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755© Springer Nature Singapore Pte Ltd. 2019
J. Hu et al. (eds.), Taurine 11, Advances in Experimental Medicine and Biology
1155, https://doi.org/10.1007/978-981-13-8023-5_66
Thiotaurine: FromChemical
andBiological Properties toRole inH2S
Signaling
AlessiaBaseggioConrado, ElisabettaCapuozzo, LucianaMosca,
AntonioFrancioso, andMarioFontana
Abstract In the last decade thiotaurine, 2-aminoethane thiosulfonate, has been
investigated as an inammatory modulating agent as a result of its ability to release
hydrogen sulde (H2S) known to play regulatory roles in inammation. Thiotaurine
can be included in the “taurine family” due to structural similarity to taurine and
hypotaurine, and is characterized by the presence of a sulfane sulfur moiety.
Thiotaurine can be produced by different pathways, such as the spontaneous trans-
sulfuration between thiocysteine– a persulde analogue of cysteine– and hypotau-
rine as well as invivo from cystine. Moreover, the enzymatic oxidation of cysteamine
to hypotaurine and thiotaurine in the presence of inorganic sulfur can occur in ani-
mal tissues and last but not least thiotaurine can be generated by the transfer of
sulfur from mercaptopyruvate to hypotaurine catalyzed by a sulfurtransferase.
Thiotaurine is an effective antioxidant agent as demonstrated by its ability to coun-
teract the damage caused by pro-oxidants in the rat. Recently, we observed the inu-
ence of thiotaurine on human neutrophils functional responses. In particular,
thiotaurine has been found to prevent human neutrophil spontaneous apoptosis sug-
gesting an alternative or additional role to its antioxidant activity. It is likely that the
sulfane sulfur of thiotaurine may modulate neutrophil activation via persuldation
This work is dedicated to the memory of Professor Doriano Cavallini and Professor Carlo De
Marco
A. BaseggioConrado
Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
Photobiology Unit, University of Dundee, Ninewells Hospital & Medical School,
Dundee, UK
E. Capuozzo · L. Mosca · M. Fontana (*)
Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
e-mail: mario.fontana@uniroma1.it
A. Francioso
Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry,
Halle, Germany
756
of target proteins. In conclusion, thiotaurine can represent a biologically relevant
sulfur donor acting as a biological intermediate in the transport, storage and release
of sulde.
Keywords Thiotaurine · Hypotaurine · Sulfane sulfur · H2S donor · H2S signaling ·
Reactive sulfur species · Hydrogen sulde · Antioxidant · Inammation · Neutrophils
Abbreviations
APAP Acetaminophen
CAT Cysteine aminotransferase
CBS Cystathionine β-synthase
CDO Cysteine dioxygenase
CN− Cyanide
CSAD Cysteine sulnate decarboxylase
CSE Cystathionine γ-lyase
GAPDH Glyceraldehyde 3-phosphate dehydrogenase
GSH Glutathione
GSSH Glutathione persulde
H2S Hydrogen sulde
HSSH Hydrogen persulde
MDA Malondialdehyde
MST Mercaptopyruvate sulfurtransferase
NAC N-acetylcysteine
PLP Pyridoxal 5′-phosphate
PMA Phorbol 12-myristate 13-acetate
ROS Reactive oxygen species
RS− Thiolate anion
RSH Thiol
RSO2H Sulnate/Hypotaurine
RSO2SH Thiosulfonate/Thiotaurine
RSO3H Sulfonate/Taurine
RSOH Sulfenate
RSSH Persulde/Thiocysteine
RSSnSR Polysulde
RSSR Disulde
S0 Zero-valent sulfur
S2− Sulde
−S2O2− Thiosulfonate group
S2O32− Thiosulfate
S8 Elemental sulfur
SCN− Thiocyanate
SO32− Sulte
STZ Streptozotocin
A. BaseggioConrado et al.
757
1 Introduction
Thiotaurine, 2-aminoethane thiosulfonate, is a sulfur containing compound charac-
terised by the presence of a thiosulfonate group (−S2O2−) containing one sulfur
bound to another sulfur atom, often referred as sulfane sulfur (Fig.1).
Due to structural similarity to sulnate and sulfonate related compounds, respec-
tively hypotaurine (RSO2H) and taurine (RSO3H), thiotaurine (RSO2SH) can be
included in the “taurine family” (Fig.2).
Interestingly, the presence of the sulfane sulfur modulates the biological proper-
ties of thiotaurine compared to that of sulfur biomolecules structurally related
(Westley and Heyse 1971; Luo and Horowitz 1994; Acharya and Lau-Cam 2013;
Capuozzo etal. 2015). Thiotaurine is a cysteine-derived metabolite, discovered in
1957 by Sörbo while studying the enzymatic reaction between mercaptopyruvate
and sulte in which thiosulfate is formed. When sulte, as sulfur acceptor, is
replaced in this transsulfuration reaction by the structurally related sulnates, thio-
sulfonates are formed instead of thiosulfate. In particular, thiotaurine is generated
by a sulfurtransferase that catalyzed the transfer of sulfur from mercaptopyruvate to
hypotaurine (Scheme 1).
Afterwards, in 1959, Cavallini and co-workers (1959a) rstly reported the bio-
logical occurrence of thiotaurine in mammals as a metabolic product of cystine
invivo, by demonstrating that rats fed with a diet supplemented in cystine excreted
taurine, hypotaurine and a newly unknown compound identied as the thiosulfonate
analogue of taurine, thiotaurine. Thiotaurine was also detected by autoradiography
of rat kidney in rats injected with 35S-cystine (Cavallini etal. 1960a). Thiotaurine
was also reported in 1986 in deep-sea symbiotic mussels in high concentrations
along with hypotaurine and taurine (Alberic 1986), where its role seems to be
related to the metabolism of the symbionts (Pruski etal. 1997).
The aim of the present review is to sum up the current knowledge of the bio-
chemical properties of thiotaurine as well as looking to its antioxidant properties
and to highlight the potential biological signicance of thiotaurine in the H2S sig-
naling mechanisms.
S
NH
2
HS
O
O
S
NH
2
HO
S
O
AB
Fig. 1 Thiotaurine:
thiosulfonate (A) and
thiosulfoxide (B)
tautomers
S
NH
2
HS
O
O
S
NH
2
HO
O
O
S
NH
2
O
OH
hypotaurine taurine thiotaurine
Fig. 2 Taurine family
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
758
2 Chemistry andBiochemistry ofThiotaurine
Thiotaurine contains a highly reactive sulfur atom, which has been dened in differ-
ent ways, such as “zero-valent sulfur (S0)”, “sulfane sulfur”, and “sulfur-bonded
sulfur”. Even if the chemical lability of sulfane sulfur has not yet been claried, it
seems to be correlated to its presence in a thiosulfoxide form (−S=S), either by
structure, as in thiosulfate, or by tautomerization (Fig. 1) (Kutney and Turnbull
1982; Toohey 1989; Toohey 2011; Toohey and Cooper 2014). The sulfur in the
thiosulfoxide form exists in an oxidation state of zero and it is easily removed by
nucleophilic acceptors such as thiolate anion (RS−), sulte (SO32−) and cyanide
(CN−) whereas, sulfane sulfur is also often named cyanolysable sulfur (Iciek and
Włodek 2001; Toohey 2011). The thiosulfoxide form is a weak bond (Steudel etal.
1997) where the sulfur atom can be released as elemental sulfur and transferred to
another sulfur atom or reduced to hydrogen sulde (H2S) by thiols, such as glutathi-
one (GSH). Thiotaurine could exist in the tautomeric thiosulfoxide form that would
then act as a perfect sulfane sulfur donor, however, neither experimental nor compu-
tational data support the existence of this tautomeric form. Anyhow, sulfane sulfur
of thiotaurine can be readily removed and transferred to an appropriate acceptor
(Westley and Heyse 1971). This transferable sulfur atom has an electrophilicity
index intermediate between that of thiosulfate ion and that of the most reactive sul-
fur compounds including hydropersulde, simply called here persulde, (RSSH)
and polysulde (RSSnSR). The sulfur-sulfur bond of thiosulfonates is readily
cleaved by simple thiol compounds forming persulde or by reduction to H2S by
thiols. Interestingly, it has been reported that the positive charged ammonium group
of thiotaurine confers an advantage in this reactivity by diminishing the electron
density of the sulfur-sulfur bond (Chauncey and Westley 1983) (Scheme 2).
From a biochemical point of view, thiotaurine is an intermediate in the cysteine/
cystine metabolic pathway. Cysteine is the main source of sulfur in the animal and
human body. It is metabolized via two metabolic routes. The rst one, called the
cysteine sulnate-dependent (aerobic) pathway, is a series of oxidative steps leading
to hypotaurine and taurine. The second one, a transsulfuration path, is independent
of cysteine sulnate (anaerobic pathway) and is a source of sulfane sulfur- containing
compounds as well as hydrogen sulde/sulde (H2S/S2−) (Stipanuk and Beck
1982;Stipanuk and Ueki 2011).
As thiotaurine is formed by the direct reaction of hypotaurine with sulde
(Cavallini etal. 1963), it can act as a link between the aerobic and anaerobic metabo-
lism of cysteine. Hypotaurine, the metabolic precursor of thiotaurine, is synthesized
S
NH2
O
OH
HO
SH
O
O
+S
NH2
HS
O
O
+
HO
O
O
S
NH2
HO
S
O
S-transferase
mercaptopyruvate hypotaurine pyruvate thiotaurine
Scheme 1 Thiotaurine synthesis catalyzed by sulfurtransferase
A. BaseggioConrado et al.
759
by the combined action of cysteine dioxygenase (CDO) that oxidizes the thiol group
of cysteine to form cysteine sulnate and of cysteine sulnate decarboxylase (CSAD)
that subsequently generates hypotaurine. Hydrogen sulde (H2S) is produced mainly
from desulfhydration of L-cysteine (Stipanuk and Ueki 2011). The enzymes involved
in the H2S production include pyridoxal 5′-phosphate (PLP)-dependent cystathio-
nine γ-lyase (CSE) and cystathionine β-synthase (CBS) as well as cysteine amino-
transferase (CAT) in conjunction with PLP-independent mercaptopyruvate
sulfurtransferase (MST) (Scheme 3) (Kabil and Banerjee 2014; Beltowski 2015).
3-Mercaptopyruvate formed by the CAT-catalysed transamination of L-cysteine
can play the role of the sulfur donor for different acceptors, including thiols and
sulte/sulnates with the formation of persuldes and thiosulfate/thiosulfonates,
respectively (Nagahara and Sawada 2006; Hildebrandt and Grieshaber 2008; Yadav
et al. 2013). In turn, thiocysteine (the persulde analogue of cysteine, RSSH) is
produced from cystine by transsulfuration enzymes, CSE and CBS (Cavallini etal.
1960b, 1962a, b; Chiku et al. 2009; Singh et al. 2009; Majtan et al. 2018).
Consequently, the sulfane sulfur of thiocysteine can be transferred to various accep-
tors (i.e. sulte, hypotaurine). Rhodanese, an important enzyme known for its abil-
ity to utilize sulfane sulfur in cyanide detoxication, transfers sulfur from
thiocysteine (RSSH) to sulte or hypotaurine (RSO2H) to generate thiosulfate or
thiotaurine (RSO2SH), respectively, and cysteine (RSH) (Reaction 1) (Cavallini
etal. 1960b; Luo and Horowitz 1994).
SO Hypotaurine RSSH SO ThiotaurineRSH
3
2
23
2
−−
+→ +//
(1)
According to this pathway, thiotaurine is produced invivo from cystine (Cavallini
etal. 1959a, 1960a) and is generated spontaneously by transsulfuration between the
persulde analogue of cysteine (RSSH) and hypotaurine (RSO2H) (De Marco etal.
1961). In several animal tissues, thiol oxidation to sulnates and thiosulfonates can
enzymatically occur when inorganic sulfur is present (De Marco and Tentori 1961;
Cavallini etal. 1961, 1963). Furthermore, thiotaurine is formed by a sulfurtransfer-
ase catalyzing sulfur transfer from mercaptopyruvate to hypotaurine (Sörbo 1957;
Sörbo 1958; Chauncey and Westley 1983).
S
NH2
HO
S
O
RSH / RS-
SO32-
CN-
RSSH
S2O32- SCN
-
H2S
Scheme 2 Thiotaurine spontaneous organic/inorganic transsulfuration reactions
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
760
3 Protective Roles ofThiotaurine
Different studies have been carried out to investigate the antioxidant activity of
thiotaurine compared with taurine or hypotaurine, which are both known as power-
ful antioxidants (Acharya and Lau-Cam 2013; Budhram etal. 2013; Mathew etal.
2013; Pandya etal. 2013; Rosenberg etal. 2006; Yancey etal. 2002, 2009; Joyner
etal. 2003; Inoue etal. 2008; Chaimbault etal. 2004).
One of the factors that seem to play a relevant role in the development of diabetic
complications is the hyperglycemia and its close relation with the development of
oxidative stress. In particular, hyperglycemia inuences the production of reactive
oxygen species (ROS) at the mitochondrial electron transport chain level (Brownlee
2005). To manage diabetes and its complications, numerous antioxidants can be
used to improve the response against the excess of ROS during oxidative stress
(Rahimi etal. 2005). Extensive work has been carried out to understand the role of
thiotaurine as antioxidant in diabetic rats, from the biochemical and cellular altera-
tion to the damage caused to the aorta and heart, and to the effect to on nephropathy
associated with this disease (Budhram etal. 2013; Mathew etal. 2013; Pandya etal.
2013). Taurine has received extensive evaluation due to its ability to protect against
oxidative damage and lately, also thiotaurine has been studied to understand the role
of thiosulfonate group compared to the sulfonate group of taurine on diabetes
(Acharya and Lau-Cam 2010; Acharya and Lau-Cam 2013).
The researches carried out by Lau-Cam and his collaborators evaluated the role
of thiotaurine in male Sprague-Dawley rats treated with streptozotocin (Budhram
Scheme 3 Metabolic pathways of cystine/cysteine
A. BaseggioConrado et al.
761
etal. 2013; Mathew et al. 2013; Pandya et al. 2013) to induce diabetes or with
acetaminophen (APAP) to induce liver damage (Acharya and Lau-Cam 2013) tar-
geting different biochemical and cellular compounds.
The protective effect of thiotaurine against hepatocellular damage has been
investigated in male rats treated with a high dose of APAP, that can cause depletion
of glutathione and of protein thiol groups and consequently a high oxidative/nitra-
tive stress condition (Acharya and Lau-Cam 2013). The liver damage was analysed
by evaluating plasma aminotransferases and lactate dehydrogenase and also oxida-
tive stress indices such as malondialdehyde (MDA), catalase, reduced glutathione,
superoxide dismutase, glutathione disulde, peroxidase in plasma and liver homog-
enates from rats treated intraperitoneally with 2.4mmol/kg dose of thiotaurine or
taurine and using N-acetylcysteine (NAC) as comparison. The results showed a
protective action of thiotaurine comparable to that exerted by NAC and better than
that of taurine (Acharya and Lau-Cam 2013). Indeed, the MDA level in liver was
attenuated in the presence of thiotaurine the reduction of glutathione/glutathione
disulde ratio was preserved.
In the three studies using the streptozotocin (STZ) (60mg/kg, i.p., for 2weeks),
chronic type 2 diabetes has been induced in male Sprague-Dawley rats. From
15days after STZ treatment and for 6weeks, a daily dose of thiotaurine or taurine
(2.4mmol/kg) has been administered and isophane insulin at 4 U/kg as reference
group has been used. On day 57 the rats were sacriced and blood, plasma, urine,
heart and thoracic aorta as well kidney samples have been collected. Different
parameters have been tested such as the glutathione redox status, insulin and gly-
cated hemoglobin levels, antioxidant enzymes activities, cholesterol and triglycer-
ides, malondialdehyde, creatinine, sodium and potassium levels. Data from all these
studies demonstrate that thiotaurine has generally an effect comparable to insulin
against the changes associated with diabetes. A greater effect of thiotaurine has
been shown on hyperglycemia, hypoinsulinemia and hyperlipidemia compared with
taurine. These ndings suggest a better antioxidant effect of thiotaurine due to the
presence of the thiosulfonate group.
Studies performed on deep-sea animals have detected a high level of thiotaurine
as well hypotaurine (Pruski etal. 1997; Yancey etal. 2009). These two sulfur amino
acids seem to serve as osmolytes, to balance internal osmotic pressure with that of
the ocean but mainly, thiotaurine seems to transport and/or detoxify sulde
(Rosenberg etal. 2006; Yancey etal. 2002). The studies suggested that hypotaurine
could interact with the excess of sulde, through a hypothesis not supported by
experimental data where the oxygen of hypotaurine sulnic group should interact
with the sulde radical to form thiotaurine. Being a toxic compound, hydrogen sul-
de can interact with iron and consequently bind proteins resulting in cellular dam-
age (Inoue etal. 2008).
The presence of thiotaurine in these animals seems to be correlated to their need
to decrease the level of sulde, consequently thiotaurine can be included in the
mechanisms developed to contrast the presence of sulde radical in the deep-sea
animals. Moreover, thiotaurine has been proposed as a marker in animals with a
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
762
sulde-based symbiosis. Inoue and co-workers (2008) have also proved that the
taurine transport in the deep-sea mussel Bathymodiolus septemdierum has an afn-
ity for thiotaurine and hypotaurine suggesting an involvement of this transporter in
sulde detoxication.
4 Thiotaurine: H2S Donor/Reactive Sulfane-Sulfur Species
Thiotaurine (RSO2SH) has the ability to release hydrogen sulde (H2S) in a thiol-
dependent reaction. In particular, a thiosulfate reductase activity occurring in vari-
ous animal cells uses electrons of thiols, such as glutathione, to reduce sulfane
sulfur of thiosulfonates, such as thiotaurine (Koj etal. 1967; Chauncey and Westley
1983; Hildebrandt and Grieshaber 2008). The reaction mechanism involves the for-
mation of a persulde (RSSH) (Reaction 2) that spontaneously releases hydrogen
sulde (Reaction 3) in the presence of excess thiols (RSH).
RSOSHRSH RSOH RSSH
22
+→ +
(2)
RSSH RSHRSSR
HS+→ +
2 (3)
In general, H2S can be easily released from sulfane sulfur compounds in the pres-
ence of reducing agents (Mikami etal. 2011). Accordingly, it has been observed that
human neutrophils generate H2S and hypotaurine (RSO2H) from thiotaurine with
GSH as catalyst (Capuozzo etal. 2013). As a result, thiotaurine can be considered a
thiol-activated H2S-donor molecule.
In absence of thiols, thiotaurine is quite stable, but exposed to irradiation decom-
poses to hypotaurine and elemental sulfur (Reaction 4) (Cavallini etal. 1959b).
RSOSHRSO
HS
22
8
→+
(4)
It is possible that thiotaurine is also involved in the sulde oxidation pathways.
In this reactions, H2S is oxidized by the mitochondrial sulde:quinone oxidoreduc-
tase (SQR) generating a protein-bound persulde, which is subsequently transferred
to acceptors, such as GSH or sulte/sulnate, resulting in the formation of GSH
persulde (GSSH) or thiosulfate/thiosulfonate (Kabil and Banerjee 2010, 2014;
Jackson etal. 2012). In the latter case, the sulfane sulfur of thiosulfate/thiosulfonate
can be remobilized by a sulfurtransferase, including thiosulfate reductase as in the
Reactions 2 and 3 (Scheme 4).
According to these reactions, there is a close relationship between H2S and the
sulfane sulfur compounds, which are regarded as a large and highly regulated physi-
ological H2S reservoir in biological systems (Kimura 2011). In this regard, thiotau-
rine with its sulfane sulfur moiety can be part of the sulfur store pool and represent
A. BaseggioConrado et al.
763
a biologically relevant sulfur donor. Recently, sulfane sulfur and H2S have been
included in the family of reactive sulfur species (RSS). The initial concept of RSS
postulated by Giles etal. (2001) has now expanded to include a variety of sulfur-
containing secondary metabolites, such as reactive sulfane-sulfur species, and con-
sequently, thiotaurine can be considered as a reactive sulfane-sulfur species with
regulatory functions in the cells (Giles etal. 2017). Besides thiosulfonates such as
thiotaurine, the group of biologically reactive sulfane-sulfur species includes persul-
de (RSSH) and hydrogen persulde (HSSH), thiosulfate (S2O32−), organic
(RSSnSR, n≥1) and inorganic (H2Sn, n≥3) polysuldes, and elemental sulfur (S8).
5 Thiotaurine Involvement inH2S Signaling
The biological role of thiotaurine in the cell regulatory processes resides in the close
relationship between its ability to release H2S in a thiol-dependent mechanism and
its property of bearing a sulfane sulfur atom. Owing to these characteristics, thiotau-
rine takes part in the H2S signaling pathways. H2S is a gaseous signaling molecule
able to act as neurotransmitter, modulator of inammation, vasorelaxant (Abe and
Kimura 1996; Zanardo etal. 2006; Yang etal. 2008; Whiteman and Winyard 2011;
Predmore etal. 2012). However, the actual mechanism of H2S-mediated signaling
remains to be fully understood. One proposed mechanism whereby H2S signals is
the modication of protein cysteine residues by persuldation, also called
S-sulfhydration (Mustafa etal. 2009; Paul and Snyder 2012; Filipovic etal. 2018).
Therefore, the transmission of sulde-based signals includes activation or inactiva-
tion of enzymes via post-translational modication of reactive cysteine thiols (RSH)
to persuldes (RSSH) (Toohey 2011; Yadav etal. 2016). To ensure that this post-
translational modication occurs, H2S must react with oxidized protein cysteine
residues, such as sulfenates (RSOH) (Reaction 5) or disuldes (RSSR) (Reaction 6)
to give persuldes (RSSH) (Kabil and Banerjee 2010; Finkel 2012; Francoleon
etal. 2011; Cuevasanta etal. 2015).
Scheme 4 Transsulfuration pathway of thiotaurine
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
764
RSOH HS RSSH
HO+→ +
22
(5)
RSSR HS RSSH RSH
+→ +
2 (6)
However, the reaction of disuldes with H2S is unlikely to occur under physio-
logical conditions, due to the low concentration invivo and the non-sufcient reduc-
tion potential of H2S (Kabil and Banerjee 2010; Toohey 2011). Conversely, sulfane
sulfur (S0) can be readily transferred to thiols (Reaction 7) and disuldes (Reaction
8) with the formation of persuldes and trisuldes, respectively, via the thiosulfox-
ide (−S=S) tautomer as transient intermediate (Toohey 1989; Toohey and Cooper
2014).
RSHS RS SH RSSH
+→
()
→
0
(7)
RSSR SRSSSRRSSSR
+→
()
→
0
(8)
Analogously, sulfane sulfur and a thiosulfoxide intermediate are involved in the
direct reaction of thiols with H2S (Chen and Morris 1972; Kotronarou and Hoffmann
1991; Toohey 2011). The reaction can be considered the combination of two reac-
tions: the reaction of H2S with oxygen to give rise to sulfane sulfur; and the transfer
of the sulfane sulfur to thiols (Reaction 9).
RSHHSORSSH
HO++ →+
22 2
½ (9)
Recent studies indicate that reactive intermediates other than H2S react with thi-
ols to generate persuldes (Ida etal. 2014; Mishanina etal. 2015). These reactive
sulfur species are formed during sulde oxidation reactions and sulfur amino acid
metabolism. Some of these reactive intermediates have been identied among the
sulfane sulfur compounds. In this regard, thiotaurine with its sulfane sulfur moiety
can represent a biologically relevant sulfur donor intermediate in protein cysteine
persuldation reactions (Reactions 10 and 11).
RSOSHRSH RSOH RSSH
22
+→ +
(10)
RSOSHRSSR RSOH RSSSR
22
+→ +
(11)
Interestingly, persuldation reactions occur at high level in the mitochondria
during the H2S oxidation pathway, where protein-bound persuldes and GSSH are
formed (Jackson etal. 2012). Mitochondrial rhodanese-catalyzed reactions generate
other sulfane sulfur intermediates, such as thiosulfates and possibly thiosulfonates
from the sulfane sulfur of persuldes (Reaction 12) (Sörbo 1958; Hildebrandt and
Grieshaber 2008; Libiad etal. 2014).
SO RSOH RSSH SO RSOSHRSH
3
2
223
2
2
−−
+→ +//
(12)
A. BaseggioConrado et al.
765
Taking into account these reactions, sulde oxidation pathways can be considered a
way for generation of sulfane sulfur compounds, such as persuldes, polysuldes,
thiosulfate and thiosulfonates. Sulfane sulfur generation can be perceived as a res-
ervoir of H2S and a pathway for elemental sulfur release. Consequently, the thiotau-
rine formation can be proposed as one of the methods of H2S storage in cells, from
which it can be released by thiosulfate reductase (Reactions 2 and 3). Furthermore,
the body uid and tissue concentration of this thiosulfonate can be considered as an
indicator of H2S biogenesis in the biological systems.
6 Thiotaurine andInammation
In the last years, the regulatory role of thiotaurine in the innate immune response
has been reported. In particular, the ability of thiotaurine to act as a bioactive com-
pound able to regulate inammation has been investigated in human neutrophils,
cells of the innate immune response that constitute the major players during acute
inammation. Leukocytes can eliminate pathogens by two different microbicidal
mechanisms: an oxygen-dependent mechanism, which produces reactive oxygen
species by NADPH oxidase complex, and an oxygen-independent mechanism,
which acts through the production of antimicrobial peptides and proteolytic
enzymes. In this context, it has been demonstrated that thiotaurine is an effective
antioxidant agent due to its ability to counteract ROS generation and superoxide
anion production in activated human neutrophils (Capuozzo etal. 2015). Moreover,
it has been reported that thiotaurine prevents human neutrophil spontaneous apop-
tosis by inhibiting caspase-3 activation, suggesting an alternative or additional role
to besides its antioxidant activity (Capuozzo etal. 2013). Interestingly, it has been
showed that the effects exerted by thiotaurine on human neutrophil responses are
signicantly higher than taurine and its derivatives or related compounds (Capuozzo
et al. 2015). Specically, thiotaurine inhibits human neutrophil activation in
response to PMA, a diacylglycerol substitute that activates protein kinase C
(Capuozzo etal. 2015). In this regard, in a recent paper, the proteomic proling of
PMA-activated human neutrophils has been applied to study and identify proteins
that change their expression level or undergo biochemical modications after thio-
taurine pre-treatment of granulocytes (Capuozzo etal. 2017). In particular, it has
been demonstrated that thiotaurine affects glyceraldehyde-3-phosphate dehydroge-
nase (GAPDH) expression and induces down-regulation of this enzyme in activated
leukocytes. They suggest that thiotaurine plays an active role in the mechanisms
underlying the inammatory process inuencing the energy metabolism of acti-
vated granulocytes, and propose an intriguing molecular mechanism by which thio-
taurine modulates human leukocyte activation in which persuldation of target
proteins very likely occurs (Capuozzo etal. 2017).
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
766
7 Other Biological Effects ofThiotaurine
Thiotaurine participates in the endogenous detoxication of cyanide by the coupled
action of two enzymes, CSE and rhodanese (Szczepkowski and Wood 1967). In this
mechanism, the cyanide (CN−) is eventually metabolized by the sulfurtransferase
activity of rhodanese to the less toxic thiocyanate (SCN−). The persulde analogue
of cysteine, thiocysteine, is produced from cystine by CSE, the rst enzyme of the
coupled system. Afterwards, thiocysteine transsulfurates hypotaurine to thiotaurine
(Cavallini etal. 1960b). The formed thiotaurine is an excellent sulfur substrate for
rhodanese-catalyzed transsulfuration of cyanide to thiocyanate (Luo and Horowitz
1994). Noteworthy, thiotaurine increases survival of mouse following a lethal dose
of cyanide (Dulaney etal. 1989). Thiotaurine has been also tested invivo as a sulfur
donor for detoxication of cyanide in the chicken and it has been found that thiotau-
rine supported thiocyanate urinary excretion to a similar extent to other rhodanese
sulfur donors (Mousa and Davis 1991). However, it has been also reported that
prophylactic treatment with thiotaurine does not protect nearly as much against cya-
nide exposure as the sulfur donor thiosulfate (Marziaz etal. 2013).
Recently, the neuroprotective effect of thiotaurine in isolated cerebellar granule
cells has been investigated. This is a well-established system to study cell survival
and apoptosis. Thiotaurine protects mouse cerebellar granule cells by potassium
deprivation-induced apoptosis by inhibiting caspase-3 (Dragotto et al. 2015).
Thiotaurine showed also a displacing effect of 3H-GABA binding to GABAA recep-
tors in bovine brain cortical membranes (Costa etal. 1990). Thiotaurine is similar in
displacing potency to taurine and hypotaurine, which for a long time have been
investigated for a neurophysiological role (Oja and Kontro 1982). Interestingly, the
thiotaurine higher homologue, homothiotaurine, exhibits also a good afnity for the
GABA sites (Costa etal. 1990).
Several anionic sulfur compounds reduce the toxicity of mustard agents.
Consequently, thiotaurine has been tested as a protective agent against DNA dam-
age caused by sulfur and nitrogen mustards. Baskin and co-workers (2000) pro-
posed that the interaction of thiotaurine with DNA could protect against sulfur
mustard intoxication.
8 Conclusions
Thiotaurine is a thiosulfonate compound bearing a sulfane sulfur atom metaboli-
cally generated in body uids and tissues. Thiotaurine constitutes an interconnec-
tion molecule between aerobic and anaerobic pathways of cysteine metabolism.
Thiotaurine formed as a result of the reaction between hypotaurine and sulde may
be converted back to H2S and hypotaurine. Thus, thiotaurine may be considered as
a safe, non-toxic storage form of H2S and an important key intermediate in the bio-
chemical routes of transport, storage and release of sulde. Sulfane sulfur- containing
A. BaseggioConrado et al.
767
compounds efciently regulate the activity of enzymes and exhibit antioxidative
properties. Interestingly, thiotaurine inuences inammatory processes modulating
functional responses of human neutrophils and exhibits a protective effect against
oxidative damage. In many papers is widely recognized that thiotaurine-related
compounds such as taurine, hypotaurine and taurine chloramine exert a regulatory
role in acute inammation (Green etal. 1991; Marcinkiewicz and Kontny 2014;
Kim and Cha 2014), whereas, thiotaurine shows a more powerful effect compared
to the related compounds, hypotaurine and taurine (Capuozzo etal. 2015).
All these reasons suggest that thiotaurine is a signaling biomolecule exerting
regulative functions in the cells. The inuence of thiotaurine on biological cell
responses can be attributed to its involvement in H2S signaling, as H2S donor and/or
as reactive sulfane-sulfur species. Noteworthy, it has been reported that biological
effects initially attributed to H2S actually are caused by sulfane sulfur compounds
(Ida etal. 2014; Mishanina et al. 2015). Protein persuldation of key regulatory
cysteine residues is considered as a major mechanism of sulde signaling. In this
regard, thiotaurine can represent a biologically relevant sulfur donor in persulde
formation in proteins. In summary, thiotaurine, due to its peculiar properties and its
ability to modulate and control H2S signal, seems to be a very interesting biomole-
cule whose regulatory pathways are worth to be investigated more in depth.
Acknowledgement The authors are grateful to Dr. Alessandro Chinazzi (Department of
Biochemical Sciences– Sapienza University of Rome) for the technical assistance.
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