremely high levels in liver tissue (2-5), where CDO plays an important role in maintaining the hepatic concentration of intracellular free cysteine within a proper narrow range (6). When the levels of cysteine decrease below this range, the increase of CDO ubiquitination rate results in rapid degradation of the ubiquitinated portion by the 26 S proteasome system (7,8). However, the precise means by which cysteine regulates CDO ubiquitination remain unknown.Intracellular free cysteine is cytotoxic and neuroexcitotoxic due to oxidative damage via formation of free radicals in the presence of iron (9 -11). Elevated cysteine levels were reported previously in relation to several neurodegenerative diseases, including the well known Parkinson and Alzheimer diseases (12-14), and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (15, 16). CDO is considered to be involved in these diseases due to its function in regulating free cysteine levels.Sequence alignment classifies CDO as a member of the cupin superfamily (see Fig. 1), whose members possess what may be the most diverse range of functions, encompassing ϳ18 subclasses. Nonetheless, neither of the exact characteristic conserved sequenc...

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Abnormal sulphur oxidation in systemic lupus erythematosus

Cited by 50 publications

References 5 publications

Analysis of microRNAs in patients with systemic lupus erythematosus, using Solexa deep sequencing

Analysis of microRNAs in patients with systemic lupus erythematosus, using Solexa deep sequencing

Thiol dioxygenase turnover yields benzothiazole products from 2-mercaptoaniline and O2-dependent oxidation of primary alcohols

An Insight into the Mechanism of Human Cysteine Dioxygenase

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