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Thiotaurine: From Chemical and Biological Properties to Role in H2S Signaling

Authors:

Abstract

In the last decade thiotaurine, 2-aminoethane thiosulfonate, has been investigated as an inflammatory modulating agent as a result of its ability to release hydrogen sulfide (H2S) known to play regulatory roles in inflammation. 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 transsulfuration between thiocysteine - a persulfide analogue of cysteine - and hypotaurine as well as in vivo from cystine. Moreover, the enzymatic oxidation of cysteamine to hypotaurine and thiotaurine in the presence of inorganic sulfur can occur in animal 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 counteract the damage caused by pro-oxidants in the rat. Recently, we observed the influence of thiotaurine on human neutrophils functional responses. In particular, thiotaurine has been found to prevent human neutrophil spontaneous apoptosis suggesting an alternative or additional role to its antioxidant activity. It is likely that the sulfane sulfur of thiotaurine may modulate neutrophil activation via persulfidation 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 sulfide.
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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: FromChemical
andBiological Properties toRole inH2S
Signaling
AlessiaBaseggioConrado, ElisabettaCapuozzo, LucianaMosca,
AntonioFrancioso, andMarioFontana
Abstract In the last decade thiotaurine, 2-aminoethane thiosulfonate, has been
investigated as an inammatory modulating agent as a result of its ability to release
hydrogen sulde (H2S) known to play regulatory roles in inammation. 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 persulde analogue of cysteine– and hypotau-
rine as well as invivo 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 inu-
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 persuldation
This work is dedicated to the memory of Professor Doriano Cavallini and Professor Carlo De
Marco
A. BaseggioConrado
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 sulde.
Keywords Thiotaurine · Hypotaurine · Sulfane sulfur · H2S donor · H2S signaling ·
Reactive sulfur species · Hydrogen sulde · Antioxidant · Inammation · Neutrophils
Abbreviations
APAP Acetaminophen
CAT Cysteine aminotransferase
CBS Cystathionine β-synthase
CDO Cysteine dioxygenase
CN Cyanide
CSAD Cysteine sulnate decarboxylase
CSE Cystathionine γ-lyase
GAPDH Glyceraldehyde 3-phosphate dehydrogenase
GSH Glutathione
GSSH Glutathione persulde
H2S Hydrogen sulde
HSSH Hydrogen persulde
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 Sulnate/Hypotaurine
RSO2SH Thiosulfonate/Thiotaurine
RSO3H Sulfonate/Taurine
RSOH Sulfenate
RSSH Persulde/Thiocysteine
RSSnSR Polysulde
RSSR Disulde
S0 Zero-valent sulfur
S2 Sulde
S2O2 Thiosulfonate group
S2O32 Thiosulfate
S8 Elemental sulfur
SCN Thiocyanate
SO32 Sulte
STZ Streptozotocin
A. BaseggioConrado 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 sulnate 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 etal. 2015). Thiotaurine is a cysteine-derived metabolite, discovered in
1957 by Sörbo while studying the enzymatic reaction between mercaptopyruvate
and sulte in which thiosulfate is formed. When sulte, as sulfur acceptor, is
replaced in this transsulfuration reaction by the structurally related sulnates, 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
invivo, by demonstrating that rats fed with a diet supplemented in cystine excreted
taurine, hypotaurine and a newly unknown compound identied as the thiosulfonate
analogue of taurine, thiotaurine. Thiotaurine was also detected by autoradiography
of rat kidney in rats injected with 35S-cystine (Cavallini etal. 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 etal. 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 signicance 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: FromChemical andBiological Properties toRole inH2S Signaling
758
2 Chemistry andBiochemistry ofThiotaurine
Thiotaurine contains a highly reactive sulfur atom, which has been dened 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 claried, 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), sulte (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 etal.
1997) where the sulfur atom can be released as elemental sulfur and transferred to
another sulfur atom or reduced to hydrogen sulde (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 hydropersulde, simply called here persulde, (RSSH)
and polysulde (RSSnSR). The sulfur-sulfur bond of thiosulfonates is readily
cleaved by simple thiol compounds forming persulde 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 sulnate-dependent (aerobic) pathway, is a series of oxidative steps leading
to hypotaurine and taurine. The second one, a transsulfuration path, is independent
of cysteine sulnate (anaerobic pathway) and is a source of sulfane sulfur- containing
compounds as well as hydrogen sulde/sulde (H2S/S2) (Stipanuk and Beck
1982;Stipanuk and Ueki 2011).
As thiotaurine is formed by the direct reaction of hypotaurine with sulde
(Cavallini etal. 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. BaseggioConrado et al.
759
by the combined action of cysteine dioxygenase (CDO) that oxidizes the thiol group
of cysteine to form cysteine sulnate and of cysteine sulnate decarboxylase (CSAD)
that subsequently generates hypotaurine. Hydrogen sulde (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
sulte/sulnates with the formation of persuldes and thiosulfate/thiosulfonates,
respectively (Nagahara and Sawada 2006; Hildebrandt and Grieshaber 2008; Yadav
et al. 2013). In turn, thiocysteine (the persulde analogue of cysteine, RSSH) is
produced from cystine by transsulfuration enzymes, CSE and CBS (Cavallini etal.
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. sulte, hypotaurine). Rhodanese, an important enzyme known for its abil-
ity to utilize sulfane sulfur in cyanide detoxication, transfers sulfur from
thiocysteine (RSSH) to sulte or hypotaurine (RSO2H) to generate thiosulfate or
thiotaurine (RSO2SH), respectively, and cysteine (RSH) (Reaction 1) (Cavallini
etal. 1960b; Luo and Horowitz 1994).
SO Hypotaurine RSSH SO ThiotaurineRSH
3
2
23
2
−−
+→ +//
(1)
According to this pathway, thiotaurine is produced invivo from cystine (Cavallini
etal. 1959a, 1960a) and is generated spontaneously by transsulfuration between the
persulde analogue of cysteine (RSSH) and hypotaurine (RSO2H) (De Marco etal.
1961). In several animal tissues, thiol oxidation to sulnates and thiosulfonates can
enzymatically occur when inorganic sulfur is present (De Marco and Tentori 1961;
Cavallini etal. 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: FromChemical andBiological Properties toRole inH2S Signaling
760
3 Protective Roles ofThiotaurine
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 etal. 2013; Mathew etal.
2013; Pandya etal. 2013; Rosenberg etal. 2006; Yancey etal. 2002, 2009; Joyner
etal. 2003; Inoue etal. 2008; Chaimbault etal. 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 inuences 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 etal. 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 etal. 2013; Mathew etal. 2013; Pandya etal.
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. BaseggioConrado et al.
761
etal. 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 disulde, peroxidase in plasma and liver homog-
enates from rats treated intraperitoneally with 2.4mmol/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
disulde ratio was preserved.
In the three studies using the streptozotocin (STZ) (60mg/kg, i.p., for 2weeks),
chronic type 2 diabetes has been induced in male Sprague-Dawley rats. From
15days after STZ treatment and for 6weeks, a daily dose of thiotaurine or taurine
(2.4mmol/kg) has been administered and isophane insulin at 4 U/kg as reference
group has been used. On day 57 the rats were sacriced 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 etal. 1997; Yancey etal. 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 sulde
(Rosenberg etal. 2006; Yancey etal. 2002). The studies suggested that hypotaurine
could interact with the excess of sulde, through a hypothesis not supported by
experimental data where the oxygen of hypotaurine sulnic group should interact
with the sulde 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 etal. 2008).
The presence of thiotaurine in these animals seems to be correlated to their need
to decrease the level of sulde, consequently thiotaurine can be included in the
mechanisms developed to contrast the presence of sulde radical in the deep-sea
animals. Moreover, thiotaurine has been proposed as a marker in animals with a
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
762
sulde-based symbiosis. Inoue and co-workers (2008) have also proved that the
taurine transport in the deep-sea mussel Bathymodiolus septemdierum has an afn-
ity for thiotaurine and hypotaurine suggesting an involvement of this transporter in
sulde detoxication.
4 Thiotaurine: H2S Donor/Reactive Sulfane-Sulfur Species
Thiotaurine (RSO2SH) has the ability to release hydrogen sulde (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 etal. 1967; Chauncey and Westley
1983; Hildebrandt and Grieshaber 2008). The reaction mechanism involves the for-
mation of a persulde (RSSH) (Reaction 2) that spontaneously releases hydrogen
sulde (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 etal. 2011). Accordingly, it has been observed that
human neutrophils generate H2S and hypotaurine (RSO2H) from thiotaurine with
GSH as catalyst (Capuozzo etal. 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 etal. 1959b).
RSOSHRSO
HS
22
8
→+
(4)
It is possible that thiotaurine is also involved in the sulde oxidation pathways.
In this reactions, H2S is oxidized by the mitochondrial sulde:quinone oxidoreduc-
tase (SQR) generating a protein-bound persulde, which is subsequently transferred
to acceptors, such as GSH or sulte/sulnate, resulting in the formation of GSH
persulde (GSSH) or thiosulfate/thiosulfonate (Kabil and Banerjee 2010, 2014;
Jackson etal. 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. BaseggioConrado 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 etal. (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 etal. 2017). Besides thiosulfonates such as
thiotaurine, the group of biologically reactive sulfane-sulfur species includes persul-
de (RSSH) and hydrogen persulde (HSSH), thiosulfate (S2O32), organic
(RSSnSR, n1) and inorganic (H2Sn, n3) polysuldes, and elemental sulfur (S8).
5 Thiotaurine Involvement inH2S 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 inammation, vasorelaxant (Abe and
Kimura 1996; Zanardo etal. 2006; Yang etal. 2008; Whiteman and Winyard 2011;
Predmore etal. 2012). However, the actual mechanism of H2S-mediated signaling
remains to be fully understood. One proposed mechanism whereby H2S signals is
the modication of protein cysteine residues by persuldation, also called
S-sulfhydration (Mustafa etal. 2009; Paul and Snyder 2012; Filipovic etal. 2018).
Therefore, the transmission of sulde-based signals includes activation or inactiva-
tion of enzymes via post-translational modication of reactive cysteine thiols (RSH)
to persuldes (RSSH) (Toohey 2011; Yadav etal. 2016). To ensure that this post-
translational modication occurs, H2S must react with oxidized protein cysteine
residues, such as sulfenates (RSOH) (Reaction 5) or disuldes (RSSR) (Reaction 6)
to give persuldes (RSSH) (Kabil and Banerjee 2010; Finkel 2012; Francoleon
etal. 2011; Cuevasanta etal. 2015).
Scheme 4 Transsulfuration pathway of thiotaurine
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
764
RSOH HS RSSH
(5)
RSSR HS RSSH RSH
+→ +
2 (6)
However, the reaction of disuldes with H2S is unlikely to occur under physio-
logical conditions, due to the low concentration invivo and the non-sufcient reduc-
tion potential of H2S (Kabil and Banerjee 2010; Toohey 2011). Conversely, sulfane
sulfur (S0) can be readily transferred to thiols (Reaction 7) and disuldes (Reaction
8) with the formation of persuldes and trisuldes, 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 persuldes (Ida etal. 2014; Mishanina etal. 2015). These reactive
sulfur species are formed during sulde oxidation reactions and sulfur amino acid
metabolism. Some of these reactive intermediates have been identied 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
persuldation reactions (Reactions 10 and 11).
RSOSHRSH RSOH RSSH
22
+→ +
(10)
RSOSHRSSR RSOH RSSSR
22
+→ +
(11)
Interestingly, persuldation reactions occur at high level in the mitochondria
during the H2S oxidation pathway, where protein-bound persuldes and GSSH are
formed (Jackson etal. 2012). Mitochondrial rhodanese-catalyzed reactions generate
other sulfane sulfur intermediates, such as thiosulfates and possibly thiosulfonates
from the sulfane sulfur of persuldes (Reaction 12) (Sörbo 1958; Hildebrandt and
Grieshaber 2008; Libiad etal. 2014).
SO RSOH RSSH SO RSOSHRSH
3
2
223
2
2
−−
+→ +//
(12)
A. BaseggioConrado et al.
765
Taking into account these reactions, sulde oxidation pathways can be considered a
way for generation of sulfane sulfur compounds, such as persuldes, polysuldes,
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 andInammation
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 inammation has been investigated in human neutrophils,
cells of the innate immune response that constitute the major players during acute
inammation. 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 etal. 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 etal. 2013). Interestingly, it has been
showed that the effects exerted by thiotaurine on human neutrophil responses are
signicantly higher than taurine and its derivatives or related compounds (Capuozzo
et al. 2015). Specically, thiotaurine inhibits human neutrophil activation in
response to PMA, a diacylglycerol substitute that activates protein kinase C
(Capuozzo etal. 2015). In this regard, in a recent paper, the proteomic proling of
PMA-activated human neutrophils has been applied to study and identify proteins
that change their expression level or undergo biochemical modications after thio-
taurine pre-treatment of granulocytes (Capuozzo etal. 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 inammatory process inuencing the energy metabolism of acti-
vated granulocytes, and propose an intriguing molecular mechanism by which thio-
taurine modulates human leukocyte activation in which persuldation of target
proteins very likely occurs (Capuozzo etal. 2017).
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
766
7 Other Biological Effects ofThiotaurine
Thiotaurine participates in the endogenous detoxication 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 persulde analogue
of cysteine, thiocysteine, is produced from cystine by CSE, the rst enzyme of the
coupled system. Afterwards, thiocysteine transsulfurates hypotaurine to thiotaurine
(Cavallini etal. 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 etal. 1989). Thiotaurine has been also tested invivo as a sulfur
donor for detoxication 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 etal. 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 etal. 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 afnity for the
GABA sites (Costa etal. 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 sulde 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 sulde. Sulfane sulfur- containing
A. BaseggioConrado et al.
767
compounds efciently regulate the activity of enzymes and exhibit antioxidative
properties. Interestingly, thiotaurine inuences inammatory 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 inammation (Green etal. 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 etal. 2015).
All these reasons suggest that thiotaurine is a signaling biomolecule exerting
regulative functions in the cells. The inuence 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 etal. 2014; Mishanina et al. 2015). Protein persuldation of key regulatory
cysteine residues is considered as a major mechanism of sulde signaling. In this
regard, thiotaurine can represent a biologically relevant sulfur donor in persulde
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.
References
Abe K, Kimura H (1996) The possible role of hydrogen sulde as an endogenous neuromodulator.
JNeurosci 16:1066–1071
Acharya M, Lau-Cam CA (2010) Comparison of the protective actions of N-acetylcysteine, hypo-
taurine and taurine against acetaminophen-induced hepatotoxicity in the rat. J Biomed Sci
17(Suppl 1):S35
Acharya M, Lau-Cam CA (2013) Comparative evaluation of the effects of taurine and thiotaurine
on alterations of the cellular redox status and activities of antioxidant and glutathione-related
enzymes by acetaminophen in the rat. Adv Exp Med Biol 776:199–215
Alberic P (1986) Occurrence of thiotaurine and hypotaurine in the tissues of Riftia pachyptila.
Comptes Rendus de l’Académie des Sciences Paris 302:503–508
Baskin SI, Prabhaharan V, Bowman JD, Novak MJ (2000) In vitro effects of anionic sulfur com-
pounds on the spectrophotometric properties of native DNA.J Appl Toxicol 20:S3–S5
Bełtowski J(2015) Hydrogen sulde in pharmacology and medicine– an update. Pharmacol Rep
67:647–658
Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes
54:1615–1625
Budhram R, Pandya KG, Lau-Cam CA (2013) Protection by taurine and thiotaurine against
biochemical and cellular alterations induced by diabetes in a rat model. Adv Exp Med Biol
775:321–343
Capuozzo E, Pecci L, Baseggio Conrado A, Fontana M (2013) Thiotaurine prevents apoptosis of
human neutrophils: a putative role in inammation. Adv Exp Med Biol 775:227–236
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signaling
768
Capuozzo E, Baseggio Conrado A, Fontana M (2015) Thiotaurine modulates human neutrophil
activation. Adv Exp Med Biol 803:145–155
Capuozzo E, Giorgi A, Canterini S, Baseggio Conrado A, Giarrusso P, Schininà ME, Fontana M
(2017) A proteomic approach to study the effect of thiotaurine on human neutrophil activation.
Adv Exp Med Biol 975:563–571
Cavallini D, De Marco C, Mondovì B (1959a) Chromatographic evidence of the occurence of
thiotaurine in the urine of rats fed with cystine. JBiol Chem 234:854–857
Cavallini D, Mondovì B, Giovanella B, De Marco C (1959b) Degradation of thiotaurine by ion-
izing radiations. Nature 184:61
Cavallini D, De Marco C, Mondovì B, Tentori L (1960a) Radioautographic detection of metabo-
lites of 35S-DL-cystine. JChromatogr 3:20–24
Cavallini D, De Marco C, Mondovì B, Mori BG (1960b) The cleavage of cystine by cystathionase
and the transulfuration of hypotaurine. Enzymologia 22:161–173
Cavallini D, De Marco C, Mondovì B (1961) Detection and distribution of enzymes for oxidizing
thiocysteamine. Nature 192:557–558
Cavallini D, Mondovì B, De Marco C, Scioscia-Santoro A (1962a) Inhibitory effect of mercap-
toethanol and hypotaurine on the desulfhydration of cysteine by cystathionase. Arch Biochem
Biophys 96:456–457
Cavallini D, Mondovì B, De Marco C, Scioscia-Santoro A (1962b) The mechanism of desulphy-
dration of cysteine. Enzymologia 24:253–266
Cavallini D, Scandurra R, De Marco C (1963) The enzymatic oxidation of cysteamine to hypotau-
rine in the presence of sulde. JBiol Chem 238:2999–3005
Chaimbault P, Alberic P, Elfakir C, Lafosse M (2004) Development of an LC-MS-MS method for
the quantication of taurine derivatives in marine invertebrates. Anal Biochem 332:215–225
Chauncey TR, Westley J (1983) The catalytic mechanism of yeast thiosulfate reductase. J Biol
Chem 258:15037–15045
Chen KY, Morris JC (1972) Kinetics of oxidation of aqueous sulde by O2. Environ Sci Technol
6:529–537
Chiku T, Padovani D, Zhu W, Singh S, Vitvitsky V, Banerjee R (2009) H2S biogenesis by human
cystathionine γ-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine
and is responsive to the grade of hyperhomocysteinemia. JBiol Chem 284:11601–11612
Costa M, Vesci L, Fontana M, Solinas SP, Duprè S, Cavallini D (1990) Displacement of [3H]GABA
binding to bovine brain receptors by sulfur-containing analogues. Neurochem Int 17:547–551
Cuevasanta E, Lange M, Bonanata J, Coitiño EL, Ferre-Sueta G, Filipovic MR, Alvarez B (2015)
Reaction of hydrogen sulde with disulde and sulfenic acid to form the strongly nucleophilic
persulde. JBiol Chem 290:26866–26880
De Marco C, Tentori L (1961) Sulfur exchange between thiotaurine and hypotaurine. Experientia
17:345–346
De Marco C, Coletta M, Cavallini D (1961) Spontaneous transulfuration of sulnates by organic
persuldes. Arch Biochem Biophys 93:179–180
Dragotto J, Capuozzo E, Fontana M, Curci A, Fiorenza MT, Canterini S (2015) Thiotaurine pro-
tects mouse cerebellar granule neurons from potassium deprivation-induced apoptosis by
inhibiting the activation of caspase-3. Adv Exp Med Biol 803:513–523
Dulaney MD Jr, Pellicore LS, Wisler JS (1989) The efcacy of alpha-ketoglutaric acid and
2- aminoethanesulfonate as a prophylactic antidote against cyanide. In: Proceedings of the
medical defense bioscience review. US Army Medical Research Institute of Chemical Defense,
Aberdeen Proving Ground, pp25–31
Filipovic M, Zivanovic J, Alvarez B, Banerjee R (2018) Chemical biology of H2S signaling through
persuldation. Chem Rev 118:1253–1337
Finkel T (2012) From sulfenylation to sulfhydration: what a thiolate needs to tolerate. Sci Signal
5:pe10
Francoleon NE, Carrington SJ, Fukuto JM (2011) The reaction of H2S with oxidized thiols: gen-
eration of persuldes and implications to H2S biology. Arch Biochem Biophys 516:146–153
A. BaseggioConrado et al.
769
Giles GI, Tasker KM, Jacob C (2001) Hypothesis: the role of reactive sulfur species in oxidative
stress. Free Radic Biol Med 31:1279–1283
Giles GI, Nasim MJ, Ali W, Jacob C (2017) The reactive sulfur species concept: 15 years on.
Antioxidants 6:38
Green TR, Fellman JH, Eichert AL, Pratt KL (1991) Antioxidant role and subcellular localisation
of hypotaurine and taurine in human neutrophils. Biochim Biophys Acta 1073:91–97
Hildebrandt TM, Grieshaber MK (2008) Three enzymatic activities catalyze the oxidation of sul-
de to thiosulfate in mammalian and invertebrate mitochondria. FEBS J275:3352–3361
Iciek M, Włodek L (2001) Biosynthesis and biological properties of containing highly reactive,
reduced sulfane sulfur. Pol JPharmacol 53:215–225
Ida T, Sawa T, Ihara H, Tsuchiya Y, Watanabe Y, Kumagai Y, Suematsu M, Motohashi H, Fujii S,
Matsunaga T, Yamamoto M, Ono K, Devarie-Baez NO, Xian M, Fukuto JM, Akaike T (2014)
Reactive cysteine persuldes and S-polythiolation regulate oxidative stress and redox signal-
ing. Proc Natl Acad Sci U S A 111:7606–7611
Inoue K, Tsukuda K, Koito T, Miyazaki Y, Hosoi M, Kado R, Miyazaki N, Toyohara H (2008)
Possible role of a taurine transporter in the deep-sea mussel Bathymodiolus septemdierum in
adaptation to hydrothermal vents. FEBS Lett 582:1542–1546
Jackson MR, Melideo S, Jorns MS (2012) Human sulde:quinone oxidoreductase catalyzes the rst
step in hydrogen sulde metabolism and produces a sulfane sulfur metabolite. Biochemistry
51:6804–6815
Joyner JL, Peyer SM, Lee RW (2003) Possible roles of sulfur-containing amino acids in a chemo-
autotrophic bacterium-mollusc symbiosis. Biol Bull 205:331–338
Kabil O, Banerjee R (2010) The redox biochemistry of hydrogen sulde. J Biol Chem
285:21903–21907
Kabil O, Banerjee R (2014) Enzymology of H2S biogenesis, decay and signaling. Antiox Red
Signal 20:770–782
Kim C, Cha YN (2014) Taurine chloramine produced from taurine under inammation provides
anti-inammatory and cytoprotective effects. Amino Acids 46:89–100
Kimura H (2011) Hydrogen sulde: its production, release and functions. Amino Acids 41:113–121
Koj A, Frendo J, Janik Z (1967) [35S]Thiosulphate oxidation by rat liver mitochondria in the pres-
ence of glutathione. Biochem J103:791–795
Kotronarou A, Hoffmann MR (1991) Catalytic autoxidation of hydrogen sulde in wastewater.
Environ Sci Technol 25:1153–1160
Kutney GW, Turnbull K (1982) Compounds containing the S=S bond. Chem Rev 82:333–357
Libiad M, Yadav PK, Vitvitsky V, Martinov M, Banerjee R (2014) Organization of the human mito-
chondrial hydrogen sulde oxidation pathway. JBiol Chem 289:30901–30910
Luo GX, Horowitz PM (1994) The sulfurtransferase activity and structure of rhodanese are affected
by site-directed replacement of Arg-186 or Lys-249. JBiol Chem 269:8220–8225
Majtan T, Krijt J, Sokolovà J, Krızkovà M, Ralat MA, Kent J, Gregory JF III, Kozich V, Kraus JP
(2018) Biogenesis of hydrogen sulde and thioethers by cystathionine beta-synthase. Antiox
Redox Signal 28:311–323
Marcinkiewicz J, Kontny E (2014) Taurine and inammatory diseases. Amino Acids 46:7–20
Marziaz M, Frazier K, Guidry PB, Ruiz RA, Petrikovics I, Haines DC (2013) Comparison of brain
mitochondrial cytochrome c oxidase activity with cyanide LD50 yields insight into the efcacy
of prophylactics. JAppl Toxicol 33:50–55
Mathew E, Barletta MA, Lau-Cam CA (2013) The effects of taurine and thiotaurine on oxidative
stress in the aorta and heart of diabetic rats. Adv Exp Med Biol 775:345–369
Mikami Y, Shibuya N, Kimura Y, Nagahara N, Ogasawara Y, Kimura H (2011) Thioredoxin and
dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen
sulde. Biochem J439:479–485
Mishanina TV, Libiad M, Banerjee R (2015) Biogenesis of reactive sulfur species for signaling by
hydrogen sulde oxidation pathways. Nat Chem Biol 11:457–464
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signali ng
770
Mousa HM, Davis RH (1991) Alternative sulfur donors for detoxication of cyanide in the chicken.
Comp Biochem Physiol 99C:309–315
Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder
SH (2009) H2S signals through protein S-sulfhydration. Sci Signal 2:ra72
Nagahara N, Sawada N (2006) The mercaptopyruvate pathway in cysteine catabolism: a physi-
ological role and related disease of the multifunctional 3-mercaptopyruvate sulfur transferase.
Curr Med Chem 13:1219–1230
Oja S, Kontro P (1982) Taurine. In: Lajitha A (ed) Handbook of neurochemistry, vol 3, 2nd edn.
Plenum Press, NewYork, pp501–553
Pandya KG, Budhram R, Clark G, Lau-Cam CA (2013) Comparative evaluation of taurine and
thiotaurine as protectants against diabetes-induced nephropathy in a rat model. Adv Exp Med
Biol 775:371–394
Paul BD, Snyder SH (2012) H2S signalling through protein sulfhydration and beyond. Nat Rev
Mol Cell Biol 13:499–507
Predmore BL, Lefer DJ, Gojon G (2012) Hydrogen sulde in biochemistry and medicine. Antioxid
Redox Signal 17:119–140
Pruski AM, Fiala-Medioni A, Colomines JC (1997) High amounts of sulphur-amino acids in three
symbiotic mytilid bivalves from deep benthic communities. C R Acad Sci III 320:791–796
Rahimi R, Nikfar S, Larijani B, Abdollahi M (2005) A review on the role of antioxidants in the
management of diabetes and its complications. Biomed Pharmacother 59:365–373
Rosenberg NK, Lee RW, Yancey PH (2006) High contents of hypotaurine and thiotaurine in
hydrothermal- vent gastropods without thiotrophic endosymbionts. JExp Zool A Comp Exp
Biol 305:655–662
Singh S, Padovani D, Leslie RA, Chiku T, Banerjee R (2009) Relative contributions of cystathio-
nine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans- sulfuration
reactions. JBiol Chem 284:22457–22466
Sörbo B (1957) Enzymic transfer of sulfur from mercaptopyruvate to sulte or sulnates. Biochim
Biophys Acta 24:324–329
Sörbo B (1958) On the formation of thiosulfate from inorganic sulde by liver tissue and heme
compounds. Biochim Biophys Acta 27:324–329
Steudel R, Drozdova Y, Miaskiewicz K, Hertwig RH, Koch W (1997) How unstable are thiosulf-
oxides? An ab initio MO study of various disulfanes RSSR (R=H, Me, Pr, All), their branched
isomers R2SS, and the related transition states. JAm Chem Soc 119:1990–1996
Stipanuk MH, Beck PW (1982) Characterization of the enzymic capacity for cysteine desulph-
hydration in liver and kidney of the rat. Biochem J206:267–277
Stipanuk MH, Ueki I (2011) Dealing with methionine/homocysteine sulfur: cysteine metabolism
to taurine and inorganic sulfur. JInherit Metab Dis 34:17–32
Szczepkowski TW, Wood JL (1967) The cystathionase-rhodanese system. Biochim Biophys Acta
139:469–478
Toohey JI (1989) Sulphane sulphur in biological systems: a possible regulatory role. Biochem
J264:625–632
Toohey JI (2011) Sulfur signalling: is the agent sulde or sulfane? Anal Biochem 413:1–7
Toohey JI, Cooper AJL (2014) Thiosulfoxide (sulfane) sulphur: new chemistry and new regulatory
roles in biology. Molecules 19:12789–12813
Westley J, Heyse D (1971) Mechanisms of sulfur transfer catalysis. Sulfhydryl-catalyzed transfer
of thiosulfonate sulfur. JBiol Chem 246:1468–1474
Whiteman M, Winyard PG (2011) Hydrogen sulde and inammation: the good, the bad, the ugly
and the promising. Expert Rev Clin Pharmacol 4:13–32
Yadav PK, Yamada K, Chiku T, Koutmos M, Banerjee R (2013) Structure and kinetic analysis of
H2S production by human mercaptopyruvate sulfurtransferase. JBiol Chem 288:20002–20013
Yadav PK, Martinov M, Vitvitsky V, Seravalli J, Wedmann R, Filipovic MR, Banerjee R (2016)
Biosynthesis and reactivity of cysteine persuldes in signaling. JAm Chem Soc 138:289–299
A. BaseggioConrado et al.
771
Yancey PH, Blake WR, Conley J(2002) Unusual organic osmolytes in deep-sea animals: adap-
tations to hydrostatic pressure and other perturbants. Comp Biochem Physiol A Mol Integr
Physiol 133:667–676
Yancey PH, Ishikawa J, Meyer B, Girguis PR, Lee RW (2009) Thiotaurine and hypotaurine con-
tents in hydrothermal-vent polychaetes without thiotrophic endosymbionts: correlation with
sulde exposure. JExp Zool A Ecol Genet Physiol 311:439–447
Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder
SH, Wang R (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of
cystathionine γ-lyase. Science 322:587–590
Zanardo RCO, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, Wallace JL (2006) Hydrogen sul-
de is an endogenous modulator of leukocyte-mediated inammation. FASEB J20:2118–2120
Thiotaurine: FromChemical andBiological Properties toRole inH2S Signali ng
... Moreover, Ttau has been proposed as a marker in animals with a sulfidebased symbiosis. This organic thiosulfate has the ability to release hydrogen sulfide (H 2 S) in a thiol-dependent reaction [37]. In particular, a thiosulfate reductase activity occurring in various cells uses electrons of thiols, such as GSH, to reduce sulfane sulfur of thiosulfonates, such as Ttau to H 2 S [38]. ...
... Overall, Ttau formed as a result of the reaction between Htau and RSSH may be converted back to H 2 S and Htau ( Figure 18). It is likely that Ttau, due to its peculiar biochemical properties, takes part in the modulation and control of H 2 S signal as suggested by the effect of Ttau on human neutrophil functional responses [37,[195][196][197]. ...
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... This sulfur atom can be released as elemental sulfur and transferred to another sulfur atom or reduced to hydrogen sulfide (H 2 S) by thiols. Recent investigations suggest that thiosulfonate effect on biological cell responses can be attributed to its involvement in H 2 S signaling, as H 2 S donors and/or as reactive sulfane-sulfur species [20]. Thiosulfonates are obtained by reacting sulfinates with elemental sulfur. ...
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The last century has been very important from the point of view of research and investigation in the fields of the chemistry and biochemistry of sulfur-containing natural products. One of the most important contributions to the discovery and study of human sulfur-containing metabolites was performed by the research group of Professor Doriano Cavallini at Sapienza University of Rome, during the last 80 years. His research brought to light the discovery of unusual sulfur metabolites that were chemically synthesized and determined in different biological specimens. Most of his synthetical strategies were performed in aqueous conditions, which nowadays can be considered totally in line with the recent concepts of the green chemistry. The aim of this paper is to describe and summarize synthetic procedures, and purification and analytical methods from the Cavallini’s school, with the purpose to provide efficient and green methodologies for the preparation and obtainment of peculiar unique sulfur-containing metabolites.
... Still far from being elucidated, the potential mechanisms underlying the overall inhibitory influence of taurine and its derivatives on platelet activity can be summarized as follows: decreased platelet TxA 2 [41] and TxB 2 production [113]; suppression of platelet cyclooxygenase activity [144,158]; stimulation of calmodulin-mediated platelet Ca, Mg-ATPase activity [140,162], attenuation of platelet Ca 2+ influx [141,154] and suppression of intraplatelet Ca 2+ response to activating agonists [156]; platelet stabilization against PAF [126,143,156]; suppression of β-TG and ATP release response to agonists, as markers of discharge from alpha and dense platelet granules [154]; preservation of platelet glutathione pool [113]; increased affinity of covalent inhibitors (e.g., DT, PCT, IPCT) to molecular targets, i.e., sulfur-containing groups on platelet surface (such might be the thiol group of P2Y 12 ADP receptor) [135][136][137][138][139]; and pronounced enhancement of hydrogen sulfide (H 2 S) plasma level [163][164][165][166], H 2 S being known to inhibit platelet activation and aggregation [167][168][169][170][171][172]. Taurine may also interfere with platelet activity by generating complementary processes such as an increase of the endothelial NO release [173][174][175][176], decrease of epinephrine and norepinephrine circulant level [177][178][179], suppression of CD147-dependent MMP-9 pathway on ischemic brain endothelium [54], reduction of serum TxB 2 [175], decrease of TxA 2 and TxB 2 release from various organs [127,[180][181][182][183], while increasing PgI 2 production [127,183]. ...
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... Thiotaurine (2-aminoethane thiosulfonate) induces the immunomodulatory action by the activation of human neutrophils due to persulfidation of target proteins [14]. ...
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Hydrogen sulfide (H2S) is now recognized as an endogenous signaling gasotransmitter in mammals. It is produced by mammalian cells and tissues by various enzymes - predominantly cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) - but part of the H2S is produced by the intestinal microbiota (colonic H2S-producing bacteria). Here we summarize the available information on the production and functional role of H2S in the various cell types typically associated with innate immunity (neutrophils, macrophages, dendritic cells, natural killer cells, mast cells, basophils, eosinophils) and adaptive immunity (T and B lymphocytes) under normal conditions and as it relates to the development of various inflammatory and immune diseases. Special attention is paid to the physiological and the pathophysiological aspects of the oral cavity and the colon, where the immune cells and the parenchymal cells are exposed to a special “H2S environment” due to bacterial H2S production. H2S has many cellular and molecular targets. Immune cells are “surrounded” by a “cloud” of H2S, as a result of endogenous H2S production and exogenous production from the surrounding parenchymal cells, which, in turn, importantly regulates their viability and function. Downregulation of endogenous H2S producing enzymes in various diseases, or genetic defects in H2S biosynthetic enzyme systems either lead to the development of spontaneous autoimmune disease or accelerate the onset and worsen the severity of various immune-mediated diseases (e.g. autoimmune rheumatoid arthritis or asthma). Low, regulated amounts of H2S, when therapeutically delivered by small molecule donors, improve the function of various immune cells, and protect them against dysfunction induced by various noxious stimuli (e.g. reactive oxygen species or oxidized LDL). These effects of H2S contribute to the maintenance of immune functions, can stimulate antimicrobial defenses and can exert anti-inflammatory therapeutic effects in various diseases.
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Aims: The transsulfuration pathway enzymes cystathionine beta-synthase (CBS) and cystathionine gamma lyase (CGL) are thought to be the major source of hydrogen sulfide (H2S). Here, we assessed the role of CBS in H2S biogenesis. Results: We show that despite discouraging enzyme kinetics of alternative H2S-producing reactions utilizing cysteine compared to the canonical condensation of serine and homocysteine, our simulations of substrate competitions at biologically relevant conditions suggest that cysteine is able to partially compete with serine on CBS, thus leading to generation of appreciable amounts of H2S. The leading H2S-producing reaction is a condensation of cysteine with homocysteine, while cysteine desulfuration plays dominant role when cysteine is more abundant than serine and homocysteine is limited. We found that serine to cysteine ratio is the main determinant of CBS H2S productivity. Abundance of cysteine over serine in e.g. plasma allowed for up to 43% of CBS activity being responsible for H2S production, while excess of serine typical for intracellular levels effectively limited such activity to less than 1.5%. CBS also produced lanthionine from serine and cysteine and a third of lanthionine coming from condensation of two cysteines contributed to H2S pool. Innovation: Our study characterizes the H2S-producing potential of CBS under biologically relevant conditions and highlights serine to cysteine ratio as the main determinant of H2S production by CBS in vivo. Conclusion: Our data clarifies the function of CBS in H2S biogenesis and the role of thioethers as surrogate H2S markers.
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Fifteen years ago, in 2001, the concept of “Reactive Sulfur Species” or RSS was advocated as a working hypothesis. Since then various organic as well as inorganic RSS have attracted considerable interest and stimulated many new and often unexpected avenues in research and product development. During this time, it has become apparent that molecules with sulfur-containing functional groups are not just the passive “victims” of oxidative stress or simple conveyors of signals in cells, but can also be stressors in their own right, with pivotal roles in cellular function and homeostasis. Many “exotic” sulfur-based compounds, often of natural origin, have entered the fray in the context of nutrition, ageing, chemoprevention and therapy. In parallel, the field of inorganic RSS has come to the forefront of research, with short-lived yet metabolically important intermediates, such as various sulfur-nitrogen species and polysulfides (Sx2–), playing important roles. Between 2003 and 2005 several breath-taking discoveries emerged characterising unusual sulfur redox states in biology, and since then the truly unique role of sulfur-dependent redox systems has become apparent. Following these discoveries, over the last decade a “hunt” and, more recently, mining for such modifications has begun—and still continues—often in conjunction with new, innovative and complex labelling and analytical methods to capture the (entire) sulfur “redoxome”. A key distinction for RSS is that, unlike oxygen or nitrogen, sulfur not only forms a plethora of specific reactive species, but sulfur also targets itself, as sulfur containing molecules, i.e., peptides, proteins and enzymes, preferentially react with RSS. Not surprisingly, today this sulfur-centred redox signalling and control inside the living cell is a burning issue, which has moved on from the predominantly thiol/disulfide biochemistry of the past to a complex labyrinth of interacting signalling and control pathways which involve various sulfur oxidation states, sulfur species and reactions. RSS are omnipresent and, in some instances, are even considered as the true bearers of redox control, perhaps being more important than the Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS) which for decades have dominated the redox field. In other(s) words, in 2017, sulfur redox is “on the rise”, and the idea of RSS resonates throughout the Life Sciences. Still, the RSS story isn’t over yet. Many RSS are at the heart of “mistaken identities” which urgently require clarification and may even provide the foundations for further scientific revolutions in the years to come. In light of these developments, it is therefore the perfect time to revisit the original hypotheses, to select highlights in the field and to question and eventually update our concept of “Reactive Sulfur Species”.
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Hydrogen sulfide (H2S) is increasingly recognized to modulate physiological processes in mammals through mechanisms that are currently under scrutiny. H2S is not able to react with reduced thiols (RSH). However, H2S -precisely, HS(-)- is able to react with oxidized thiol derivatives. We performed a systematic study of the reactivity of HS- toward symmetric low molecular weight disulfides (RSSR) and mixed albumin (HSA) disulfides. Correlations with thiol acidity and computational modeling showed that the reaction occurs through a concerted mechanism. Comparison to analogous reactions of thiolates indicated that the intrinsic reactivity of HS- is one order of magnitude lower than that of thiolates. In addition, H2S is able to react with sulfenic acids (RSOH). The rate constant of the reaction of H2S with the sulfenic acid formed in HSA was determined. Both reactions of H2S with disulfides and sulfenic acids yield persulfides (RSSH), recently identified post-translational modifications. The formation of this derivative in HSA was determined and the rate constants of its reactions with a reporter disulfide and with peroxynitrite revealed that persulfides are better nucleophiles than thiols, consistent with the alpha effect. Experiments with cells in culture showed that treatment with hydrogen peroxide enhanced the formation of persulfides. Biological implications are discussed. Our results give light on the mechanisms of persulfide formation and provide quantitative evidence for the high nucleophilicity of these novel derivatives, setting the stage for understanding the contribution of the reactions of H2S with oxidized thiol derivatives to H2S effector processes. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
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The chemical species involved in H2S signaling remain elusive despite the profound and pleiotropic physiological effects elicited by this molecule. The dominant candidate mechanism for sulfide signaling is persulfidation of target proteins. However, the relatively poor reactivity of H2S toward oxidized thiols, such as disulfides, the low concentration of disulfides in the reducing milieu of the cell and the low steady-state concentration of H2S raise questions about the plausibility of persulfide formation via reaction between an oxidized thiol and a sulfide anion or a reduced thiol and oxidized hydrogen disulfide. In contrast, sulfide oxidation pathways, considered to be primarily mechanisms for disposing of excess sulfide, generate a series of reactive sulfur species, including persulfides, polysulfides and thiosulfate, that could modify target proteins. We posit that sulfide oxidation pathways mediate sulfide signaling and that sulfurtransferases ensure target specificity.
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Signaling by H2S is proposed to occur via persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH). Persulfidation provides a framework for understanding the physiological and pharmacological effects of H2S. Due to the inherent instability of persulfides, their chemistry is understudied. In this review, we discuss the biologically relevant chemistry of H2S and the enzymatic routes for its production and oxidation. We cover the chemical biology of persulfides and the chemical probes for detecting them. We conclude by discussing the roles ascribed to protein persulfidation in cell signaling pathways.
Chapter
Thiotaurine, a thiosulfonate related to taurine and hypotaurine, is formed by a metabolic process from cystine and generated by a transulfuration reaction between hypotaurine and thiocysteine. Thiotaurine can produce hydrogen sulfide (H2S) from its sulfane sulfur moiety. H2S is a gaseous signaling molecule which can have regulatory roles in inflammatory process. In addition, sulfane sulfur displays the capacity to reversibly bind to other sulfur atoms. Thiotaurine inhibits PMA-induced activation of human neutrophils, and hinders neutrophil spontaneous apoptosis. Here, we present the results of a proteomic approach to study the possible effects of thiotaurine at protein expression level. Proteome analysis of human neutrophils has been performed comparing protein extracts of resting or PMA-activated neutrophils in presence or in absence of thiotaurine. In particular, PMA-stimulated neutrophils showed high level of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression compared to the level of the same glycolytic enzyme in the resting neutrophils. Conversely, decreased expression of GAPDH has been observed when human neutrophils were incubated with 1 mM thiotaurine before activation with PMA. This result, confirmed by Western blot analysis, suggests again that thiotaurine shows a bioactive role in the mechanisms underlying the inflammatory process, influencing the energy metabolism of activated leukocytes and raises the possibility that thiotaurine, acting as a sulfur donor, could modulate neutrophil activation via persulfidation of target proteins, such as GAPDH.
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Hydrogen sulfide (H2S) elicits pleiotropic physiological effects ranging from modulation of cardiovascular to CNS functions. A dominant method for transmission of sulfide-based signals is via posttranslational modification of reactive cysteine thiols to persulfides. However, the source of the persulfide donor and whether its relationship to H2S is as a product or precursor is controversial. The transsulfuration pathway enzymes can synthesize cysteine persulfide (Cys-SSH) from cystine and H2S from cysteine and/or homocysteine. Recently, Cys-SSH was proposed as the primary product of the transsulfuration pathway with H2S representing a decomposition product of Cys-SSH. Our detailed kinetic analyses demonstrate a robust capacity for Cys-SSH production by the human transsulfuration pathway enzymes, cystathionine beta-synthase and γ-cystathionase (CSE) and for homocysteine persulfide synthesis from homocystine by CSE only. However, in the reducing cytoplasmic milieu where the concentration of reduced thiols is significantly higher than of disulfides, substrate level regulation favors the synthesis of H2S over persulfides. Mathematical modeling at physiologically relevant hepatic substrate concentrations predicts that H2S rather than Cys-SSH is the primary product of the transsulfuration enzymes with CSE being the dominant producer. The half-life of the metastable Cys-SSH product is short and decomposition leads to a mixture of polysulfides (Cys-S-(S)n-S-Cys). These in vitro data, together with the intrinsic reactivity of Cys-SSH for cysteinyl versus sulfur transfer, are consistent with the absence of an observable increase in protein persulfidation in cells in response to exogenous cystine and evidence for the formation of polysulfides under these conditions.
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Hydrogen sulfide (H2S) is the endogenously produced gasotransmitter involved in the regulation of nervous system, cardiovascular functions, inflammatory response, gastrointestinal system and renal function. Together with nitric oxide and carbon monoxide, H2S belongs to a family of gasotransmitters. H2S is synthesized from l-cysteine and/or l-homocysteine by cystathionine β-synthase, cystathionine γ-lyase and cysteine aminotransferase together with 3-mercaptopyruvate sulfurtransferase. Significant progress has been made in recent years in our understanding of H2S biochemistry, signaling mechanisms and physiological role. H2S-mediated signaling may be accounted for not only by the intact compound but also by its oxidized form, polysulfides. The most important signaling mechanisms include reaction with protein thiol groups to form persulfides (protein S-sulfhydration), reaction with nitric oxide and related species such as nitrosothiols to form thionitrous acid (HSNO), nitrosopersulfide (SSNO−) and nitroxyl (HNO), as well as reaction with hemoproteins. H2S is enzymatically oxidized in mitochondria to thiosulfate and sulfate by specific enzymes, sulfide:quinone oxidoreductase, persulfide dioxygenase, rhodanese and sulfite oxidase. H2S donors have therapeutic potential for diseases such as arterial and pulmonary hypertension, atherosclerosis, ischemia-reperfusion injury, heart failure, peptic ulcer disease, acute and chronic inflammatory diseases, Parkinson's and Alzheimer's disease and erectile dysfunction. The group of currently available H2S donors includes inorganic sulfide salts, synthetic organic slow-releasing H2S donors, H2S-releasing non-steroidal antiinflammatory drugs, cysteine analogs, nucleoside phosphorothioates and plant-derived polysulfides contained in garlic. H2S is also regulated by many currently used drugs but the mechanism of these effects and their clinical implications are only started to be understood.