Cysteine Abstracts 1

Cystathionine beta synthase modulates senescence of human endothelial cells

            (Albertini, Koziel et al. 2012) Download

Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescencein vitro, involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease.

N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency

            (Atkuri, Mantovani et al. 2007) Download

Glutathione (GSH) deficiency is associated with numerous pathological conditions. Administration of N-acetylcysteine (NAC), a cysteine prodrug, replenishes intracellular GSH levels. NAC, best known for its ability to counter acetaminophen toxicity, is a safe, well-tolerated antidote for cysteine/GSH deficiency. NAC has been used successfully to treat GSH deficiency in a wide range of infections, genetic defects and metabolic disorders, including HIV infection and COPD. Over two-thirds of 46 placebo-controlled clinical trials with orally administered NAC have indicated beneficial effects of NAC measured either as trial endpoints or as general measures of improvement in quality of life and well-being of the patients.

Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?

         (Droge 2005) Download

Reactive oxygen species (ROS) are constantly produced in biological tissues and play a role in various signalling pathways. Abnormally high ROS concentrations cause oxidative stress associated with tissue damage and dysregulation of physiological signals. There is growing evidence that oxidative stress increases with age. It has also been shown that the life span of worms, flies and mice can be significantly increased by mutations which impede the insulin receptor signalling cascade. Molecular studies revealed that the insulin-independent basal activity of the insulin receptor is increased by ROS and downregulated by certain antioxidants. Complementary clinical studies confirmed that supplementation of the glutathione precursor cysteine decreases insulin responsiveness in the fasted state. In several clinical trials, cysteine supplementation improved skeletal muscle functions, decreased the body fat/lean body mass ratio, decreased plasma levels of the inflammatory cytokine tumour necrosis factor alpha (TNF-alpha), improved immune functions, and increased plasma albumin levels. As all these parameters degenerate with age, these findings suggest: (i) that loss of youth, health and quality of life may be partly explained by a deficit in cysteine and (ii) that the dietary consumption of cysteine is generally suboptimal and everybody is likely to have a cysteine deficiency sooner or later.

Cystathionine beta-synthase deficiency causes fat loss in mice

            (Gupta and Kruger 2011) Download

Cystathionine beta synthase (CBS) is the rate-limiting enzyme responsible for the de novo synthesis of cysteine. Patients with CBS deficiency have greatly elevated plasma total homocysteine (tHcy), decreased levels of plasma total cysteine (tCys), and often a marfanoid appearance characterized by thinness and low body-mass index (BMI). Here, we characterize the growth and body mass characteristics of CBS deficient TgI278T Cbs(-/-) mice and show that these animals have significantly decreased fat mass and tCys compared to heterozygous sibling mice. The decrease in fat mass is accompanied by a 34% decrease in liver glutathione (GSH) along with a significant decrease in liver mRNA and protein for the critical fat biosynthesizing enzyme Stearoyl CoA desaturase-1 (Scd-1). Because plasma tCys has been positively associated with fat mass in humans, we tested the hypothesis that decreased tCys in TgI278T Cbs(-/-) mice was the cause of the lean phenotype by placing the animals on water supplemented with N-acetyl cysteine (NAC) from birth to 240 days of age. Although NAC treatment in TgI278T Cbs(-/-) mice caused significant increase in serum tCys and liver GSH, there was no increase in body fat content or in liver Scd-1 levels. Our results show that lack of CBS activity causes loss of fat mass, and that this effect appears to be independent of low serum tCys.

A deficiency of cysteine impairs fibrillin-1 deposition: implications for the pathogenesis of cystathionine beta-synthase deficiency

            (Majors and Pyeritz 2000) Download

Cystathionine beta-synthase (CBS) deficiency is an inborn error of amino acid metabolism that has pleiotropic manifestations and is commonly called "homocystinuria." The features include skeletal, ocular, and vascular defects, some of which are reminiscent of those found in Marfan syndrome (MFS). Because of the spectrum of clinical effects, the pathogenesis of homocystinuria has long been thought to involve the extracellular matrix (ECM), and the condition has been classified as a heritable disorder of connective tissue. Because of the superficial similarities with MFS, we and others (Pyeritz, in McKusicks Heritable Disorders of Connective Tissue, St. Louis, Mosby-Year Book Inc., 5th ed., pp 137-178, 1993; Pyeritz, in Principles and Practice of Medical Genetics, New York, Churchill Livingstone, 3rd ed., pp 1027-1066, 1997; Mudd, Levy, and Skovby, in The Metabolic and Molecular Bases of Inherited Disease, New York, McGraw-Hill Publishing Co., 7th ed., pp 1279-1327, 1995) have speculated how CBS deficiency might affect fibrillin-1, the protein altered in MFS. For example, the altered plasma concentrations of homocysteine and/or cysteine in patients with CBS deficiency may hinder fibrillin-1 synthesis, deposition, or both. When arterial smooth muscle cells were cultured under conditions of cysteine deficiency, fibrillin-1 deposition into the ECM was greatly diminished as revealed by immunocytochemistry. Excessive homocysteine, in contrast, had little, if any, effect on fibrillin-1 deposition. When cysteine concentrations were returned to normal, the smooth muscle cells began to accumulate a matrix rich in fibrillin-1. Type I collagen, the major matrix component synthesized by these smooth muscle cells, was not reduced by low cysteine concentrations nor high homocysteine concentrations. These results demonstrate that a deficiency of cysteine and subsequent inhibition of fibrillin-1 accumulation in CBS deficient patients may be at least partly responsible for their phenotype, and suggest that maintenance of normal plasma cyst(e)ine levels may be an important therapeutic goal.

Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans

            (Mannery, Ziegler et al. 2010) Download

Variations in plasma sulfur amino acid (SAA) pools are associated with disease risks, but little information is available about the factors affecting plasma SAA pools. Drug metabolism by glutathione (GSH) and sulfate conjugation can, in principle, represent a quantitatively important burden on SAA supply. The present study was designed to determine whether therapeutic doses of acetaminophen (APAP) alter SAA metabolism in healthy human adults. A double-blind, crossover design incorporating four treatment periods with diets providing 100% of the recommended dietary allowance (RDA) for SAA without or with APAP (15 mg/kg) and 0% RDA for SAA without or with APAP, in randomized order. After a 3-day equilibration period, chemically defined diets with 100 or 0% RDA for SAA were given for 2 complete days. On day 3, APAP or placebo was given in two successive doses (6-h interval), and timed plasma samples were collected. With SAA intake at 100% RDA, APAP administration oxidized the plasma cysteine/cystine redox potential (E(h)CySS) but not the plasma GSH/GSSG redox potential (E(h)GSSG). The extent of oxidation caused by APAP was similar to that seen with 0% SAA and no APAP. However, APAP administration with 0% SAA did not cause further oxidation beyond APAP or 0% SAA alone. In contrast, an oxidation of the plasma E(h)GSSG was apparent for SAA insufficiency only with APAP. The results suggest a need to evaluate possible effects of APAP in association with SAA insufficiency as a contributing factor in disease risk.

Oxidation of the glutathione/glutathione disulfide redox state is induced by cysteine deficiency in human colon carcinoma HT29 cells

            (Miller, Watson et al. 2002) Download

Glutathione (GSH) has a central role in the maintenance of the thiol-disulfide redox state in mammalian cells. GSH synthesis can be physiologically limited by the availability of cysteine (Cys), and Cys and its precursors are variable in the human diet. The purpose of this study was to determine the effect of severe Cys deficiency and readdition of Cys on the redox state of the GSH/glutathione disulfide (GSSG) pool in human colon carcinoma HT29 cells. Cells were cultured in Cys- (and cystine-)limiting medium for 48 h followed by culture in medium containing either Cys or cystine for 24 h. GSH and GSSG were measured by HPLC. Cys limitation decreased cellular GSH and GSSG concentrations with an associated >80 mV oxidation of the GSH/GSSG redox state. Upon addition of either Cys or its disulfide cystine (CySS), redox of GSH/GSSG recovered in 4 h, whereas GSH concentration continued to increase over 12 h. Maximal GSH concentrations attained were 200% of control cell values. These results show that severe Cys deficiency can have marked effects on cellular redox state but that redox recovers rapidly upon resupply. The magnitude of oxidation during Cys limitation in this cell model is sufficient to result in a >100-fold change in the reduced/oxidized ratio of redox-sensitive dithiol/disulfide motifs in proteins. If redox changes occur in vivo in association with variations in dietary Cys and its precursors, these changes could have important physiologic effects through altered redox signaling and control of cell proliferation and apoptosis.

Are we getting enough sulfur in our diet?

         (Nimni, Han et al. 2007) Download

Sulfur, after calcium and phosphorus, is the most abundant mineral element found in our body. It is available to us in our diets, derived almost exclusively from proteins, and yet only 2 of the 20 amino acids normally present in proteins contains sulfur. One of these amino acids, methionine, cannot be synthesized by our bodies and therefore has to be supplied by the diet. Cysteine, another sulfur containing amino acid, and a large number of key metabolic intermediates essential for life, are synthesized by us, but the process requires a steady supply of sulfur.Proteins contain between 3 and 6% of sulfur amino acids. A very small percentage of sulfur comes in the form of inorganic sulfates and other forms of organic sulfur present in foods such as garlic, onion, broccoli, etc.The minimal requirements (RDA) for all the essential amino acids have always been estimated in terms of their ability to maintain a nitrogen balance. This method asses amino acid requirements for protein synthesis, only one of the pathways that methionine follows after ingestion. To adequately evaluate the RDA for methionine, one should perform, together with a nitrogen balance a sulfur balance, something never done, neither in humans nor animals.With this in mind we decided to evaluate the dietary intake of sulfur (as sulfur amino acids) in a random population and perform sulfur balance studies in a limited number of human volunteers. Initially this was done to try and gain some information on the possible mode of action of a variety of sulfur containing compounds (chondroitin sulfate, glucosamine sulfate, and others, ) used as dietary supplements to treat diseases of the joints. Out of this study came information that suggested that a significant proportion of the population that included disproportionally the aged, may not be receiving sufficient sulfur and that these dietary supplements, were very likely exhibiting their pharmacological actions by supplying inorganic sulfur.


Albertini, E., R. Koziel, et al. (2012). "Cystathionine beta synthase modulates senescence of human endothelial cells." Aging (Albany NY) 4(10): 664-73 PMID: 23117410

Atkuri, K. R., J. J. Mantovani, et al. (2007). "N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency." Curr Opin Pharmacol 7(4): 355-9 PMID: 17602868

Droge, W. (2005). "Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?" Philos Trans R Soc Lond B Biol Sci 360(1464): 2355-72 PMID: 16321806

Gupta, S. and W. D. Kruger (2011). "Cystathionine beta-synthase deficiency causes fat loss in mice." PLoS One 6(11): e27598 PMID: 22096601

Majors, A. K. and R. E. Pyeritz (2000). "A deficiency of cysteine impairs fibrillin-1 deposition: implications for the pathogenesis of cystathionine beta-synthase deficiency." Mol Genet Metab 70(4): 252-60 PMID: 10993712

Mannery, Y. O., T. R. Ziegler, et al. (2010). "Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans." J Pharmacol Exp Ther 333(3): 939-47 PMID: 20207721

Miller, L. T., W. H. Watson, et al. (2002). "Oxidation of the glutathione/glutathione disulfide redox state is induced by cysteine deficiency in human colon carcinoma HT29 cells." J Nutr 132(8): 2303-6 PMID: 12163679

Nimni, M. E., B. Han, et al. (2007). "Are we getting enough sulfur in our diet?" Nutr Metab (Lond) 4: 24 PMID: 17986345