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SULFUR-CONTAINING AMINO ACIDS:
A NEUROCHEMICAL PERSPECTIVE
Gethin J. McBean, PhD
School of Biomolecular and Biomedical Science,
Conway Institute, University College, Dublin, Ireland
ABSTRACT
This review charts recent developments in understanding the
neurochemistry of endogenous sulfur-containing amino acids as
neuromodulators, metabolic intermediates and potential toxins. The
amino acids discussed include L-cysteine, L-cysteine sulfinic acid, Lcysteic acid, L-homocysteine, L-homocysteine sulfinic acid, Lhomocysteic acid and taurine. Particular emphasis is placed on examining
the mechanism and regulation of biochemical pathways that contribute to
the synthesis and metabolism of cysteine, especially in its capacity as
precursor of glutathione, taurine and hydrogen sulfide. Evidence
concerning the role of cysteine and its oxidised form, cystine, in the
control of intracellular and extracellular redox potentials and in the
response of cells to oxidative stress is presented. Lastly, the therapeutic
potential of intervention in the pathways of sulfur-containing amino acid
metabolism in the brain is discussed.

Email: [email protected]; Tel: +353 1 7166770.
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Gethin J. McBean
ABBREVIATIONS
AD, Alzheimer’s disease;
CA, cysteic acid;
CBS, cystathionine--synthase;
CDO, cysteine dioxygenase;
CSA, cysteine sulfinic acid;
CSF, cerebrospinal fluid;
CSE, cystathionine--lyase;
Cys, cysteine;
CySS, cystine;
EAAT3, excitatory amino acid transporter 3;
FGF, fibroblast growth factor;
GABA, -aminobutyric acid;
GCL, glutamate cysteine ligase;
GSH, glutathione (reduced form);
GSK, glycogen synthase kinase;
GSSG, glutathione disulfide;
hCA, homocysteic acid;
hCSA, homocysteine sulfinic acid;
hCys, homocysteine;
hCySS, homocystine;
mGluR, metabotropic glutamate receptor;
NAC, N-acetylcysteine;
NMDA, N-methyl-D-aspartate;
Nrf2, nuclear factor (erythroid derived 2)-like 2;
ROS, reactive oxygen species;
SAA, sulfur-containing amino acid;
SAS, sulfasalazine;
TS, transsulfuration pathway;
xc-, cystine-glutamate exchanger.
INTRODUCTION
During the period up to and including the 1990s, much research was
focussed on establishing the role of sulfur-containing amino acids (SAAs) as
activators of glutamate receptors, particularly concerning their association
Sulfur-Containing Amino Acids
3
with receptor-mediated neurotoxicity. It was also the era when many of the
SAAs were being considered as endogenous neurotransmitters, but, as time
has shown, few, if any of these molecules are now regarded in that light. In
many cases, research is now directed towards understanding the role of SAAs
in metabolism (mostly within astrocytes), thiol redox homeostasis and their
contribution to the synthesis of important neuroprotective molecules, including
glutathione (-glutamyl-cysteinyl-glycine; GSH), taurine and hydrogen sulfide
(H2S). It is on these more recent investigations that this review concentrates.
Each of the principal SAAs is discussed in light of its presence within the
brain, its role in sulfur metabolism and contribution to neuronal homeostasis
and antioxidant protection.
For the purposes of this review, the SAAs include cysteine (Cys), cystine
(CySS), cysteine sulfinic acid (CSA), homocysteine (hCys), homocysteine
sulfinic acid (hCSA), cysteic acid (CA), homocysteic acid (hCA) and taurine.
For reasons of brevity, methionine is discussed only in the context of its role
as precursor to homocysteine and cysteine. The chemistry and biological
activity of amino acid derivatives and protein adducts, for example,
homocysteine-thiolactone, are excluded from the discussion.
Figure 1. Structure of sulfur-containing amino acids.
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The chemical reactivity of the sulfur atom in SAAs is central to the
biological activity of the SAAs and the range of reactions in which they
participate. Sulfur has multiple oxidation states, ranging from +6 in neutral
conditions to -2 in an oxidising environment. Thus, Cys, CSA and CA
(frequently referred to as ‘cysteate’) are structurally identical, apart from the
oxidation state of the S atom. CySS, with its intramolecular disulfide bond, is
the oxidised form of cysteine. hCys, hCSA and hCA are homomers of Cys,
CSA and CA, respectively. Taurine is unique amongst the SAAs discussed,
because it does not contain a carboxylic acid group. The chemical structures of
the SAAs are provided in Figure 1.
CYSTEINE AND CYSTINE
As mentioned, the free thiol (-SH) group in Cys is highly reactive and
underlies the participation of this amino acid in numerous biological processes
that include catalysis, metal binding and acting as a ‘molecular switch’ that
controls the activation or deactivation of proteins. Free Cys readily oxidises to
the disulfide form, CySS and the ratio of each is governed by the redox
potential. Oxidising conditions outside the cell dictate that the amino acid
exists almost exclusively as CySS. The opposite is the case in the cytosol,
where the electron transferring capacity of other thiol redox systems, such as
glutathione/glutathione disulfide (GSH/GSSG), maintain Cys in the reduced
state (Banerjee, 2012). Further discussion of intracellular and extracellular
thiol redox potentials can be found in McBean et al. (2015). It is notable that
the extracellular Cys/CySS ratio becomes progressively more oxidised with
aging and this is viewed as a significant risk factor for disease (Roede et al.,
2013).
Cys is the immediate precursor of a number of important neuroprotective
and antioxidant molecules, including GSH, taurine and H2S. Both GSH and
taurine exist intracellularly at millimolar concentrations in the brain, which is
an order of magnitude higher than the concentration of free Cys. This means
that the availability of Cys is rate-limiting for provision of GSH or taurine.
H2S is also derived from Cys, but, being a gas with a very short half-life, it is
regulated differently and H2S is only produced in small amounts according to
specific needs (Ishigami et al., 2009). In the brain, most Cys is supplied by
specific and selective plasma membrane transporters. There is increasing
evidence that this is a tightly regulated process that differs according to
whether Cys is taken up into neurons or glial cells. Neurons use the EAAT3
Sulfur-Containing Amino Acids
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(also known as EAAC1 and is coded by the gene SLC1a1) subtype of high
affinity glutamate transporters to import Cys, whereas astrocytes and
microglial cells preferentially take up CySS, using a plasma-membrane
transport protein, known as the xc- cystine-glutamate exchanger. As the
extracellular ratio of Cys/CySS favours CySS, it follows that the majority of
Cys in the brain enters astrocytes and microglial cells as CySS, where it is
reduced on entry to Cys. As the name suggests, the xc- cystine-glutamate
exchanger operates on a one-to-one exchange of glutamate for each molecule
of cystine imported, in which the driving force is the high intracellular
concentration of glutamate relative to the extracellular compartment (Douaud
et al., 2013). Glutamate released via the exchanger is rapidly re-cycled into
astrocytes/microglial cells via high-affinity sodium-dependent transporters, but
evidence is emerging to suggest that glutamate released via the exchanger is a
significant regulator of neuronal excitability and synaptic transmission
(Augustin et al., 2007).
GSH is synthesised from Cys in the first two reactions of the glutamyl
cycle (Figure 2). Most of the GSH required for antioxidant defence in neurons
comes from astrocytes. Much research has been devoted to understanding the
supply-and-demand relationship between astrocytes and neurons in the context
of GSH synthesis. Essentially, de novo synthesis of GSH takes place in
astrocytes, but the tripeptide is then exported to the extracellular space and
broken down by the consecutive action of -glutamyltranspeptidase, followed
by peptidases. The -glutamyl component of GSH combines with an acceptor
amino acid and returns to astrocytes, where it is converted into 5-oxoproline in
the second half of the -glutamyl cycle. Cys is transferred to neurons, where
GSH is re-synthesised (Cooper & Kristal, 1997; Dringen et al., 1999).
In addition to Cys import via the xc- cystine-glutamate exchanger, work
from a number of laboratories has shown that astrocytes also use the
transsulfuration (TS) pathway to convert methionine to Cys via hCys (Figure
3) (Kandil et al., 2010; McBean, 2012; Vitvitsky et al., 2006). In vitro
experiments with astrocytes have shown that, under normal conditions, the TS
pathway supplies one third of the Cys required for GSH, but that the
significance of the pathway increases during oxidative stress, or under
conditions in which the xc- cystine glutamate exchanger is blocked – as might
occur during neurodegenerative disease in which there is an increase in the
extracellular concentration of glutamate (Kandil et al., 2010; McBean, 2012).
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Figure 2. GSH synthesis in astrocytes and neurons. CySS is imported into astrocytes
(1) and is reduced to Cys in the cytosol. Cys and glutamate (Glu) form glutamylcysteine (-Glu-Cys) in a reaction catalysed by -glutamate cysteine ligase (2).
Addition of glycine (Gly), catalysed by glutathione synthase (3), forms GSH. GSH is
exported from astrocytes where it is hydrolysed by -glutamyltranspeptidase (4) to
cysteinylglycine (Cys-Gly) and a peptide composed of -glutamate and an acceptor
amino acid (X). Cys-Gly is hydrolysed by an ectopeptidase (5). Cys enters the neuron
by the EAAT3 transporter (6) and is used to generate GSH (7).
Figure 3. The methionine cycle and transsulfuration pathway. CBS, cystathionine-synthase; CDO, cysteine dioxygenase; CSA, cysteine sulfinic acid; CSE,
cystathionine--lyase; GCS, glutamate cysteine ligase; GS, glutatmine synthase.
Sulfur-Containing Amino Acids
7
To date, little information is available on the relationship, in terms of
reciprocal regulation, of the other pathways of Cys usage and the conditions
that determine the ultimate fate of Cys are poorly understood. Further research
is needed in order to fully understand the complexities of cysteine metabolism
in the brain. In terms of oxidative stress, the emerging view is that the TS
pathway (in astrocytes) is upregulated by oxidative stress due to increased
expression of cystathionine--lyase (CSE), leading to increased GSH (Kandil
et al., 2010; McBean, 2012). Further discussion of the TS pathway can be
found in the section on hCys.
It is well documented that the xc- exchanger in both astrocytes and
microglial cells is upregulated in response to oxidative stress as first
demonstrated by Piani and co-workers in 1994 using cultured macrophages
(Kigerl et al., 2012; Mysona et al., 2009; Piani & Fontana, 1994). More recent
work has shown that both the exchanger and the regulatory enzyme of GSH
synthesis, -glutamate cysteine ligase (GCL) are under transcriptional control
by nuclear factor (erythroid-derived 2)-like 2 (Nrf2). This transcription factor,
often dubbed the ‘master regulator’ of antioxidant pathways, is itself activated
by electrophiles and controls the expression level of several enzymes and
proteins associated with oxidant defence, amongst these, the xc- exchanger and
GCL. Other positive regulators of the xc- exchanger on astrocytes include
fibroblast growth factor (FGF) (Liu et al., 2014). This stimulatory effect was
demonstrated following exposure of mixed glial and neuronal cultures to FGF2 for 48 h. After this time, FGF-2 caused AMPA/kainate receptor –mediated
toxicity arising from release of glutamate via the exchanger. Finally, it has also
been shown that pro-inflammatory cytokines and reactive oxygen species
cause an increase in the expression of xCT (Massie et al., 2015).
One of the most intriguing aspects of the xc- cystine-glutamate exchanger
is that it lies at the interface between redox balance and excitatory signalling.
Import of cystine to maintain redox status is matched by export of glutamate,
which, if not recycled by the high affinity transporters back into astrocytes,
becomes a potential toxicant. Increased expression of the exchanger occurs
following activation of microglial cells in vitro through stimulation of toll-like
receptors by bacterial lipopolysaccharides. Similarly, increased expression of
the exchanger has been noted in multiple sclerosis and in response to the HIVassociated protein, Tat (Gupta et al., 2010; Pampliega et al., 2011). Brain
tumor cells (gliomas and astrocytomas) also display increased expression of
the xc- exchanger, which is accompanied by either low or absent expression
and functional activity of the high affinity glutamate transporters. Thus, in
gliomas, the balance between efflux of glutamate via the exchanger and uptake
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via the high affinity glutamate transporters shifts in favour of an increased
extracellular concentration of glutamate (De Groot & Sontheimer, 2011; Ye et
al., 1999). The implication of this imbalance, in terms of glutamate release and
the development of strategies to combat neuronal death, is the subject of a
Nova review (McBean, 2013).
Much effort has been expended in searching for therapeutic strategies to
limit neurodegeneration in brain tumours. For example, Savaskan and
colleagues used siRNA-mediated silencing of xCT (the functional unit of the
xc- exchanger) to reduce the extent of neurodegeneration and prevent brain
edema (Savaskan et al., 2008). Others have worked on the development of
pharmacological agents that target the xc- exchanger. Foremost amongst these
is sulfasalazine (SAS), a selective inhibitor of the exchanger, which has shown
effective blockade in cell experiments and animal models. However, SAS has
proven unsuitable for human application, due to an absence of clinical effect
and the appearance of undesirable side-effects in a number of patients. It was
withdrawn from a phase 1 / 2 prospective randomised study (Robe et al.,
2009). A more promising molecule to emerge in recent years is erastin, which
is a potent and selective inhibitor of the xc- exchanger (Dixon et al., 2014).
Through inhibition of the exchanger, erastin causes an endoplasmic reticulum
(ER) stress response and ferroptosis. Sorafenib, a clinically-approved anticancer drug, also inhibits xc- with a similar ER/ferroptosis effect. Erastin may
be particularly beneficial, as recent work by Chen and collegues demonstrates
that it blocks both the xc- exchanger and CSE, a regulatory enzyme of the TS
pathway, thus contributing to a more significant reduction in GSH than would
be achieved by blockade of the xc- exchanger alone (Chen et al., 2015). For this
reason, the sensitivity of glioma cells to the anti-cancer drug, temozolomide
was enhanced when co-applied with erastin and produced a greater decrease in
GSH than was observed in the presence of SAS (Chen et al., 2015).
N-acetylcysteine (NAC) is a structural analog of Cys that readily gains
access to brain cells independently of the xc- exchanger. NAC is converted to
Cys intracellularly, leading to an increase in GSH (Holmay et al., 2013). NAC
is entering clinical trials for adrenoleukodystrophy, Parkinson’s disease,
schizophrenia and other disorders in which there is a high probability that
oxidative stress contributes to disease progression (Reyes et al., 2016). A
system to determine the concentration of NAC in cerebrospinal fluid (CSF)
that corresponds to elevation of GSH and an increase in neuronal antioxidant
capacity has been developed. Using mice supplied with increasing doses of
NAC, Reyes and co-workers determined that NAC doses that produced peak
CSF NAC concentrations (50 nM or above) were effective in increasing GSH
Sulfur-Containing Amino Acids
9
and reducing neuronal oxidative stress. Other therapeutic interventions that
aim to boost GSH in vivo include activation of Nrf2 by hyperbaric oxygen
therapy, dimethylfumarate, phytochemicals including curcumin, resveratrol
and cinnamon, and folate supplementation.
Regulation of Cysteine Uptake into Neurons: The Other Side of
the Coin
In contrast to astrocytes, cysteine uptake by the EAAT3 high affinity
glutamate transporter is the principal channel for provision of cysteine for
GSH synthesis in neurons (Figure 2) (Hayes et al., 2005; Himi et al., 2003).
Here, cysteine uptake is inhibited by glutamate, just as cystine uptake into
astrocytes or microglial cells is also blocked by an elevation in extracellular
glutamate. Thus, any pathology that is associated with an increase in
extracellular glutamate would cause depletion of GSH in both neurons and
astrocytes because of inhibition of the respective transporters in each cell type
(Himi et al., 2003). In other words, GSH levels in neurons and glial cells are
universally vulnerable to a change in the extracellular concentration of
glutamate. Mice lacking EAAT3 have a reduced concentration of neuronal
GSH (Cao et al., 2012) and increased presence of oxidised proteins and the
lipid by-product of oxidative stress, 4-hydroxy-2-nonenal. Notably, both these
indices of oxidative stress were improved by application of NAC to the mice,
which suggests that NAC is equally effective in boosting GSH in neurons as in
astrocytes.
EAAT3 is upregulated following Nrf2 activation in mouse brain, leading
to an increase in the neuronal GSH content (Escartin et al., 2011), which
strongly suggests that GSH synthesis in neurons maps to increased provision
of cysteine by astrocytes. EAAT3 is expressed on all neurons, but is
particularly dense on neurons of the substantia nigra, pars compacta.
Information on altered expression and /or functional activity of EAAT3 in
disease states is beginning to accumulate, but not all of these necessarily relate
to changes in cysteine and subsequent alteration in neuronal GSH. Besides
transporting cysteine, EAAT3 has other functions, such as in limiting spillover
of synaptically-released glutamate and provision of glutamate for GABA
synthesis in GABAergic terminals. Therefore, there is an argument that a
reduction in EAAT3 activity may, in fact, be beneficial. For instance, Lane
and colleagues showed that genetic deletion of EAAT3 in mice resulted in
decreased neuronal death after pilocarpine-induced epilepsy (Lane et al.,
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2014). In this case, the benefit was in reducing glutamate uptake, making more
glutamate available for GABA synthesis. This strategy does not sit well with
the negative impact of disruption in EAAT3 on GSH and the antioxidant
capacity of neurons. Indeed, soluble oligomers of amyloid- (A) reduce
cysteine uptake by EAAT3 in cultured human neuronal cells, leading to a
decrease in cellular GSH content (Hodgson et al., 2013). Furthermore, aging
mice with an EAAT3 deletion display progressive neurodegeneration that is
attenuated by NAC. Also, EAAT3 -/- mice have less cysteine uptake, lower
GSH and are more susceptible to chronic oxidative stress (Berman et al.,
2011). EAAT3 expression is altered in a number of other neurodegenerative
conditions, including hypoxia/ischemia, multiple sclerosis, schizophrenia and
epilepsy. This topic is discussed in more detail in the excellent review by
Bianchi et al. (2014).
HOMOCYSTEINE
Homocysteine (hCys) is a metabolite of the indespensible amino acid,
methionine, and occupies a position in the methionine cycle at the intersection
between S-adenosylmethionine, vitamin B12 and folic acid (Figure 3). High
blood levels of homocysteine (hyperhomocysteinemia) signify a breakdown in
the cycle that has implications in many disease processes, including cognitive
impairment and a link with Alzheimer’s disease, stroke, dementia and
Parkinson’s disease (Herrmann & Knapp, 2002; Miller, 2003).
Hyperhomocysteinemia arises as a consequence of enzyme and / or vitamin
B12 deficiency and is a proven risk factor in several atherosclerotic
cardiovascular diseases.
An elevated concentration of hCys in the brain has, through pleiotropic
mechanisms, a profound effect on glutamate-mediated neurotransmission that
markedly enhances the vulnerability of neuronal cells to excitotoxic, apoptotic
and oxidative injury in vivo and in vitro. hCys is an excitatory amino acid and
agonist of glutamatergic N-methyl-D-aspartate (NMDA) receptors. One of the
side-effects of Levodopa therapy for Parkinson’s disease patients is an
elevation in hCys, thereby increasing the threat of neuronal death by
hyperactivation of NMDA glutamate receptors (Shin et al., 2012). It has been
proposed that adjunct therapy with NMDA receptor antagonists may be
beneficial. hCys also negatively affects glutamate transporters, which also
increases the likelihood of over-stimulation of glutamate receptors. For
example, acute hyperhomocysteinemia in rats causes a reduction in glutamate
Sulfur-Containing Amino Acids
11
transport in the parietal cortex of neonate and young animals (Matte et al.,
2010). Interestingly, uptake rates in the young animals returned to normal after
12 h, but not so in neonates. Under chronic conditions, hyperhomocysteinemia
reduced expression of the EAAT2 and EAAT1 subtypes of glutamate
transporter, with an associated reduction in transporter activity, as well as a
reduction in the activity of Na+/K+ ATPase, catalase and superoxide dismutase
(Machado et al., 2011).
hCys is known to increase reactive oxygen species (ROS) production in
cultured cortical astrocytes (Loureiro et al., 2010). Similarly, hCys causes
activation of microglial cells and an increase in the activity of NADPH
oxidase (Zou et al., 2010) and release of superoxide that again contributes to
the disease-promoting effects of the amino acid. In experimental systems, ROS
production by hCys could be resolved by co-application with ascorbic acid
(Machado et al., 2011), but it is not yet known whether this strategy is an
effective therapy for human disease.
Acute hyperhomocysteinemia has been shown to increase Akt
phosphorylation and expression of cytosolic and nuclear NFkB/p65 protein,
but has the opposite effect on GSK-3phosphorylation (da Cunha et al.,
2012). In the case of Alzheimer’s disease (AD), hyperhomocysteinemia
increases -amyloid through enhanced expression of -secretase and
phosphorylation of amyloid precursor protein, as determined in rat brain
(Zhang et al., 2009). hCys is also known to induce hyperphosphorylation of
tau protein, possibly through a reduction in the activity of protein phosphatase
2A activity, as was observed in vivo following injection of hCys into the
lateral ventricle of rats (Luo et al., 2007). However, the association between
hyperhomocysteinemia and AD is unclear as to which is cause or effect. On
the one hand, the condition may contribute to neurodegeneration, but
hyperhomocysteinemia may also be triggered by neurodegenerative processes.
Certainly, chronic exposure to hCys promotes changes to the
electrophysiology of cultured hippocampal neurons that heralds the onset of
neurodegeneration (Schaub et al., 2013). A lowering of plasma hCys through
dietary supplementation with B vitamins is viewed as lowering the risk factor
for AD (Douaud et al., 2013). The mean plasma level of hCys in patients with
neurodegenerative disease is 20 µM. At this concentration, hCys causes loss of
35% of cultured neuronal (SHSY5Y) cells that was accompanied by a 4-fold
increase in ROS after 5 days’ exposure (Curró et al., 2014).
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Metabolism of Homocysteine
Homocysteine, when not required for re-methylation to methionine, enters
the TS pathway for a two-step conversion to cysteine (Figure 3). This pathway
plays a significant role in S-amino acid metabolism in liver and kidney, but
has only relatively recently been recognised as fulfilling a similar function in
brain. Indeed, there are conflicting views on whether the TS pathway is
functional in both neurons and astrocytes. More than 30 years ago, Wisniewski
and colleagues postulated that cystathionine was specifically located in
neurons (Wisniewski et al., 1985). This view was founded on the observation
that the intermediate in the pathway, cystathionine, disappeared as a result of
neuronal loss from the cortex and cerebellum of two patients with ceroid
lipofuscinosis. However, no delineation between the cystathionine content of
glial cells and neurons was performed in that analysis. Some years later,
Dringen and co-workers noted that generation of Cys from methionine did not
occur in cultured neurons derived from embryonic rat brain, from which it was
concluded that the TS pathway is non-functional in these cells (Dringen et al.,
1999). However, Vitvitsky and colleagues have, more recently, used similar
rat neuronal cultures derived from embryonic mouse to demonstrate radiolabel
incorporation into GSH from [35S]methionine, which could only occur via the
TS pathway (Vitvitsky et al., 2006). The same results were obtained using
astrocyte cultures, and also human-derived neurons and astrocytes and brain
slices (Vitvitsky et al., 2006). Thus, it is evident that the pathway is operative
in both astrocytes and neurons, although the significance of the pathway in
neurons remains to be determined. To date, most work on the pathway has
been performed in astrocytes (Kandil et al., 2010; McBean, 2012; Vitvitsky et
al., 2006). Data suggest that the TS pathway operates in a reserve capacity
when provision of Cys for GSH may be limited, or when the demand for GSH
increases, such as during oxidative stress. Current indications are that
microglial cells do not generate Cys from methionine by the TS pathway
(McBean, unpublished observations).
The first enzyme of the TS pathway, cystathionine--synthase (CBS) is
ubiquitous in brain, particularly in astrocytes. It is most highly expressed in the
immature brain (Enokido et al., 2005) and is believed to be the principal
enzyme used in generation of H2S in cerebral tissue. A deficiency in CBS
leads to homocystinuria, which is characterised by mental retardation, seizures
and psychiatric abnormalities. The peripheral symptoms of homocystinuria
include skeletal abnormalities and vascular dysfunction. CBS is also highly
expressed in the rat retina, most likely in the Müller cells (Markand et al.,
Sulfur-Containing Amino Acids
13
2013). Visual function is impaired in CBS -/- mice, due to accumulation of
hCys, leading to anatomical abnormalities in multiple retinal layers, including
the photoreceptors and ganglion cells (Yu et al., 2012).
The second enzyme of the TS pathway is CSE, which catalyses the
conversion of cystathionine to Cys and -ketobutyrate. The cystathionine
content of brain is higher than in peripheral tissues, signifying that CSE is the
chief regulator of flux through this pathway in the CNS (Vitvitsky et al.,
2010). CBS and CSE have a broad spectrum of activity that extends beyond
their canonical role in the TS pathway. One aspect of the catalytic activity of
CSE that is gaining interest is its ability to generate sulfane sulfur from the
mixed disulfide, cysteine-homocysteine (Toohey, 2011). Sulfane sulfur is a
form of sulfur that has six valence electrons, no charge (So) and the unique
ability to reversibly attach to other sulfur atoms. The presence of sulfane sulfur
is often indistinguishable from H2S and, increasingly, activities that have been
assigned to H2S are being re-evaluated in the context of So (Toohey, 2011). In
contrast to H2S, sulfane sulfur has a high potency and low toxicity in
biological systems and, due to its effectivity in the nanomolar concentration
range, may be a more effective signalling molecule than H2S. Measurement of
sulfane sulfur may have potential as a biomarker for high grade gliomas, as,
for example, Wrobel and colleagues noted that the level of sulfane sulfur in
high grade gliomas was high in comparison to normal controls (Wrobel et al.,
2014).
There remains much to be learned about regulation of the TS pathway. For
instance, what determines whether Cys should be directed towards GSH,
taurine or H2S? In addition, derivatives of cystathionine may have significant
roles in brain function and protection from oxidative stress (Hensley &
Denton, 2015). To date, little has been done to examine the association (if any)
between the TS pathway and neurodegenerative disease, notwithstanding the
observation that Hcys is elevated in Alzheimer’s and Parkinson’s disease
patients, which could signify TS dysfunction (Vitvitsky et al., 2006). It is
worth noting that hCys treatment of experimental animals decreases
expression of CBS and CSE in brain and inhibits production of endogenous
H2S in hippocampal neurons (Wei et al., 2014).
CYSTEINE SULFINIC ACID
Cysteine sulfinic acid (CSA) is an intermediate in the conversion of Cys to
taurine and is a product of the reaction catalysed by cysteine dioxygenase
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Gethin J. McBean
CDO (Figure 3), which is the rate-limiting enzyme for taurine biosynthesis and
is expressed in brain (Stipanuk et al., 2004). Hypotaurine is formed from CSA
by the action of CSA decarboxylase. CSA is an agonist at phospholipase Dcoupled metabotropic glutamate receptors (mGluRs), but, because activation
of these receptors is negatively coupled to other (Group 1) mGluRs, the
presence of CSA desensitises the Group 1 receptors, leading to an inhibition in
epileptiform activity (Cuellar et al., 2005).
Until recently, there was little evidence of an association of CSA with
neurodegenerative disease, other than that both hCys and CSA concentrations
in the CSF of lymphoma patients was elevated following treatment with
methotrexate (Becker et al., 2007). However, in a recent study in which 69
patient-derived glioma specimens underwent metabolic profiling by highthroughput liquid and gas chromatography-based mass spectrometry, CSA was
ranked as one of the most significant metabolites whose concentration
differentiated glioblastoma from low grade tumors (Prabhu et al., 2014). There
was a strong correlation between elevated levels of CSA and increased activity
of CDO. Further study revealed that high activity of CDO caused inhibition of
oxidative phosphorylation in glioblastoma cells, which was attributed to
inhibition of pyruvate dehydrogenase by CSA. Oppositely, in vivo blockade of
CDO by lentiviral-mediated short hairpin RNA resulted in significant tumour
growth inhibition in a glioblastoma mouse model. This was the first
demonstration of a metabolic pathway directly contributing to growth of
aggressive high-grade gliomas and has opened up a new approach to the
design of effective therapies.
CYSTEIC ACID, HOMOCYSTEIC ACID
AND HOMOCYSTEINE SULFINIC ACID
This group of SAAs are all minor players in sulfur amino acid metabolism
in the brain. Most work on their presence in the brain dates from the late
1980s, when experiments were directed towards investigating their activity as
glutamate-like toxicants and receptor agonists. Homocysteic acid (hCA) and
homocysteine sulfinic acid (hCSA) are both oxidised forms of Hcys (Figure
1). hCA was first identified as a derivative of methionine and an endogenous
agonist of the NMDA receptor in 1988 (Do et al., 1988). hCA is
predominantly found in astrocytes and is a substrate for CSA decarboxylase,
meaning that it effectively inhibits formation of hypotaurine from CSA in vitro
Sulfur-Containing Amino Acids
15
(Benz et al., 2004; Do & Tappaz, 1996). However, at the concentration
recorded in brain, it is unlikely that this is true in vivo. hCSA is neither a
substrate nor an inhibitor of CSA decarboxylase (Benz et al., 2004; Do &
Tappaz, 1996).
hCA and hCSA, in addition to CSA and cysteic acid (CA), are cytotoxic
when tested on cerebral cortical neurons in vitro (Frandsen et al., 1993). The
ED50 values for CSA, CA, hCSA and hCA are 30-50 µM. Inhibition of the
glutamate high affinity transporters increased the toxicity of CSA and CA, but
not the other two, implying that they may be substrates of the transporters.
Toxicity of CA, CSA and hCSA was prevented by NMDA receptor
antagonists. In the case of hCSA, toxicity was blocked by inhibition of nonNMDA receptors. For CSA, toxicity was blocked by inhibition of both NMDA
and non-NMDA receptors (Frandsen et al., 1993).
CSA, CA, hCA and hCSA have all been identified as mGluR agonists that
display lower efficiacy but greater potency than glutamate in their ability to
stimulate phosphatidyl inositol bis phosphate hydrolysis in rat pup
cerebrocortical slices (Porter & Roberts, 1993). CA and CSA both act at presynaptic mGluRs, particularly mGlu5, to enhance synaptic glutamate release
from rat forebrain in vitro, as measured as an increase in the electricallyevoked release of D-[3H]aspartate from rat forebrain hemisections (Croucher
et al., 2001). More recent interest in hCA stems from observations of
glutamate-stimulated release of hCA from astrocytes (Benz et al., 2004).
Release of hCA is both calcium- and sodium-dependent, which gave rise to the
view that hCA is one of a number of substances released from astrocytes that
augment activation of receptors during glutamate-mediated excitatory
signalling. hCA is released from astrocytes in response to stress and following
activation of astrocytic -adrenergic receptors (Benz et al., 2004).
TAURINE
As an end-product of SAA metabolism in the brain, the physiological and
pathological functions of taurine (2-aminoethane sulfonic acid) have received
much attention in the literature. Taurine is one of the most abundant free
amino acids in the brain, retina, muscle and other organs, and is particularly
associated with development and neuroprotection (Ripps & Shen, 2012). In the
retina, it is essential for photoreceptor development, where it acts as a
protectant against neuronal damage. Many of its roles compliment that of
classical neurotransmitters, yet taurine is not considered a neurotransmitter per
16
Gethin J. McBean
se, especially as no receptor has yet been identified that is selectively activated
by taurine. Early demonstration of the neuroprotective properties of taurine
came from studies looking at glutamate-mediated toxicity in the retina: it was
observed that exogenously applied glutamate caused neurodegeneration of
cells in the inner layer, whereas cells located in the distal layers were resistant.
Further research has clarified the neuroprotective action of taurine against
retinal ganglion cell degeneration (Froger et al., 2012).
Intracellularly, taurine is synthesised from Cys, via CSA and hypotaurine
(Figure 3). To my knowledge, no-one has determined the relative contribution
of cysteine/cystine import, as opposed to derivation from methionine, to
taurine biosynthesis. In addition, taurine can be taken up by selective high
affinity transport (Smith et al., 1992). This transporter has a Michaelis constant
(Km) of 18 µM, and taurine is transported together with 2-3 sodium anions and
one chloride cation. Beta-alanine, -amino butyric acid (GABA) and
guanidinoethyl-sulfonate are competitive inhibitors (Rasmussen et al., 2016).
Alternatively, taurine may be derived from cysteamine, which is a catabolite
of coenzyme A. In fact, the enzyme that catalyses this conversion, cysteamine
dioxygenase, is expressed at relatively high levels in the brain (Dominy et al.,
2007), although the full significance of this pathway for taurine synthesis has
not been evaluated.
The relationship between astrocytes and neurons in regard to taurine
biosynthesis has parallels with that of GSH. Neurons express neither CDO, nor
CSA decarboxylase and therefore may require provision of hypotaurine and /
or taurine from astrocytes. It is possible that the absence of a complete
biosynthetic pathway for taurine in neurons may be to preserve cysteine for
GSH synthesis, but this point has not been investigated.
Taurine works by a number of mechanisms. It is an organic osmolyte,
involved in cell volume regulation and modulation of the intracellular
concentration of free calcium ions. It was first isolated from the bile of ox
(hence its name, derived from ‘taurus’) in the first half of the nineteenth
century. As mentioned, taurine is synthesised from Cys by the rate-limiting
enzyme, CDO. CDO levels are low in cats and primates, including humans;
therefore, taurine must be supplemented by dietary intake. However,
exogenous taurine does not readily cross the blood-brain barrier. Thus,
peripheral application of taurine is not a good source of anti-convulsant
therapy.
Work on the mechanism of neuroprotection by taurine has revealed that,
in primary neuronal cultures, taurine is neuroprotective due to inhibition of
calcium influx via L-, N- and P/Q type voltage sensitive calcium channels
Sulfur-Containing Amino Acids
17
(Leon et al., 2009; Wu et al., 2005; Wu et al., 2009). In addition, taurine
prevents downregulation of the apoptotic protein Bcl2 and upregulation of
Bax, thereby preventing mitochondrial release of cytochrome C during
apoptosis. Taurine also prevents glutamate-induced activation of calpain,
which acts to preserve Bcl2 by preventing its cleavage (Ripps & Shen, 2012).
Taurine has particular importance as a neuroprotectant in young animals
during development, and this has been studied in the tauT K/O mouse. These
mice display mitochondrial birth defects and abnormal development of
myocardial and skeletal muscle. In the brain, taurine transporter deficiency
leads to delayed differentiation and cell migration in the cerebellum,
pyramidal cells and the visual cortex. Taurine is also important in promoting
neuronal developments in adult brain regions. For example, experiments have
shown that taurine acts as a trophic factor to promote proliferation of neural
progenitor cells in vitro (Hernández-Benítez et al., 2010).
Other developments in understanding the role of taurine in neuronal
signalling has come from work on the jellyfish, Cynea Capillata (Anderson &
Trapido-Rosenthal, 2009). Excitatory responses were observed by taurine and
homotaurine (3-aminopropane-sulfonic acid), which resembled mGluRmediated responses in timecourse (slow, long-lasting), rather than the
inhibitory profile expected of vertebrate taurine effects.
CONCLUSION AND FUTURE DIRECTIONS IN THE FIELD
OF S-CONTAINING AMINO ACIDS
In summary, the sulfur-containing amino acids have several roles within
cerebral metabolism that warrant further investigation, both in the context of
normal physiological function, or in relation to neurodegenerative disease.
Even at this stage of understanding, the role of astrocytes in providing
precursors or metabolites for neuronal sulfur amino acid activity is significant.
Future investigations into the regulation and importance of biosynthetic
pathways and the interaction of sulfur-containing amino acids with glutamatemediated excitatory signalling will doubtless reveal information of benefit to
the design and development of therapies for neurodegenerative disease. There
are several aspects of sulfur amino acid metabolism that are only beginning to
be understood, in particular, the identification of new compounds that may
have significant biological activity. Already, work has begun on the
physiological role of several derivatives of the transsulfuration pathway. For
18
Gethin J. McBean
instance, Hensley and Denton describe how transamination of intermediates of
the transsulfuration pathway generates unusual cyclic ketimines that may be
biologically active (Hensley & Denton, 2015). For example, lanthionine
ketimine (LK), has potent antioxidant, neuroprotective, neurotrophic and antiinflammatory activity in experimental systems. The therapeutic potential of
derivatives of LK to lessen neurodegeneration in conditions such as AD,
stroke, amyotrophic lateral sclerosis and glioma, is considerable.
ACKNOWLEDGMENTS
The author acknowledges the support of Science Foundation Ireland for
her research on the transulfuration pathway in astrocytes.
REFERENCES
Anderson PAV, & Trapido-Rosenthal HG (2009). Physiological and chemical
analysis of neurotransmitter candidates at a fast excitatory synapse in the
jellyfish Cyanea Capillata (Cnidaria, Scyphozoa). Invert Neurosci 9: 167173.
Augustin H, Grosjean Y, Chen K, Sheng Q, & Featherstone DE (2007).
Nonvesicular release of glutamate by glial xCT transporters suppresses
glutamate receptor clustering in vivo. J Neurosci 27: 111-123.
Banerjee R (2012). Redox outside the box: linking extracellular redox
remodelling with intracellular redox metabolism. J Biol Chem 287: 43974402.
Becker A, Vezmar S, Linnebank M, Pels H, Bode U, Schlegel U, et al.,
(2007). Marked elevation in homocysteine and homocysteine sulfinic acid
in the cerebrospinal fluid of lymphoma patients receiving intensive
treatment with methotrexate. Int J Clin Pharmacol Ther 45: 504-515.
Benz B, Grima G, & Do KQ (2004). Glutamate-induced homocysteic acid
release from astrocytes: possible implication in glia-neuron signaling.
Neuroscience 124: 377-386.
Berman AE, Chan WY, Brennan AM, Reyes RC, Adler BL, Suh SW, et al.,
(2011). N-acetylcysteine prevents loss of dopaminergic neurons in the
EAAC1-/- mouse. Ann Neurol 69: 509-520.
Sulfur-Containing Amino Acids
19
Bianchi MG, Bardelli D, Chiu M, & Bussolati O (2014). Changes in the
expression of the glutamate transporter EAAT3/EAAC1 in health and
disease. Cell Mol Life Sci 71: 2001-2015.
Cao L, Li L, & Zuo Z (2012). N-acetylcysteine reverses existing cognitive
impairment and increased oxidative stress in glutamate transporter type 3
deficient mice. Neuroscience 220: 85-89.
Chen L, Li X, Liu L, Yu G, Xue Y, & Liu Y (2015). Erastin sentizes
glioblastoma cells to temozolomide by restraining xCT and cystathionine-lyase function. Oncol Reports 33: 1456-1474.
Cooper AJ, & Kristal BS (1997). Multiple roles for glutathione in the central
nervous system. Biol Chem 378: 793-802.
Croucher MJ, Thomas LS, Ahmadi H, Lawrence V, & Harris JR (2001).
Endogenous sulphur-containing amino acids: potent agonists at
presynaptic metabotropic glutamate autoreceptors in the rat central
nervous system. Br J Pharmacol 133: 815-824.
Cuellar JC, Griffith EL, & Merlin LR (2005). Contrasting roles of protein
kinase C in induction versus suppression of group I mGluR-mediated
epileptogenesis in vitro. J Neurophysiol 94: 3643-3647.
Curró M, Gugliandolo A, Gangemi C, Risitano R, Ientile R, & Caccamo D
(2014). Toxic effects of mildly elevated homocysteine concentrations in
neuronal-like cells. Neurochem Res 39: 1485-1495.
da Cunha AA, Horn AP, Hoppe JB, Grudzinski PB, Loureiro SO, Ferreira AG,
et al., (2012). Evidence that AKT and GSK-3beta pathway are involved in
acute hyperhomocysteinemia. Int J Dev Neurosci 30: 369-374.
De Groot JF, & Sontheimer H (2011). Glutamate and the biology of the
gliomas. Glia 59: 1181-1189.
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al., (2014).
Pharmacological inhibition of cystine-glutamate exchange induces
endoplasmic reticulum stress and ferroptosis. Elife 3: e02523.
Do KQ, Herrling PL, Streit P, & Cuenod M (1988). Release of neuroactive
substances: homocysteic acid as an endogenous agonist of the NMDA
receptor. J Neural Transm 72: 185-190.
Do KQ, & Tappaz ML (1996). Specificity of cysteine sulfinate decarboxylase
(CSD) for sulfur-containing amino-acids. Neurochem Int 28: 363-371.
Dominy JE, Jr., Simmons CR, Hirschberger LL, Hwang J, Coloso RM, &
Stipanuk MH (2007). Discovery and characterization of a second
mammalian thiol dioxygenase, cysteamine dioxygenase. J Biol Chem 282:
25189-25198.
20
Gethin J. McBean
Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, et al.,
(2013). Preventing Alzheimer's disease-related gray matter atrophy by Bvitamin treatment. Proc Natl Acad Sci U S A 110: 9523-9528.
Dringen R, Pfeiffer B, & Hamprecht B (1999). Synthesis of the antioxidant
glutathione in neurons: supply by astrocytes of CysGly as precursor for
neuronal glutathione. J Neurosci 19: 562-569.
Enokido Y, Suzuki E, Iwasawa K, Namekata K, Okazawa H, & Kimura H
(2005). Cystathionine beta-synthase, a key enzyme for homocysteine
metabolism, is preferentially expressed in the radial glia/astrocyte lineage
of developing mouse CNS. Faseb J 19: 1854-1856.
Escartin C, Won SJ, Malgorn C, Auregan G, Berman AE, Chen P-C, et al.,
(2011). Nuclear factor Erythroid 2-related factor facilitates neuronal
glutathione synthesis by upregulating neuronal excitatory amino acid
transporter 3 expression. J Neurosci 31: 7392-7401.
Frandsen A, Schousboe A, & Griffiths R (1993). Cytotoxic actions and effects
on intracellular Ca2+ and cGMP concentrations of sulphur-containing
excitatory amino acids in cultured cerebral cortical neurons. J Neurosci
Res 34: 331-339.
Froger N, Cadetti L, Lorach H, Martins J, Bemelmans AP, Dubus E, et al.,
(2012). Taurine provides neuroprotection against retinal ganglion cell
degeneration. PLoS One 7: e42017.
Gupta S, Knight AG, Gupta S, Knapp PE, Hauser KF, Keller JN, et al., (2010).
HIV-Tat elicits microglial glutamate release: role of NADPH oxidase and
the cystine-glutamate antiporter. Neurosci Lett 485: 233-236.
Hayes D, Wiessner M, Rauen T, & McBean GJ (2005). Transport of L[14C]cystine and L-[14C]cysteine by subtypes of high affinity glutamate
transporters over-expressed in HEK cells. Neurochem Int 46: 585-594.
Hensley K, & Denton TT (2015). Alternative functions of the brain
transsulfuration pathway represent an underappreciated aspect of brain
redox biochemistry with significant potential for therapeutic engagement.
Free Radic Biol Med 78: 123-134.
Hernández-Benítez RI, Pasantes-Morales H, Saldaña IT, & RamosManduhano G (2010). Taurine stimulates proliferation of mice embryonic
culture neural progenitor cells. J Neurosci Res 88: 1673-1681.
Herrmann WI, & Knapp JP (2002). Hyperhomocysteinemia: a new risk factor
for neurodegenerative disease. Clin Lab 48: 471-481.
Himi T, Ikeda M, Yasuhara T, Nishida M, & Morita I (2003). Role of neuronal
glutamate transporter in the cysteine uptake and intracellular glutathione
Sulfur-Containing Amino Acids
21
levels in cultured cortical neurons. J Neural Transm (Vienna) 110: 13371348.
Hodgson N, Trivedi M, Muratore C, Li S, & Deth R (2013). Soluble oligomers
of amyloid-beta cause changes in redox state, DNA methylation, and gene
transcription by inhibiting EAAT3 mediated cysteine uptake. J Alzheimers
Dis 36: 197-209.
Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Oz G, et al.,
(2013). N-Acetylcysteine boosts brain and blood glutathione in Gaucher
and Parkinson diseases. Clin Neuropharmacol 36: 103-106.
Ishigami M, Hiraki K, Umemura K, Ogasawara Y, Ishii K, & Kimura H
(2009). A source of hydrogen sulfide and a mechanism of its release in the
brain. Antioxid Redox Signal 11: 205-214.
Kandil S, Brennan L, & McBean GJ (2010). Glutathione depletion causes a
JNK and p38MAPK-mediated increase in expression of cystathionine-lyase and upregulation of the transsulfuration pathway in C6 glioma cells.
Neurochem Int 56: 611-619.
Kigerl KA, Ankeny DA, Garg SK, Wei P, Guan Z, Wenmin L, et al., (2012).
System xc- regulated microglia and macrophage glutamate excitotoxicity
in vivo. Exp Neurol 233: 333-341.
Lane MC, Jackson JG, Krizman EN, Rothstein JD, Porter BE, & Robinson
MB (2014). Genetic deletion of the neuronal glutamate transporter,
EAAC1, results in decreased neuronal death after pilocarpine-induced
status epilepticus. Neurochem Int 73: 152-158.
Leon R, Wu H, Jin Y, Wei J, Buddhala C, Prentice H, et al., (2009). Protective
function of taurine in glutamate-induced apoptosis in cultured neurons.
Neurochem Res 87: 1185-1194.
Liu X, Albano R, & Lobner D (2014). FGF-2 induces neuronal death through
upregulation of system xc. Brain Res 1547: 25-33.
Loureiro SO, Romao L, Alves T, Fonseca A, Heimfarth L, Moura Neto V, et
al., (2010). Homocysteine induces cytoskeletal remodeling and production
of reactive oxygen species in cultured cortical astrocytes. Brain Res 1355:
151-164.
Luo Y, Zhou X, Yang X, & Wang J (2007). Homocysteine induces tau
hyperphosphorylation in rats. Neuroreport 18: 2005-2008.
Machado FR, Ferreira AG, da Cunha AA, Tagliari B, Mussulini BH, Wofchuk
S, et al., (2011). Homocysteine alters glutamate uptake and Na+, K+ATPase activity and oxidative status in rats hippocampus: protection by
vitamin C. Metab Brain Dis 26: 61-67.
22
Gethin J. McBean
Markand S, Tawfik A, Ha Y, Gnana-Prakasam J, Sonne S, Ganapathy V, et
al., (2013). Cystathionine beta synthase expression in mouse retina. Curr
Eye Res 38: 597-604.
Massie A, Boillee S, Hewett S, Knackstedt L, & Lewerenz J (2015). Main path
and byways: non-vesicular glutamate release by system xc (-) as an
important modifier of glutamatergic neurotransmission. J Neurochem 135:
1062-1079.
Matte C, Mussulini BH, dos Santos TM, Soares FM, Simao F, Matte A, et al.,
(2010). Hyperhomocysteinemia reduces glutamate uptake in parietal
cortex of rats. Int J Dev Neurosci 28: 183-187.
McBean GJ (2012). The transsulfuration pathway: a source of cysteine for
glutathione in astrocytes. Amino Acids 42: 199-205.
McBean GJ (2013). The thiol redox system in glioma biology: clinical target
and significance in resistance to glioma chemotherapy. In Gliomas:
symptoms, diagnosis and treatment options. ed Wiranowska M.a.V., F. D.,
Eds Nova Science Publishers Inc.: New York, pp 321-340.
McBean GJ, Aslan M, Griffiths HR, & Torrão RC (2015). Thiol redox
homeostasis in neurodegenerative disease. Redox Biol 5: 186-194.
Miller AL (2003). The methionine-homocysteine cycle and its effects on
cognitive diseases. Altern Med Rev 8: 7-19.
Mysona B, Dun Y, Duplantier J, Ganapathy V, & Smith SB (2009). Effects of
hyperglycaemia and oxidative stress on the glutamate transporters GLAST
and system xc- in mouse retinal Müller glial cells. Cell Tissue Res 335.
Pampliega O, Domercq M, Soria FN, Villoslada P, Rodríguez-Antigüedad A,
& Matute C (2011). Increased expression of cystine/glutamate antiporter
in multiple sclerosis. J Neuroinflamm 8: 63-75.
Piani D, & Fontana A (1994). Involvement of the cystine transport system xcin the macrophage-induced glutamate-dependent cytotoxicity to neurons. J
Immunol 152: 3578-3585.
Porter RH, & Roberts PJ (1993). Glutamate metabotropic receptor activation
in neonatal rat cerebral cortex by sulphur-containing excitatory amino
acids. Neurosci Lett 154: 78-80.
Prabhu A, Sarcar B, Kahali S, Yuan Z, Johnson JJ, Adam KP, et al., (2014).
Cysteine catabolism: a novel metabolic pathway contributing to
glioblastoma growth. Cancer Res 74: 787-796.
Rasmussen RN, Lagunas C, Plum J, Holm R, & Nielsen CU (2016).
Interactino of GABA-mimetics with the taurine transporter (TauT, Slc6a6)
in hyperosmotic treated Caco-2, LLC-PK1 and rat renal SKPT cells. Eur J
Pharm Sci 82: 138-146.
Sulfur-Containing Amino Acids
23
Reyes RC, Cittolin-Santos GF, Kim JE, Won SJ, Brennan-Minnella AM, Katz
M, et al., (2016). Neuronal glutathione content and antioxidant capacity
can be normalized in situ by N-acetyl cysteine concentrations attained in
human cerebrospinal fluid. Neurotherapeutics 13: 217-225.
Ripps H, & Shen W (2012). Review: taurine: a 'very essential' amino acid.
Molecular Vision 18: 2673-2686.
Robe PA, Martin DH, Nguyen-Khac MT, Artesi M, Deprez M, Albert A, et
al., (2009). Early termination of ISRCTN45828668, a phase 1/2
prospective, randomized study of sulfasalazine for the treatment of
progressing malignant gliomas in adults. BMC Cancer 9: 372.
Roede JR, Uppal K, Liang Y, Promislow DE, Wachtman LM, & Jones DP
(2013). Chacterization of plasma thiol redox potential in a common
marmoset model of aging. Redox Biol 18: 387-393.
Savaskan NE, Heckl A, Hahnen E, Engelhorn T, Doerfler A, Gansladt O, et
al., (2008). Small interfering RNA-mediated xCT silencing in gliomas
inhibits neurodegeneration and alleviates brain edema. Nat Med 15: 629632.
Schaub C, Uebachs M, Beck H, & Linnebank M (2013). Chronic
homocysteine
exposure
causes
changes
in
the
intrinsic
electrophysiological properties of cultured hippocampal neurons. Exp
Brain Res 225: 527-534.
Shin JY, Ahn YH, Paik MJ, Park HJ, Sohn YH, & Lee PH (2012). Elevated
homocysteine by levodopa is detrimental to neurogenesis in parkinsonian
model. PLoS One 7: e50496.
Smith KE, Borden LA, Wang CH, Hartig PR, Branchek TA, & Weinshank RL
(1992). Cloning and expression of a high affinity taurine transporter from
rat brain. Mol Pharmacol 42: 563-569.
Stipanuk MH, Londono M, Hirchberger LL, Hickey C, D.J. T, & Wang L
(2004). Evidence for expression of a single distinct form of mammalian
cysteine dioxygenase. Amino Acids 26: 99-106.
Toohey JI (2011). Sulfur signaling: is the agent sulfide or sulfane? Anal
Biochem 413: 1-7.
Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, & Banerjee R (2006).
A functional transsulfuration pathway in the brain links to glutathione
homeostasis. J Biol Chem 281: 35785-35793.
Wei HJ, Xu JH, Li MH, Tang JP, Zou W, Zhang P, et al., (2014). Hydrogen
sulfide inhibits homocysteine-induced endoplasmic reticulum stress and
neuronal apoptosis in rat hippocampus via upregulation of the BDNFTrkB pathway. Acta Pharmacol Sin 35: 707-715.
24
Gethin J. McBean
Wisniewski K, Sturman JA, Devine E, Brown WT, Rudelli R, & Wisniewski
HM (1985). Cystathionine disappearance with neuronal loss: a possible
neuronal marker. Neuropediatrics 16: 126-130.
Wrobel M, Czubak J, Bronowicka-Adamska P, Jurkowska H, Adamek D, &
Papla B (2014). Is development of high-grade gliomas sulfur-dependent?
Molecules 19: 21350-21362.
Wu H, Jin Y, Wei J, Jin H, Sha D, & Wu JY (2005). Mode of action of taurine
as a neuroprotector. Brain Res 1038: 123-131.
Wu JY, Wu H, Jin Y, Wie J, Sha D, Prentice H, et al., (2009). Mechanism of
neuroprotective function of taurine. Adv Exp Med Biol 643: 169-179.
Ye ZC, Rothstein JD, & Sontheimer H (1999). Compromised glutamate
transport in human glioma cells: reduction- mislocalization of sodiumdependent glutamate transporters and enhanced activity of cystineglutamate exchange. J Neurosci 19: 10767-10777.
Yu M, Sturgill-Short G, Ganapathy P, Tawfik A, Peachey NS, & Smith SB
(2012). Age-related changes in visual function in cystathionine-betasynthase mutant mice, a model of hyperhomocysteinemia. Exp Eye Res
96: 124-131.
Zhang CE, Wei W, Liu YH, Peng JH, Tian Q, Liu GP, et al., (2009).
Hyperhomocysteinemia increases beta-amyloid by enhancing expression
of gamma-secretase and phosphorylation of amyloid precursor protein in
rat brain. Am J Pathol 174: 1481-1491.
Zou CG, Zhao YS, Gao SY, Li SD, Cao XZ, Zhang M, et al., (2010).
Homocysteine promotes proliferation and activation of microglia.
Neurobiol Aging 31: 2069-2079.
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