Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur

Abstract

Synthesis of cysteine as a product of the transsulfuration pathway can be viewed as part of methionine or homocysteine degradation, with cysteine being the vehicle for sulfur conversion to end products (sulfate, taurine) that can be excreted in the urine. Transsulfuration is regulated by stimulation of cystathionine β-synthase and inhibition of methylene tetrahydrofolate reductase in response to changes in the level of S-adenosylmethionine, and this promotes homocysteine degradation when methionine availability is high. Cysteine is catabolized by several desulfuration reactions that release sulfur in a reduced oxidation state, generating sulfane sulfur or hydrogen sulfide (H₂S), which can be further oxidized to sulfate. Cysteine desulfuration is accomplished by alternate reactions catalyzed by cystathionine β-synthase and cystathionine γ-lyase. Cysteine is also catabolized by pathways that require the initial oxidation of the cysteine thiol by cysteine dioxygenase to form cysteinesulfinate. The oxidative pathway leads to production of taurine and sulfate in a ratio of approximately 2:1. Relative metabolism of cysteine by desulfuration versus oxidative pathways is influenced by cysteine dioxygenase activity, which is low in animals fed low-protein diets and high in animals fed excess sulfur amino acids. Thus, desulfuration reactions dominate when cysteine is deficient, whereas oxidative catabolism dominates when cysteine is in excess. In rats consuming a diet with an adequate level of sulfur amino acids, about two thirds of cysteine catabolism occurs by oxidative pathways and one third by desulfuration pathways. Cysteine dioxygenase is robustly regulated in response to cysteine availability and may function to provide a pathway to siphon cysteine to less toxic metabolites than those produced by cysteine desulfuration reactions.

Fig. 1

Transsulfuration pathway for homocysteine degradation and cysteine synthesis

Fig. 2

Overview of cysteine sulfur metabolism

Fig. 3

The cysteinesulfinate-dependent pathway of cysteine metabolism

Fig. 4

Distribution of cysteine dioxygenase (CDO), cysteinesulfinate decarboxylase (CSD), cystathionine γ-lyase (CSE), and cystathionine β-synthase (CBS) in murine tissues. Western blots of the soluble fraction of mouse tissue homogenates are shown. The CDO antibody was raised against rat CDO, and the CSD antibody was a gift from Dr. Marcel Tappaz (Institut National de la Santé et de la Recherche Médicale). Antibody for immunoblotting of CSE was obtained from Norvus Biologicals LLC, and antibody for CBS was obtained from Proteintech Group, Inc. Equal amounts of total protein (50 μg) were loaded per lane

Fig. 5

Overview of the regulation of cysteine dioxygenase (CDO) in response to changes in intracellular cysteine levels. Elevated cysteine levels promote protein cofactor formation, which increases catalytic efficiency (k_cat/K_m) and enzyme stability. Low cysteine levels promote ubiquitination and proteasomal degradation of CDO

Fig. 6

Estimates for cysteinesulfinate-dependent and cysteinesulfinate-independent catabolism of cysteine (Cys) by freshly isolated hepatocytes from rats that had been fed diets with different levels of sulfur-containing amino acids (SAAs). Diets and the total grams of methionine equivalents [1 g Cys=1.23 g methionine (Met)] per kilogram diet are shown in the legend. Based on the data of Bagley and Stipanuk (1995) for hepatocytes incubated in vitro with 0.2 mM Cys or 0.2 mM cysteinesulfinate. Values are the mean ± standard error of mean (SEM) for hepatocyte preparations from six to seven rats. Values (bars) not designated by the same letter are significantly different at P≤0.05 by analysis of variance (ANOVA) and Dunnett’s test. Estimates of Cys catabolism by Cys desulfuration were determined by difference. The bar graph shows values as actual flux through each route. The pie chart shows relative flux as a percentage of total Cys catabolism [white = cysteine sulfinic acid (CSA)- or cysteine dioxygenase (CDO)-dependent catabolism to taurine + sulfate; black = CSA-independent catabolism to sulfate via desulfuration]

Fig. 7

Estimates of cysteinesulfinate-dependent catabolism of cysteine (Cys) in intact rats fed either a basal low sulfur-containing amino acid (SAA) diet or an adequate SAA diet. Values for hepatic cysteine dioxygenase (CDO) activity are from Bella et al. (1999a). Estimates of cysteinesulfinate-dependent catabolism of Cys are based on the urinary excretion of sulfur metabolites (taurine and sulfate) in urine of rats, as reported by Bella et al. (1999a), and estimates of cysteinesulfinate partitioning are calculated from the data of Bagley and Stipanuk (1995) and Stipanuk and Rotter (1984). Values are mean ± standard error of mean (SEM) for six to seven rats