Spectroscopic and Computational Comparisons of Thiolate-Ligated Ferric Nonheme Complexes to Cysteine Dioxygenase: Second-Sphere Effects on Substrate (Analogue) Positioning

Cysteine levels are carefully regulated in mammals to balance metabolic needs against the potential for cytotoxicity. It has been postulated that one of the major regulators of intracellular cysteine levels in mammals is cysteine dioxygenase (CDO). Hepatic expression of this catabolic enzyme increases dramatically in response to increased cysteine availability and may therefore be part of a homeostatic response to shunt excess toxic cysteine to more benign metabolites such as sulfate or taurine. Direct experimental evidence, however, is lacking to support the hypothesis that CDO is capable of altering steady-state intracellular cysteine levels. In this study, we expressed either the wild-type (WT) or a catalytically inactivated mutant (H86A) isoform of CDO in HepG2/C3A cells (which do not express endogenous CDO protein) and cultured them in different concentrations of extracellular cysteine. WT CDO, but not H86A CDO, was capable of reducing intracellular cysteine levels in cells incubated in physiologically relevant concentrations of cysteine. WT CDO also decreased the glutathione pool and potentiated the toxicity of CdCl2. These results demonstrate that CDO is capable of altering intracellular cysteine levels as well as glutathione levels.

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Substrate Analogue Renin Inhibitors Containing Replacements of Histidine in P2 or Isosteres of the Amide Bond Between P3 and P2 Sites

Advances in Experimental Medicine and Biology - Structure and Function of the Aspartic Proteinases ◽

10.1007/978-1-4684-6012-4_50 ◽

1991 ◽

pp. 387-390 ◽

Cited By ~ 1

Author(s):

P. Raddatz ◽

A. Jonczyk ◽

C. J. Schmitges ◽

J. Sombroek

Keyword(s):

Amide Bond ◽

Renin Inhibitors ◽

Substrate Analogue

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The Stabilizing Protein, Protein-A, of Cysteine Dioxygenase

Advances in Experimental Medicine and Biology - The Biology of Taurine ◽

10.1007/978-1-4899-0405-8_3 ◽

1987 ◽

pp. 29-38 ◽

Cited By ~ 5

Author(s):

Kenji Yamaguchi ◽

Yu Hosokawa

Keyword(s):

Protein A ◽

Cysteine Dioxygenase

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Effects of nonsulfur and sulfur amino acids on the regulation of hepatic enzymes of cysteine metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.1.e144 ◽

1999 ◽

Vol 277 (1) ◽

pp. E144-E153 ◽

Cited By ~ 11

Author(s):

Deborah L. Bella ◽

Christine Hahn ◽

Martha H. Stipanuk

Keyword(s):

Amino Acids ◽

Specific Activity ◽

Mrna Level ◽

Basal Diet ◽

Cysteine Dioxygenase ◽

Sulfur Amino Acids ◽

Subunit Mrna ◽

Cysteine Metabolism ◽

Glutamylcysteine Synthetase

To determine the role of nonsulfur vs. sulfur amino acids in regulation of cysteine metabolism, rats were fed a basal diet or diets supplemented with a mixture of nonsulfur amino acids (AA), sulfur amino acids (SAA), or both for 3 wk. Hepatic cysteine-sulfinate decarboxylase (CSDC), cysteine dioxygenase (CDO), and γ-glutamylcysteine synthetase (GCS) activity, concentration, and mRNA abundance were measured. Supplementation with AA alone had no effect on any of these measures. Supplementation of the basal diet with SAA, with or without AA, resulted in a higher CDO concentration (32–45 times basal), a lower CSDC mRNA level (49–64% of basal), and a lower GCS-heavy subunit mRNA level (70–76%). The presence of excess SAA and AA together resulted in an additional type of regulation: a lower specific activity of all three enzymes was observed in rats fed diets with an excess of AA and SAA. Both SAA and AA played a role in regulation of these three enzymes of cysteine metabolism, but SAA had the dominant effects, and effects of AA were not observed in the absence of SAA.

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