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

Bella, Deborah; Hahn, Christoph; Stipanuk, Martha H.

doi:10.1152/ajpendo.1999.277.1.e144

Cited by 48 publications

(66 citation statements)

References 23 publications

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“…In the wild-type animal, hepatic metabolism of cysteine is responsible for the majority of taurine synthesis (3,4,13). In the CDO Ϫ/Ϫ mouse, tissue and plasma taurine concentrations were reduced to less than 10% of wild-type levels (30).…”

Section: Discussionmentioning

confidence: 99%

Extrahepatic tissues compensate for loss of hepatic taurine synthesis in mice with liver-specific knockout of cysteine dioxygenase

Ueki

Roman

Hirschberger

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Because hepatic cysteine dioxygenase (CDO) appears to play the major role in controlling cysteine catabolism in the intact rat, we characterized the effect of a lack of hepatic CDO on the regulation of cysteine and its metabolites at the whole body level. In mice with liver-specific deletion of CDO expression, hepatic and plasma cysteine levels increased. In addition, in mice with liver-specific deletion of CDO expression, the abundance of CDO and the proportion of CDO existing as the mature, more active isoform increased in extrahepatic tissues that express CDO (kidney, brown fat, and gonadal fat). CDO abundance was also increased in the pancreas, where most of the enzyme in both control and liver CDO-knockout mice was in the more active isoform. This upregulation of CDO concentration and active-site cofactor formation were not associated with an increase in CDO mRNA and thus presumably were due to a decrease in CDO degradation and an increase in CDO cofactor formation in association with increased exposure of extrahepatic tissues to cysteine in mice lacking hepatic CDO. Extrahepatic tissues of liver CDO-knockout mice also had higher levels of hypotaurine, consistent with increased metabolism of cysteine by the CDO/cysteinesulfinate decarboxylase pathway. The hepatic CDO-knockout mice were able to maintain normal levels of glutathione, taurine, and sulfate. The maintenance of taurine concentrations in liver as well as in extrahepatic tissues is particularly notable, since mice were fed a taurine-free diet and liver is normally considered the major site of taurine biosynthesis. This redundant capacity for regulation of cysteine concentrations and production of hypotaurine/taurine is additional support for the body's robust mechanisms for control of body cysteine levels and indicates that extrahepatic tissues are able to compensate for a lack of hepatic capacity for cysteine catabolism.

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Section: Discussionmentioning

confidence: 99%

Extrahepatic tissues compensate for loss of hepatic taurine synthesis in mice with liver-specific knockout of cysteine dioxygenase

Ueki

Roman

Hirschberger

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…2) (6,15,23). With the recent discovery of a cross-linked cofactor in the active site of CDO, we hypothesized that the difference in migration could be due to two separate populations of CDO protein as follows: one population containing the internal cross-link and the other lacking the cross-link.…”

Section: Resolution Of Non-cofactor-and Cofactor-containing Species Omentioning

confidence: 99%

“…Cofactor Biosynthesis Depends upon Substrate and Catalytic Turnover-Several previous studies have demonstrated that the lower cofactor-containing band of hepatic CDO protein is highly expressed when rats are fed diets that are rich in cysteine or cysteine precursors (6,23). We further examined the course of this expression in vivo by switching rats that had been sustained for 14 days on a low protein diet (i.e.…”

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confidence: 99%

Synthesis of Amino Acid Cofactor in Cysteine Dioxygenase Is Regulated by Substrate and Represents a Novel Post-translational Regulation of Activity

Dominy

Hwang

Guo

et al. 2008

Journal of Biological Chemistry

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110

169

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Cysteine dioxygenase (CDO) catalyzes the conversion of cysteine to cysteinesulfinic acid and is important in the regulation of intracellular cysteine levels in mammals and in the provision of oxidized cysteine metabolites such as sulfate and taurine. Several crystal structure studies of mammalian CDO have shown that there is a cross-linked cofactor present in the active site of the enzyme. The cofactor consists of a thioether bond between the ␥-sulfur of residue cysteine 93 and the aromatic side chain of residue tyrosine 157. The exact requirements for cofactor synthesis and the contribution of the cofactor to the catalytic activity of the enzyme have yet to be fully described. In this study, therefore, we explored the factors necessary for cofactor biogenesis in vitro and in vivo and examined what effect cofactor formation had on activity in vitro. Like other cross-linked cofactorcontaining enzymes, formation of the Cys-Tyr cofactor in CDO required a transition metal cofactor (Fe 2؉ ) and O 2 . Unlike other enzymes, however, biogenesis was also strictly dependent upon the presence of substrate. Cofactor formation was also appreciably slower than the rates reported for other enzymes and, indeed, took hundreds of catalytic turnover cycles to occur. In the absence of the Cys-Tyr cofactor, CDO possessed appreciable catalytic activity, suggesting that the cofactor was not essential for catalysis. Nevertheless, at physiologically relevant cysteine concentrations, cofactor formation increased CDO catalytic efficiency by ϳ10-fold. Overall, the regulation of Cys-Tyr cofactor formation in CDO by ambient cysteine levels represents an unusual form of substrate-mediated feed-forward activation of enzyme activity with important physiological consequences.Recent biochemical and crystallographic studies have revealed that some enzymes contain unusual modifications to the amino acid residues residing within their active sites. Also known as amino acid-derived cofactors, these altered residues represent a new and exciting area for research in the field of protein post-translational modifications. Unlike other posttranslational modifications, which are made by attaching extrinsic molecules onto target proteins through reactions that are specifically catalyzed by third party enzymes, amino acid cofactors are generated directly from the amino acids within the proteins that contain them and are required for the production of fully competent enzymes (1, 2). From a biological perspective, amino acid-derived cofactors are significant because they can create novel structural motifs within the enzyme active site as well as alter the chemical properties of the unmodified parent amino acid residues and thus expand the otherwise limited range of catalytic reactions in which the common amino acids can participate.One recent addition to the list of enzymes known to contain an amino acid cofactor is cysteine dioxygenase (CDO).3 CDO is an iron (Fe 2ϩ )-dependent thiol dioxygenase that uses molecular oxygen to oxidize the sulfhydryl group of cys...

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“…Additionally, in vivo kinetic experiments in normal adults have shown that GSH turnover is suppressed by diets deficient in sulfur amino acids (28) and by diets with marginal amounts of protein (21). Similarly, in animal models, dietary deficiencies of the precursor amino acids, especially cysteine, resulted in decreased GSH concentrations (4,10,15,24). Therefore, it is plausible that substrate availability may constrain the in vivo synthesis of GSH in SCD, resulting in low GSH concentrations.…”

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confidence: 99%

In vivo rates of erythrocyte glutathione synthesis in adults with sickle cell disease

Reid

Badaloo²,

Forrester³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Reid, Marvin, Asha Badaloo, Terrence Forrester, and Farook Jahoor. In vivo rates of erythrocyte glutathione synthesis in adults with sickle cell disease. Am J Physiol Endocrinol Metab 291: E73-E79, 2006. First published January 24, 2006 doi:10.1152/ajpendo.00287.2005.-Despite reports of lower GSH concentration in sickle cell disease (SCD), the in vivo kinetic mechanism(s) responsible for GSH deficiency is unknown. To determine whether suppressed synthesis was responsible for the lower erythrocyte GSH concentration, we used a primed intermittent infusion of [ 2 H2]glycine to measure erythrocyte GSH synthesis in vivo in 23 individuals with homozygous ␤ s SCD and 8 healthy controls. Erythrocyte cysteine concentration, the rate-limiting precursor for GSH synthesis, plasma markers of oxidant damage, and dietary intakes of energy and protein were also measured. Compared with values of controls, SCD subjects had significantly lower erythrocyte GSH (P Ͻ 0.04) and cysteine concentrations (P Ͻ 0.004) but significantly faster fractional rates of GSH synthesis (P Ͻ 0.02). The absolute rates of GSH synthesis in SCD subjects compared with control subjects was greater by ϳ57% (P ϭ 0.062). However, the concentrations of markers of oxidative damage, plasma derivatives of reactive oxygen metabolites, plasma nitrotyrosine, urinary isoprostane-to-creatinine ratio, and GSH-to-GSSG ratio, as well as dietary intakes of energy, protein, and GSH precursor amino acids, were not different between SCD subjects and controls. The findings of this study suggest that the lower erythrocyte GSH of SCD patients is not due to suppressed synthesis or impaired regeneration but rather to increased consumption. In addition, the lower erythrocyte cysteine concentration plus the faster rate of GSH synthesis strongly suggest that the endogenous cysteine supply is not sufficient to meet all anabolic demands; hence, cysteine may be a conditionally essential amino acid in individuals with SCD.

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

Cited by 48 publications

References 23 publications

Extrahepatic tissues compensate for loss of hepatic taurine synthesis in mice with liver-specific knockout of cysteine dioxygenase

Extrahepatic tissues compensate for loss of hepatic taurine synthesis in mice with liver-specific knockout of cysteine dioxygenase

Synthesis of Amino Acid Cofactor in Cysteine Dioxygenase Is Regulated by Substrate and Represents a Novel Post-translational Regulation of Activity

In vivo rates of erythrocyte glutathione synthesis in adults with sickle cell disease

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