Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease

Mt, Heafield; Fearn, Shirley J.; Steventon, Glyn B.; Waring, R. H.; Williams, Ann C.; Sg, Sturman

doi:10.1016/0304-3940(90)90814-p

Cited by 415 publications

(214 citation statements)

References 14 publications

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“…C NMR Analysis-PA2602 (200 M) was incubated for 30 min in 10 mM phosphate buffer (pH 7.5) at 37°C in the presence of 10 mM 3-MPA. The solution was diluted 6.5-fold and measured by nuclear magnetic resonance (NMR) using a TSP-d4-capillary for 1 H NMR 500-MHz and 13 C NMR 125-MHz analysis at 25°C on a Varian 500-MHz AR NMR spectrometer using VNMRJ 2.3A software. 1 H NMR and 13 C NMR spectra of 3-SPA dissolved in D 2 O served as reference spectra for enzymatically produced 3-SPA.…”

Section: Quantitative Assessment Of 3-mpa Dioxygenase Activity Of Pa2mentioning

confidence: 99%

“…The solution was diluted 6.5-fold and measured by nuclear magnetic resonance (NMR) using a TSP-d4-capillary for 1 H NMR 500-MHz and 13 C NMR 125-MHz analysis at 25°C on a Varian 500-MHz AR NMR spectrometer using VNMRJ 2.3A software. 1 H NMR and 13 C NMR spectra of 3-SPA dissolved in D 2 O served as reference spectra for enzymatically produced 3-SPA. Considering the relatively high concentrations of reactants used in this experiment, the possibility of 3-MPA autoxidation to 3-MPA disulfide was investigated.…”

Section: Quantitative Assessment Of 3-mpa Dioxygenase Activity Of Pa2mentioning

confidence: 99%

“…High cysteine levels have been implicated in a number of neurodegenerative diseases due to its exitotoxic effect in the nervous system (8 -12). Accumulation of cysteine has been attributed to impaired function of cysteine dioxygenase (CDO) 5 (9,(13)(14)(15), an enzyme catalyzing dioxygenation of cysteine thiolate to sulfinate (CSA) (16 -21). Functional CDO occurs widely and has been identified in mammals, lower eukaryotes and in bacteria (21)(22)(23).…”

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confidence: 99%

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The Cysteine Dioxygenase Homologue from Pseudomonas aeruginosa Is a 3-Mercaptopropionate Dioxygenase

Tchesnokov

Fellner

Siakkou

et al. 2015

Journal of Biological Chemistry

117

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Background: Thiol dioxygenation is catalyzed by enzymes specific for each substrate. Results: Kinetic, structural, and spectroscopic data describe an enzyme from P. aeruginosa that is a 3-mercaptopropionate dioxygenase with secondary cysteine dioxygenase activity. Conclusion: An arginine to glutamine switch and the absence of a cis-peptide bond correlate with substrate preference. Significance: Characterization of this enzyme deepens our understanding of substrate specificity in thiol dioxygenases.

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Section: Quantitative Assessment Of 3-mpa Dioxygenase Activity Of Pa2mentioning

confidence: 99%

Section: Quantitative Assessment Of 3-mpa Dioxygenase Activity Of Pa2mentioning

confidence: 99%

mentioning

confidence: 99%

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The Cysteine Dioxygenase Homologue from Pseudomonas aeruginosa Is a 3-Mercaptopropionate Dioxygenase

Tchesnokov

Fellner

Siakkou

et al. 2015

Journal of Biological Chemistry

117

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“…dition, individuals with low blood sulfate levels have a reduced capacity to sulfonate APAP. [31][32][33][34][35] Hyposulfatemia has been found in the neurological diseases Alzheimer's, Parkinson's, motor neuron disease, and autism. 33,34 However, the etiology of hyposulfatemia in these disorders is not yet known.…”

Section: So 4 2ϫ mentioning

confidence: 99%

“…[31][32][33][34][35] Hyposulfatemia has been found in the neurological diseases Alzheimer's, Parkinson's, motor neuron disease, and autism. 33,34 However, the etiology of hyposulfatemia in these disorders is not yet known. Taken together, these findings underscore the essential role of sulfate in the detoxification of APAP and warrant further studies of APAP toxicity in individuals with loss-of-function polymorphisms in the NaS1 gene.…”

Section: So 4 2ϫ mentioning

confidence: 99%

Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen-induced hepatotoxicity

et al. 2006

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Sulfate is required for detoxification of xenobiotics such as acetaminophen (APAP), a leading cause of liver failure in humans. The NaS1 sulfate transporter maintains blood sulfate levels sufficiently high for sulfonation reactions to work effectively for drug detoxification. In the present study, we identified two loss-of-function polymorphisms in the human NaS1 gene and showed the Nas1-null mouse to be hypersensitive to APAP hepatotoxicity. APAP treatment led to increased liver damage and decreased hepatic glutathione levels in the hyposulfatemic Nas1-null mice compared with that in normosulfatemic wild-type mice. Analysis of urinary APAP metabolites revealed a significantly lower ratio of APAP-sulfate to APAPglucuronide in the Nas1-null mice. These results suggest hyposulfatemia increases sensitivity to APAP-induced hepatotoxicity by decreasing the sulfonation capacity to metabolize APAP. In conclusion, the results of this study highlight the importance of plasma sulfate level as a key modulator of acetaminophen metabolism and suggest that individuals with reduced NaS1 sulfate transporter function would be more sensitive to hepatotoxic agents. A cetaminophen (APAP; N-acetyl-p-aminophenol)-induced liver disease is the leading cause of drug-related liver failure in humans. 1 High APAP doses cause: 1) rapid depletion of GSH, 2) saturation of the sulfonation and glucuronidation pathways, and 3) increased production (and longer half-life) of the toxic reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which consequently leads to cellular damage and death. 2 Liver injury associated with high doses of APAP shows a marked dose threshold because of the protective action of hepatic GSH. 3 A decreased capacity to metabolize APAP by sulfonation could put more pressure on the existing GSH pool and hence lower the APAP dose threshold for liver injury. Sulfate conjugation (sulfonation), a major step in the metabolism of APAP in humans, relies on the availability of inorganic sulfate (SO 4 2Ϫ ) and its universal sulfonate donor 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS). 4 SO 4 2Ϫ is obtained directly from the diet and from the oxidation of sulfur containing amino acids, cysteine, and methionine. 4 Because of its hydrophilicity, SO 4 2Ϫ needs to enter cells via plasma membrane sulfate transporters. 4 We cloned a kidney sulfate transporter, NaS1, which is expressed on the brush border membrane of renal proximal tubular epithelial cells, where it is involved in the first step of SO 4 2Ϫ reabsorption. 5 Recently, we generated NaS1-null (Nas1 Ϫ/Ϫ ) mice, which have very low (Ϸ0.2 mmol/L) serum sulfate levels compared to those (Ϸ1 mmol/L) in wild-type (Nas1 ϩ/ϩ ) mice. 6 In this study, we identified two loss-of-function polymorphisms in the human NaS1 gene and characterized the Nas1 Ϫ/Ϫ mouse showing increased APAP hepatotoxicity, suggesting disturbed NaS1 function produces hyposulfatemia that leads to increased drug-induced liver damage. From the Materials and Methods Xenopus laevis

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Olfaction in Neurodegenerative Disease

Mesholam¹,

Moberg²,

Mahr³

et al. 1998

Arch Neurol

576

153

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Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease

Cited by 415 publications

References 14 publications

The Cysteine Dioxygenase Homologue from Pseudomonas aeruginosa Is a 3-Mercaptopropionate Dioxygenase

The Cysteine Dioxygenase Homologue from Pseudomonas aeruginosa Is a 3-Mercaptopropionate Dioxygenase

Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen-induced hepatotoxicity

Olfaction in Neurodegenerative Disease

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