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
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Pharmaceutical Codex for tablet coating. Acute and
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chemical markers of toxicity, suggesting keratin is safe,
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Excellent review on taurine and disease.
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Cysteine-rich proteins, such as keratin, are abundant, and
Outstanding review on sulfur amino acid metabolism.
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First peer-reviewed evidence for bioactivity of keratin peptides.
Dr. Friedman’s Guide to Estrogen Replacement There are risks and benefits with all medicines and estrogen replacement is noexception. In fact, estrogen replacement is one of the most controversial topics inEndocrinology. This is due to conflicting data on its benefits and side effects, themultitude of available hormone replacement products and regimens and the fact that moststudies on est
Good Practice in Traditional Chinese Medicine Research in the Post-genomic Era Report on the reviewed literature relating to clinical use of Document description Report on the reviewed literature relating to clinical use of CHM This document is a summary of the recent research into Chinese herbal medicine in selected conditions. Andrew Flower, George Lewith and Dan Jaing – edit