Sulphoxidation and sulphation capacity in patients with primary biliary cirrhosis

Davies, Mervyn H.; Ngong, Josephine M.; Pean, A.; Vickers, Christopher; Waring, R. H.; Elias, Elwyn

doi:10.1016/0168-8278(95)80450-1

Cited by 37 publications

(16 citation statements)

References 41 publications

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“…The prevalence of impaired cysteine catabolism has been reported to be increased in patient populations afflicted with rheumatoid arthritis, liver diseases, Parkinson disease, Alzheimer disease, motor neuron disease, and systemic lupus erythematosus (2)(3)(4)(5). These patients frequently exhibit low levels of sulfate in plasma (and in synovial fluid), elevated fasting plasma cysteine concentrations, elevated plasma cysteine to sulfate ratios, and an impaired capacity for sulfation reactions in vivo.…”

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confidence: 99%

Crystal Structure of Mammalian Cysteine Dioxygenase

Simmons

Liu

Huang

et al. 2006

Journal of Biological Chemistry

156

107

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Cysteine dioxygenase is a mononuclear iron-dependent enzyme responsible for the oxidation of cysteine with molecular oxygen to form cysteine sulfinate. This reaction commits cysteine to either catabolism to sulfate and pyruvate or the taurine biosynthetic pathway. Cysteine dioxygenase is a member of the cupin superfamily of proteins. The crystal structure of recombinant rat cysteine dioxygenase has been determined to 1.5-Å resolution, and these results confirm the canonical cupin ␤-sandwich fold and the rare cysteinyltyrosine intramolecular cross-link (between Cys 93 and Tyr 157 ) seen in the recently reported murine cysteine dioxygenase structure. In contrast to the catalytically inactive mononuclear Ni(II) metallocenter present in the murine structure, crystallization of a catalytically competent preparation of rat cysteine dioxygenase revealed a novel tetrahedrally coordinated mononuclear iron center involving three histidines (His 86 , His 88 , and His 140 ) and a water molecule. Attempts to acquire a structure with bound ligand using either cocrystallization or soaking crystals with cysteine revealed the formation of a mixed disulfide involving Cys 164 near the active site, which may explain previously observed substrate inhibition. This work provides a framework for understanding the molecular mechanisms involved in thiol dioxygenation and sets the stage for exploration of the chemistry of both the novel mononuclear iron center and the catalytic role of the cysteinyl-tyrosine linkage.The cytosolic enzyme cysteine dioxygenase (CDO) 3 (EC 1.13.11.20) catalyzes the irreversible oxidation of cysteine to cysteine sulfinate (Reaction 1). This reaction is required for a variety of critical metabolic pathways (1). CDO initiates the catabolism of cysteine to pyruvate and sulfate, which is essential for the provision of adequate inorganic sulfate and allows pyruvate to enter central pathways of metabolism. Also, the oxidation and excretion of the sulfur of methionine depends on CDO, because the sulfur atoms of methionine and homocysteine are only oxidized after their transfer, via the transsulfuration pathway, to serine to yield cysteine. In addition, CDO activity is essential for the biosynthesis of taurine, which is formed by the decarboxylation of cysteine sulfinate to hypotaurine and further oxidation of hypotaurine to taurine.Clinical evidence indicates that a block in cysteine catabolism, thought to be at CDO, leads to an altered cysteine to sulfate ratio that is associated with sulfate depletion and other adverse effects (1). The prevalence of impaired cysteine catabolism has been reported to be increased in patient populations afflicted with rheumatoid arthritis, liver diseases, Parkinson disease, Alzheimer disease, motor neuron disease, and systemic lupus erythematosus (2-5). These patients frequently exhibit low levels of sulfate in plasma (and in synovial fluid), elevated fasting plasma cysteine concentrations, elevated plasma cysteine to sulfate ratios, and an impaired capacity for sulfation reactions in...

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confidence: 99%

Crystal Structure of Mammalian Cysteine Dioxygenase

Simmons

Liu

Huang

et al. 2006

Journal of Biological Chemistry

156

107

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“…Elevated levels of cysteine have been shown to be both cytotoxic and neurotoxic (18,27,30), and high levels of total plasma cysteine have recently been found to be associated with increased risk for cardiovascular disease, adverse pregnancy outcome, and a more oxidative redox environment (14, 15). Evidence also exists that low levels of CDO can result in low rates of inorganic sulfate release from sulfur amino acids and, hence, impaired sulfation reactions (7,8,13), and low or absent CDO activity is clearly the basis of the requirement of some species for dietary taurine (38).Our previous work has demonstrated that hepatic CDO mRNA levels and the association of CDO mRNA with polysomes do not change with increases in sulfur amino acid intake, whereas CDO concentration and activity increase in …”

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confidence: 99%

“…Additionally, the high cysteine-to-cystine ratio maintained by the intestine facilitates the uptake of cysteine by the liver via neutral amino acid transport systems (11,12). The robust response of hepatic CDO in response to dietary intake, along with the high K m of the liver isozyme of methionine adenosyltransferase, provides for rapid removal of excess sulfur amino acids along with maintenance of a sufficiently high cellular cysteine level to ensure adequate rates of synthesis of glutathione, coenzyme A, and proteins.Normal regulation of cysteine metabolism appears to play an important role in health, because high levels of cysteine and low levels of sulfate, and reportedly low CDO activity, have been associated with the occurrence of rheumatoid arthritis and several neurological diseases (7,8,13,16,22). Elevated levels of cysteine have been shown to be both cytotoxic and neurotoxic (18,27,30), and high levels of total plasma cysteine have recently been found to be associated with increased risk for cardiovascular disease, adverse pregnancy outcome, and a more oxidative redox environment (14, 15).…”

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confidence: 99%

The ubiquitin-proteasome system is responsible for cysteine-responsive regulation of cysteine dioxygenase concentration in liver

Stipanuk

Hirschberger

Londono

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Hepatic cysteine dioxygenase (CDO) activity is a critical regulator of cellular cysteine concentration and availability of cysteine for anabolic processes and is markedly higher in animals fed diets containing excess sulfur amino acids compared with those fed levels at or below the requirement. Rat hepatocytes responded to a deficiency or excess of cysteine in the culture medium with a decrease or increase in CDO level but no change in CDO mRNA level. The cysteine analog, cysteamine, but not cysteine metabolites or thiol reagents, was also effective in increasing CDO. Inhibitors of the 26S proteasome blocked CDO degradation in cysteine-deficient cells but had little or no effect on CDO concentration in hepatocytes cultured with excess cysteine. High-molecular-mass CDO-ubiquitin conjugates were observed in cells cultured in cysteine-deficient medium, whether or not proteasome inhibitor was present, but these CDO-ubiquitin conjugates were not observed in cells cultured in cysteine-supplemented medium with or without proteasome inhibitor. Similar results were observed for degradation of recombinant CDO expressed in human heptocarcinoma cells cultured in cysteine-deficient or cysteine-supplemented medium. CDO is an example of a mammalian enzyme that is robustly regulated via its substrate, with the presence of substrate blocking the ubiquitination of CDO and, hence, the targeting of CDO for proteasomal degradation. This regulation occurs in primary hepatocytes in a manner that corresponds with changes observed in intact animals.hepatocytes; protein degradation; sulfur amino acids CYSTEINE DIOXYGENASE (CDO, EC 1.13.11.20) is an Fe 2ϩ metalloenzyme that adds molecular oxygen to the thiol group of cysteine to form cysteinesulfinate. CDO is a unique and highly conserved protein that has a limited tissue distribution, being expressed predominantly in liver, with lower levels in kidney, lung, and brain (23,39). By catalyzing the first step in the oxidative metabolism of cysteine, CDO plays a key role in cysteine catabolism, in provision of cysteine carbon for gluconeogenesis or oxidative metabolism, in taurine synthesis, and in supply of inorganic sulfur for sulfation reactions. Furthermore, because of its robust regulation in response to cysteine intake or supply, CDO plays a central role in controlling cellular and body cysteine concentrations (3,4,40).Hepatic CDO is regulated in response to diet (1-4, 10, 40). Marked increases in CDO level of ϳ35-fold occur when the amount of dietary protein or sulfur amino acids is increased from below-requirement levels to above-requirement levels (1-4, 40). CDO activity is barely detectable in liver of rats fed low-protein diets, but CDO activity increases up to ϳ6 nmol⅐min Ϫ1 ⅐mg protein Ϫ1 in rats fed diets containing high levels of protein, methionine, or cystine. Hepatic cysteine concentration, measured in fasted rats, increased stepwise with increments in dietary protein, from 0.02 mol/g in rats fed a 100 g casein/kg diet to 0.08 mol/g in rats fed a 400 g casein/kg diet, but i...

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“…Intracellular hydrogen sulfide accumulation may impair mitochondrial function and cause cytotoxicity in certain sensitive organs (48,49). It has been suggested that several human diseases may also be potentially linked to decreased CDO1 activities (50)(51)(52). In contrast, liver-specific Cdo1-knockout mice were phenotypically normal, did not show taurine deficiency, and appeared to have an increased hepatic free cysteine pool and increased GSH levels (53).…”

Section: Discussionmentioning

confidence: 99%