Thomson

Clinical and nutritional benefits of cysteine-enrichedprotein supplementsRobert A. and Gil aCulcairn, New South Wales, Australia and bInstitute of Food Nutrition and Human Health, Massey University, To review recently published research into the use of dietary cysteine and/or its derivatives as functional food supplements that will enhance antioxidant status and Correspondence to Gil Hardy, PhD, FRSC, Institute of improve outcome in certain diseases.
Food Nutrition and Human Health, Massey University,Albany, Auckland 0745, New Zealand Tel: +64 9373 7599 x88402; fax: +64 9367 7192; L-cysteine is now widely recognized as a conditionally essential or (indispensible) sulphur amino acid. It plays a key role in the metabolic pathways involving methionine, Current Opinion in Clinical Nutrition and taurine and glutathione (GSH), and may help fight chronic inflammation by boosting antioxidant status. In stressed and inflammatory states, sulphur amino acid metabolismadapts to meet the increased requirements for cysteine as a rate-limiting substrate forGSH. Critically ill patients receiving enteral or parenteral nutrition, enriched withcysteine, exhibit decreased cysteine catabolism and improved GSH synthesis. Thenaturally occurring cysteine-rich proteins, whey or keratin, have the potential to bemanufactured into high quality, high cysteine-containing functional foods for clinicalinvestigation.
SummaryCysteine-rich proteins, such as keratin, may have advantages over the simple amino acidor its derivatives, as nutraceuticals, to safely and beneficially improve antioxidant statusin health and disease.
Keywordscysteine, glutathione, keratin, oxidative stress Curr Opin Clin Nutr Metab Care 14:562–568ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins Cysteine contributes to many biological pathways, notably those involved in glutathione (GSH), taurine Cysteine, one of only two sulphur-containing amino acids and methionine metabolism. Cysteine metabolites play making up the 22 proteinogenic amino acids, plays a a critical role in antioxidant defenses, which help ame- critical role in cell metabolism. Its unique ability to form liorate chronic inflammation. However, as we age, levels interchain and intrachain disulphide bonds, with other decrease dramatically Cysteine is lacking in many cysteine residues, nonenzymatically, also gives it an diets, and a dietary deficiency has been linked to ageing important role in protein structure and protein folding.
and various diseases. Cysteine can be generated from A transulphurization pathway converts methionine, methionine via S-adenosylmethionine and homocys- via homocysteine to cysteine, by enzymatic action, teine, but this pathway may be inactive in neonates, in the liver, kidney, intestine and pancreas. Many of patients with liver disease, surgical stress and trauma.
the enzymes involved in methionine metabolism areincreased in activity on ingestion of a high protein diet GSH is a tripeptide of glutamate, cysteine and glycine The conversion is an irreversible process and is one of the most abundant, ubiquitous, intracellular which explains why methionine is classified as an essen- peptides, produced intracellularly in all organs. Quanti- tial or indispensible amino acid. Cysteine, on the con- tatively the most important and abundant antioxidant in trary, is dispensible – providing adequate methionine is humans, plentiful GSH is obtained in the diet from fruits available – but has been recently categorized as ‘con- and vegetables, but dietary GSH does not result in ditionally essential’ in certain pathological conditions increased plasma GSH. The majority must be synthes- associated with inflammation. Cysteine has a sparing ized, primarily in the liver. Thence around 80% is effect on methionine metabolism and indirectly increases exported to the plasma and the kidneys for detoxification.
methionine and its metabolites, markedly reducing the GSH synthesis is limited by cysteine availability and activity of the enzyme, glutamate cysteine ligase 1363-1950 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins Cysteine-enriched protein supplements McPherson and Hardy Peroxides increase the transulphurization flux that pro- vides some cysteine for GSH synthesis, whereas anti-oxidants decrease transsulphurization. Boosting GSH  Cysteine and GSH metabolism is impaired in neo- synthesis may aid in ageing, seizure, Alzheimer’s disease, Parkinson’s disease, liver disease, cystic fibrosis, sickle  Enteral nutrition enriched with cysteine can cell anaemia, HIV/AIDS, cancer, stroke, and diabetes decrease cysteine catabolism and improve GSHstatus.
 There is a positive association between plasma Taurine, the most abundant amino acid in vivo, has an cysteine and reduced cysteine redox state after intracellular concentration of 25 mmol/l and may also be ingestion of a diet high in cysteine and methionine.
‘conditionally essential’ for human infants. It is synthes-  Keratin has the highest cysteine content of all ized from cysteine in the liver and brain and is required for natural proteins, and can be processed into a high energy and antioxidant metabolism A person on a quality nutraceutical supplement for clinical investi- meat-eating diet will ingest between 40 and 400 mg taurine daily but vegetarians receive negligible taurine  delivered GSH does not produce elevated plasma GSH, Supplementation with free cysteine and its possibly due to digestive oxidation and degradation.
Likewise, supplementation with taurine can be proble- Dietary supplementation with GSH or cysteine would be matic, with issues of stability, accurate dosage and the the ideal adjunct to many antioxidant therapies, but orally important observation that dietary taurine has only a short Figure 1 Metabolic pathways for cysteine and other sulphur amino acids BHMT, betaine:homocysteine methyltransferase; CBS, cystathionine b-synthase; CGL, cystathionine g-lyase; MAT, methionine adenosyltransferase;MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; SAHH, S-adenosylhomocysteine hydrolase; SHMT, serine hydroxymethyl-transferase. Reproduced with permission from half life in plasma and may not raise plasma taurine and glycine from foods. However, in the early stages of fasting and in metabolic stress, supplies of glutamine,cysteine and methionine are interrupted or reduced Cysteine itself readily oxidizes to the insoluble cystine Consequently, GSH depletion is associated with dimer. Both free cysteine and cystine are toxic at high severity of disease, increased morbidity and mortality.
levels in the diet but dietary cysteine in protein Critically ill patients with MOF and/or chronic obstruc- form as well as cysteine derivatives, largely lack this tive pulmonary disease have depleted GSH, with higher toxicity when included in animal diets and can plasma cysteine levels than in whole blood, indicating a effectively substitute for free cysteine to boost anti- low intracellular concentration. During injury and trauma, oxidant defences. The derivative N-acetyl-cysteine ICU patients exhibit low GSH status and decreased (NAC) has promising bioactivity in vitro and has been muscle protein synthesis, suggesting that there might be trialled with some successes, but thus far, NAC has not an increased requirement for substrates such as cysteine.
lived up to its promise in large-scale controlled clinicaltrials There is considerable debate on whether In stress, muscle is known to serve as an amino acid NAC is effective at all for some conditions as well as a reservoir, delivering substrates for anabolic reactions.
growing recognition that there is a subset of individuals who might be at high risk from side-effects; including enriched with cysteine, appear to exhibit decreased nausea, rash, wheezing, gastrointestinal problems and cysteine catabolism and increased cysteine utilization, reflected by an improved sulphur balance due toincreased GSH synthesis. Oral cysteine supplementation In this review, we highlight current research on dietary at 11 g/kg in septic rats maintains blood GSH status, cysteine and suggest that cysteine-rich proteins, rather improves fractional muscle protein synthesis rates and than free cysteine compounds, may be worthy of further improves recovery This contrasts with NAC supple- study as adjuncts to established therapies and as pre- mentation in HIV/AIDS, in which cysteine and GSH ventatives against inflammatory diseases.
synthesis rates in erythrocytes are normalized, suggestinga different pathogenesis.
The redox mechanisms of cysteine and itsmetabolites A high level of oxidative stress constitutes one of the Sulphur amino acid supplementation reduces the ileal main underlying mechanisms contributing to the patho- and jejunal, but not the colonic GSH/the oxidized dimeric physiology and clinical features of many acute critical form of GSH redox state in resected (mid-jejuno-ileal) but care situations as well as chronic diseases such as AIDS, not control transected (small bowel) rats There was cancer, inflammation, cardiovascular and neurological a reduction in cysteine redox state in resected, but not diseases. Critical illness increases production of reactive control rats, which was accompanied by an increase in oxygen species (ROS) leading to oxidative stress through growth rate in ileal and partially in jejunal, but not in activation of the phagocytic cells of the immune system colonic crypt, indicating that different parts of the intestine and vascular damage caused by ischaemic reperfusion.
respond differently to dietary sulphur amino acids.
Systemic inflammatory response syndrome (SIRS) is a There is a distinct tissue-specific pattern of cysteine significant contributor to morbidity and mortality in ICU patients and it is now recognized that oxidative stress, presence or absence of cysteine metabolic enzymes in leading to a strong and persistent inflammatory response, different tissues plays a major part in determining tissue constitutes a serious factor for development of multiple and subsequent plasma cysteine levels in response to organ failure (MOF) . However, there is an elaborate dietary supplementation. For example, colon tissue has a defence system, involving antioxidants such as GSH, low amount of cysteine dioxygenase (CDO) but relatively operating to protect cells from oxidative stress. These high amounts of desulfuration enzymes. Stipanuk and antioxidants quench ROS, delay oxidation of substrates, Ueki are currently engaged in further studies of CDO and can have beneficial effects on infectious complication regulation, the results of which are eagerly awaited.
Cysteine and glutathione in disease states Oxidation of cysteine and GSH and the associated Intracellular GSH can be influenced by the availability of improvement of both the cysteine and GSH redox states exogenous GSH precursors. The body has the capacity to are correlated with markers of cardiovascular disease synthesize GSH from cysteine, methionine, glutamate A diminished cysteine redox state is accompanied Cysteine-enriched protein supplements McPherson and Hardy by cellular signalling events that are anti-inflammatory; Progression of nonalcoholic fatty liver disease is worsened conversely, increasing the cysteine redox state increases by antioxidant depletion. In a GSH-deficient knockout proinflammatory pathways. For example, the external mouse model, in which liver GSH is 15% of normal, the cysteine redox state can directly regulate monocyte mice appeared to adapt to decreased GSH A con- adhesion to aortic endothelial cells and mitochondrial, sequence of this adaption was that knockout mice, fed but not nuclear or cytoplasmic oxidation. These changes a methionine and choline-deficient diet (MCD) that are at least partially mediated by changes in plasma would induce liver disease in genetically normal animals, membrane thiols and mitochondrial thioredoxin  were protected against liver disease by the MCD diet.
This implies that reducing the plasma cysteine redox Adaptation to low GSH in the knockout mice was indi- state might be beneficial either as a preventive or treat- cated by substantial changes in gene expression of meta- ment adjunct for cardiovascular disease. Some confir- mation of this hypothesis is provided in an elegantstudy of human dietary supplementation and plasma Paracetamol (acetaminophen), one of the most fre- redox states When healthy humans ingested a quently used drugs, is detoxified by cysteine and its diet relatively high in cysteine and methionine (up to metabolites. Paracetamol intake causes oxidation of 117 mg/kg/day), there was a positive association between cysteine, but has no effect on the GSH redox state, plasma cysteine concentration and cysteine redox state.
regardless of dietary sulphur amino acid intake levels However, there was no effect on plasma GSH or GSH . Pujos-Guillot and colleagues reasoned that long- term paracetamol usage, particularly in the elderly forarthritic pain, might increase the requirement for In monocyte cultures, improving the cysteine redox cysteine . They found that older persons responded state increases proinflammatory interleukin (IL)-1 b to long-term paracetamol by increasing their dietary expression In the same study, dietary cysteine protein intake substantially and as a consequence there and methionine decreased the plasma cysteine in mice, was no depletion of cysteine and its metabolites.
but not the GSH redox state, while reducing plasma andlung IL-1 b expression in response to a proinflammatory S-allyl-cysteine, a component of garlic extract, is capable challenge. In human participants there were correlations of reducing diabetic-induced glycoproteins in rat liver between (i) plasma IL-1 b and increased cysteine redox and kidney At the same time, blood and urine sugars state, (ii) TNFa and plasma redox state increase and (iii) are partially controlled. In this context it is possible that plasma cysteine and IL-1 b decrease These data high cysteine protein is just as effective as NAC in further confirm the link between cysteine supplement- negating the effects of a high sugar diet ation and the resultant cysteine redox state and anti-inflammatory activity.
CancerThe General Population Nutrition Trial, conducted in Linxian, China, has confirmed the association between Men are more susceptible than women to liver damage.
serum cysteine and risk of some cancers. In that study, a In a study of sex differences, female mice had slightly higher serum cysteine quartile was associated with higher levels of GSH metabolism enzymes. The authors reduced risk of both gastric and oesophageal cancers hypothesize that increased levels of GSH enzymes are at This relationship was even stronger in people least partly responsible for increased resistance of female aged over 60 years. It is worth noting this trial finished around 1991, but thanks to wise planning, the storedsamples were analysed for cysteine using ‘modern’ NAC improved markers of liver health during treatment of bile duct obstruction prior to endoscopic retrogradecholangiopancreatography . The authors attributedthis effect to the mucolytic action of NAC, which might reduce the viscosity of bile. In a mouse model of liver cirrhosis, oral NAC increased survival and restored cyto- A detailed study of the fate of dietary and arterial cysteine solic and mitochondrial GSH This recovery was in minipigs showed, for the first time quantitatively, accompanied by improvements in several markers of liver that net cysteine flux accounts for only 60% of dietary health. The mouse model was a previously developed cysteine, suggesting further sequestration of 40% of liver-specific knockout of a GSH synthesis enzyme cysteine in the intestine Importantly, the portal so GSH must have either been synthesized outside of the drained viscera (PDV) released an additional 15–25% of liver tissue in response to NAC, or synthesized locally nondietary cysteine, originating either from tissue break- down, methionine metabolism or from reabsorption of cysteine from endogenous secretions of biliary GSH.
GSH was induced in response to both peroxide and EYP/ Thus, in a stress and inflammation model, sulphur amino peroxide compared with isotonic saline infusion. GSH acid metabolism adapts to cover the increased require- was induced in both the duodenum and jejunem, but not ments of cysteine, demanded by the need for increased the ileum or colon. Erythrocyte GSH was induced by GSH synthesis. These data may partly explain the reason both peroxide and EYP/peroxide infusion, with the effect for inefficient oral cysteine availability, suggesting that, being more marked in the EYP/peroxide group. EYP was during supplementation, the colon, stomach, pancreas capable of decreasing the degree of peroxide-induced and spleen (PDV) could preferentially use circulating oxidant markers in pigs. Taken collectively, the data suggest that rather than acting as a high cysteine protein, dietary cysteine to synthesize more GSH. This raises EYP functions as an antioxidant protein.
the possibility that dietary cysteine contained withinpeptides and proteins will be more effective in boosting Milk proteins, in particular cysteine-rich whey protein, cysteine metabolism in SIRS and other inflammatory are known for their ability to raise GSH. Although there is a positive relationship between milk consumption andgrowth there can be negative impacts Allergiesto cow’s milk do develop but frequently disappear by adulthood. Allergies to whey proteins occur in children The use of cysteine in parenteral nutrition has been but they can be mostly ameliorated by hydrolysation recently reviewed by Yarandi et al. who noted the Lactose intolerance, real or perceived, affects a substan- absence of convincing clinical evidence for benefits of tial segment of Western populations and an even sulphur amino acids in parenteral nutrition. In neonates larger proportion of the rest of the world Consump- the benefits of sulphur amino acids in parenteral nutrition tion of whey protein may also contribute to teen acne as a mixtures is even less clear, especially given the well consequence of its high insulinotropic activity known low solubility and instability of free cysteine inaqueous solution. Early studies showed that neonates SelenoCysteine and SelenoMethionine are abundant under stress lack enough cysteine to synthesize sufficient in eggs, and various other natural protein fractions are rich GSH . In a small study of five sick infants, Courtney- in selenium and cysteine The many selenoproteins Martin et al. studied whether added methionine are capable of modulating redox signalling, including could replace cysteine and boost GSH synthesis. They cysteine and GSH redox states Dietary selenium observed GSH was synthesized in the presence of par- can modulate selenoprotein redox activity, so it makes enteral methionine only. When cysteine was added as sense that dietary selenoproteins might also modulate well as methionine, there was no increase in erythrocyte general redox states. Selenoproteins are essential for GSH and there was no significant difference in plasma keratinocyte function and skin resistance to oxidative cysteine. Clearly, there is a need to boost cysteine metabolism in parenteral nutrition patients using newstrategies, but studies in neonates are challenging and Plant proteins tend to be deficient in sulphur amino acids.
more research is needed in this important area.
With aims towards improving both animal feed andhuman dietary applications, sulphur proteins have beenexpressed in plants. A recent study in sulphur protein- Naturally occurring cysteine-rich proteins expressing soybean raises some doubts about current The most natural, and therefore, one might argue the approaches in this area, as the new bean varieties have best source of cysteine is dietary protein, in which it is allergic potential, and may limit animal growth present as the dimer, cystine, including linked sulphur– Therefore, the sulphur-containing proteins and plants sulphur bonds. These disulphide bonds can be readily selected for insertion need to be reconsidered, or altern- cleaved in vivo, or by heat or mechanical stress in the atives for cysteine supplementation must be found.
laboratory to liberate the monomer, cysteine. However,there is a dearth of published data on the nutritional value Keratins are cysteine-rich proteins abundant in feather, skin, horn, nail, hair and wool. Hydrolysation by enzy-matic or chemical means is required to achieve digest- Defatted egg protein, a byproduct of lecithin production, ibility. Feather keratins have been trialled extensively as is digested with an enzyme mixture and then solid matter animal feed supplements and have the highest cysteine is centrifuged out to make egg yolk peptides (EYP). The of the major food proteins . Occurence of keratin in protein has antioxidant activity and reduces peroxide- the human diet is widespread. In the USA, keratin- induced secretion of IL-8, a proinflammatory cytokine containing nutritional supplements have been available . But there was no EYP rescue effect on the reduction for over 50 years and it is not considered a new dietary of cell proliferation induced by peroxide. In a pig model, ingredient. Recorded use in Europe dates back to 1911, as Cysteine-enriched protein supplements McPherson and Hardy evidenced by a monograph for keratin in the British Dro¨ge W. Oxidative stress and ageing: is ageing a cysteine deficiencysyndrome? Philos Trans R Soc Lond B Biol Sci 2005; 360:2355 –2372.
Pharmaceutical Codex for tablet coating. Acute and Lu SC. Regulation of glutathione synthesis. Mol Aspects Med 2009; 30 chronic toxicity studies in a range of animal species have demonstrated no effect on LD50 and the common bio- Wu G, Fang YZ, Yang S, et al. Glutathione metabolism and its implications for chemical markers of toxicity, suggesting keratin is safe, which is not surprising given the widespread distribution Lourenc¸o R, Camilo ME. Taurine: a conditionally essential amino acid inhumans? An overview in health and disease. Nutr Hosp 2002; 17:262–270.
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from other sources and may contain bioactive sequences J Nutr 2006; 136 (6 Suppl):1670S –1675S.
that are yet to be discovered However whether any 11 Dilger RN, Toue S, Kimura T, et al. Excess dietary L-cysteine, but not L-cystine, is lethal for chicks but not for rats or pigs. J Nutr 2007; 137:331 –338.
new studies may demonstrate allergenicity in a subset of 12 Stipanuk MH, Coloso RM, Garcia RA, Banks MF. Cysteine concentration individuals remains to be seen. Its potential as a nutra- regulates cysteine metabolism to glutathione, sulfate and taurine in rat ceutical or functional food component is currently under hepatocytes. J Nutr 1992; 122:420 –427.
13 Aitio M-L. N-acetylcysteine: passe-partout or much ado about nothing? Br J 14 Berger MM, Soguel L, Shenkin A, et al. Influence of early antioxidant supple- ments on clinical evolution and organ function in critically ill cardiac surgery,major trauma, and subarachnoid hemorrhage patients. Crit Care 2008; The sulphur amino acid, L-cysteine has a critical role in 15 Valencia E, Hardy G. Practicalities of glutathione supplementation in nutri- methionine, taurine and GSH metabolism. Oral or ent- tional support. Curr Opin Clin Nutr Metab Care 2002; 5:321–326.
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18 Stipanuk MH, Ueki I. Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J Inherit Metab Dis 2011; 34:17– Cysteine-rich proteins, such as keratin, are abundant, and Outstanding review on sulfur amino acid metabolism.
if processed correctly should result in high quality and 19 Bauchart-Thevret C, Stoll B, Burrin DG. Intestinal metabolism of sulfur amino demonstrably well tolerated nutraceuticals for use in a acids. Nutr Res Rev 2009; 22:175–187.
variety of clinical applications. Further basic research and 20 Go Y-M, Jones DP. Cysteine/cystine redox signaling in cardiovascular dis- ease. Free Radic Biol Med 2011; 50:495–509.
clinical studies to elucidate the posology, mechanisms of A comprehensive review of cysteine redox state and cardiovascular disease.
action and potential clinical benefits are now necessary.
21 Go Y-M, Park H, Koval M, et al. A key role for mitochondria in endothelial signaling by plasma cysteine/cystine redox potential. Free Radic Biol Med2010; 48:275–283.
In-vitro evidence of the influence of cysteine on redox state. The study illuminates the role of mitochondria redox state.
R.M. is a consultant to Keraplast Technologies LLC.
22 Jones DP, Park Y, Gletsu-Miller N, et al. Dietary sulfur amino acid effects on fasting plasma cysteine/cystine redox potential in humans. Nutrition 2011;27:199–205.
In-vivo evidence of the influence of dietary cysteine on redox state. Pivotal study providing evidence for potential link between diet and cardiovascular health.
23 Iyer SS, Accardi CJ, Ziegler TR, et al. Cysteine redox potential determines pro-inflammatory IL-1beta levels. PLoS One 2009; 4:e5017.
Provides a partial mechanism for how cysteine redox potential fights inflammationand therefore disease.
Papers of particular interest, published within the annual period of review, havebeen highlighted as: 24 Liang Q, Sheng Y, Jiang P, et al. The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury. Toxicology 2011; 280:61–69.
Intriguing study that suggests how sex differences in liver disease susceptibility Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 650–651).
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A useful review of the selenoproteins.
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35 Yarandi SS, Zhao VM, Hebbar G, Ziegler TR. Amino acid composition in Illustrates the role of selenoproteins as antioxidants.
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51 Dong W-ren, Zhao B-lei, Xiao Y-qing, et al. Toxicity evaluation of chicken 37 Courtney-Martin G, Moore AM, Ball RO, Pencharz PB. The addition of calamus keratin conduit as a tissue-engineering scaffold biomaterial. Nan cysteine to the total sulphur amino acid requirement as methionine does Fang Yi Ke Da Xue Xue Bao 2007; 27:931–935.
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