Latin American Journal of Aquatic Research, 52(1): 13-31, 2024

Taurine biosynthesis in fish 13

DOI: 10.3856/vol52-issue1-fulltext-3026

Review

Physiological role of genes involved in taurine biosynthesis in fishes and in silico

approach to determine transcription factors in their promoters’ zone

Talhia Martínez-Burguete1 , Emyr Saul Peña-Marín2 , Rafael Martínez-García1

Raúl Antonio Llera-Herrera3 & Carlos Alfonso Álvarez-González1
1
Laboratorio de Fisiología en Recursos Acuáticos, División Académica de Ciencias Biológicas
Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, México
2
Instituto de Investigaciones Oceanológicas, Universidad Autónoma de Baja California (UABC)
Ensenada, Baja California, México
3
Unidad Académica Mazatlán, Instituto de Ciencias del Mar y Limnología (ICMyL)
Universidad Nacional Autónoma de México (UNAM), Mazatlán, México
Corresponding author: Dr. Carlos A. Álvarez-González (alvarez_alfonso@hotmail.com)

ABSTRACT. Taurine, an amino sulfonic acid that is sometimes referred to as an amino acid, is endogenously
synthesized by the action of the key genes/enzymes: cysteine dioxygenase (cdo), cysteine sulfonate
decarboxylase (csad), glutamate decarboxylase (gad), and 2-amino ethanethiol dioxygenase (ado). The taurine
transporter (taut) also distributes this taurine formation across the plasma. These genes have been identified as
important in different physiological processes such as reproduction, digestion, olfactory, visual, circulatory, and
muscular systems. Thus, a literature review of these genes in fish has been described in the present work.
Moreover, there is null information regarding the study of regulatory elements such as transcription factors (TFs)
in taurine biosynthesis and transportation genes of fishes. In this interest and taking advantage of the availability
of different sequence databases, bioinformatics can be applied as a first approach for an in silico identification
of the putative TFs and transcription factor binding sites (TFBS) that might play an important role in regulating
these genes. The results showed that some are commonly shared, whereas TFs and TFBs vary among fish
species. Hence, binding sites for homeobox protein BarH-like 1 (BARX1), brain-specific homeobox protein
homolog (BSX), helicase-like transcription factor (HLTF), homeobox protein Hox-A7 (HOXA7), homeobox
protein Hox-B3 (HOXB3), homeobox protein Hox-B6 (HOXB6), homeobox protein Meis1 (MEIS1),
homeobox protein Meis3 (MEIS3), nuclear factor of activated T cells 1 (NFATC1), and homeobox protein Nkx-
6.2 (NKX6-2) were commonly found in the promoter regions of genes involved in taurine transportation and
biosynthesis. Additionally, our results suggested that the frequency of HOXB3, a transcription factor involved
in development, has repetitive TFBS sites in the promoter region of all species analyzed in the present study.
Although bioinformatics gives us an approach to determine putative TFs and TFBS, further work is needed to
verify how the found regulatory elements play a key role in taurine biosynthesis and transportation.
Keywords: ß-aminosulfonic acid; taurine biosynthesis; taurine transporter; transcription factor

INTRODUCTION can be found in free form in most animals and is often

called an amino acid (Huxtable & Sebring 1986).
Taurine, also known as 2-aminoethanesulfonic acid, is However, due to its structure, it is not part of the α-
a simple molecule first isolated from the bile acid of the amino acids that synthesize proteins since it lacks the
ox (Bos taurus) in 1827 by Leopold Gmelin and fundamental and less acid carboxyl group, what gives
Friedrich Tiedemann (Tiedemann & Gmelin, 1827). It it its zwitterionic nature similarity to neutral membrane

______________
Associate Editor: José Gallardo
14 Latin American Journal of Aquatic Research

phospholipids, phosphatidylcholine, and phosphatidy- Kyoto encyclopedia of genes and genomes (KEGG)
lethanolamine (Huxtable 1992); hence its high-water and found that they are mainly involved in signaling
solubility and low lipophilicity, explaining its and cell communication (GO) and olfactory trans-
impermeability of biological membranes (Lambert et duction (KEGG), allowing further insights into the
al. 2015). Moreover, some small peptides are known to detailed mechanism of the olfactory system of fishes.
exist naturally; nonetheless, there is no evidence of Consequently, this study demonstrates that using
transfer RNA (tRNA) that codes for taurine, and its transcriptomics might be a better approach to
sulfonate group replaces the carboxyl group necessary understanding taurine roles. Another example of the
for the formation of a peptide bond, therefore, cannot role of taurine in the sensory system has been the work
be part of translated peptide chains (Bittner et al. 2005). realized by Brill et al. (2019) in seabass Dicentrarchus
The taurine pool can be found in vertebrate species' labrax also fed protein diets. Although no effect on
brains, retina, liver, kidney, heart, and muscle retinal anatomy or functional properties of luminous
(Jacobsen & Smith 1968, Huxtable 1992). Furthermore, sensitivity were found in this work, authors found that
in mammals, the physiological role of taurine has been the spectral sensitivity peak of individuals fed a 5%
extensively investigated (Huxtable & Sebring 1986, taurine diet was rightward shifted (i.e. towards longer
Pion et al. 1987, Huxtable 1992, Militante et al. 2000, wavelengths) relative to that of fish fed a 0 or 1.5%
Parsons et al. 2001, Goodman et al. 2009, Ueki et al. taurine diet.
2012, Han et al. 2015) while in fishes different studies Although taurine supplementation has widely been
have demonstrated its relevance in the physiology of studied in fish species (Salze & Davis 2015, Sampath
marine and freshwater fishes (El-Sayed 2014, Salze & et al. 2020, Li et al. 2022) including the identification
Davis 2015, Mezzomo et al. 2018, Zhang et al. 2019, of genes involved in taurine biosynthesis of different
Sampath et al. 2020). As in mammals, different species such as zebrafish Danio rerio (Liu et al. 2017),
physiological roles of taurine have been observed in goldfish Carassius auratus (Luo et al. 2019), and
fishes that are involved in respiration, circulation, tropical gar Atractosteus tropicus (Martínez-Burguete
digestion, osmoregulation, sensorial system, muscular et al. 2023), there is no information regarding
system, central nervous system (CNS), and repro- regulatory elements in those genes involved in the
duction (Higuchi et al. 2012, Mezzomo et al. 2018, Brill endogenous synthesis of taurine. Gene regulatory
et al. 2019, Ceccotti et al. 2019, Salze et al. 2019). Most elements include promoters, enhancers, silencers, and
species can acquire taurine through food absorption in insulators, where the promoter includes a core promoter
the intestine or endogenous synthesis from its and a proximal promoter region (Chatterjee & Ahituy
precursor’s methionine/cysteine (Kuzmina et al. 2010). 2017). In eukaryotes, the core promoter represents the
Most studies in taurine have been focused on the use minimal elements required to initiate transcription
of supplemented taurine. Moreover, transcriptomics (Taher et al. 2015). Thus, these elements required to
has been applied to identify the effects on visual and initiate transcription in the promoter region contain the
olfactory system (Hu et al. 2018, 2020). Hu et al. (2018) general transcription machinery and transcription
studied the effects of taurine as a feed attractant in plant factors (Riethoven 2010). Transcription factors are
protein-based diets for large yellow croaker. Thus, the proteins that can bind to specific DNA sequences of
sequencing of the olfactory epithelium was conducted promoter regions (Mitsis et al. 2020). TFs and their
to identify genes differentially expressed in the taurine binding sites in these promoter regions can be predicted
group (TAU) vs. controls. They detected 77 olfactory using bioinformatic tools. Large data sets can be
receptor genes, including 37 up-regulated unigenes, analyzed using bioinformatics to find patterns among
validating the expression of eight genes (52N4 organisms, whether model or non-model species.
(olfactory receptor family 52 subfamily N member 4), Hence, in the present work, we have summarized
10C1 (olfactory receptor family 10 subfamily C the main physiological roles played by taurine
member 1), 2D3 (olfactory receptor family 2 subfamily biosynthesis and transport genes in different fish
D member 3), 13C2 (olfactory receptor family 13 species based on a literature review. Moreover, due to
subfamily C member 2), 4C11 (olfactory receptor the lack of information regarding putative transcription
family 4 subfamily C member 11), 2A12 (olfactory factors (TFs) and transcription factors binding sites
receptor family 2 subfamily A member 12) and 1361) (TFBS) that could be involved in regulating taurine
using quantitative reverse transcription-PCR (RT- biosynthesis and transportation genes in fishes, a
qPCR). The function of the differentially expressed bioinformatic approach was applied to investigate
genes was defined by the gene ontology (GO) and the them.
 Taurine biosynthesis in fish 15

Taurine biosynthesis and its transporters generate CDO-/-, CDO+/- and CDO+/+ mice and
In fishes, the biosynthesis of taurine occurs through observed that CDO-/- mice had higher postnatal
three different pathways (Fig. 1), and the predominant mortality, deficit growth and pathology of the
pathway will depend on the species, type of tissue, connective tissue in the elastic fibers of the foot, as well
stage of development, feeding habits, and the as low levels of taurine and high levels of cysteine,
environment in which they live (Haga et al. 2015, Salze which is due to the lack of flow of the CDO dependent
& Davis 2015, Sampath et al. 2020). One different catabolic pathways. However, in fishes, the depletion
pathway is pathway I (cysteine sulfinate-dependent through knockout models of CDO has not been
pathway), where cysteine is oxidized by cysteine explored. The reported works in fishes regarding CDO
dioxygenase (CDO) and converted into cysteine are focused on the identification, isolation, and
sulfinic acid, which is then decarboxylated by cysteine regulation of the gene in some species like rainbow
sulfonate decarboxylase (CSAD) to form hypotaurine trout Oncorhynchus mykiss (Wang et al. 2015),
which is converted in taurine by hypotaurine zebrafish D. rerio (Liu et al. 2017) and goldfish C.
dehydrogenase (HP-DH), CDO regulates the cysteine auratus (Luo et al. 2019).
concentration, and CSAD enzyme is the rate-limiting
step in taurine biosynthesis; pathway II (cysteine acid Cysteine sulfonate decarboxylase (csad)
pathway), is also regulated by CDO. However, the The cysteine sulfonate decarboxylase (csad) gene is a
product is metabolized to cysteic acid and converted to gene that codes for the CSAD protein (EC 4.1.1.29) and
taurine by decarboxylation through glutamate decar- is considered the limiting enzyme in the production of
boxylase (GAD). In pathway III (cysteamine pathway), taurine, which is produced mainly in the liver (De la
taurine is obtained by converting cysteine into Rosa & Stipanuk 1985). CSAD catalyzes a decarboxy-
coenzyme A and then converted to cysteamine, which lation reaction to cysteine sulfinic acid to form
is oxidized by 2-aminoethanethiol dioxygenase (ADO) hypotaurine, which is then converted to taurine
to form hypotaurine and form taurine by HP-DH. (Yokoyama et al. 2001). It is known that the lack of
However, in the case of hypotaurine to taurine enzyme activity in cats can cause blindness, which is
conversion by the action of HP-DH in pathways I and why taurine is considered an essential nutrient in their
III, it is known that this reaction can also occur diet (Hayes et al. 1975). Its expression has been
spontaneously, in addition to the fact that HP-DH has measured in organs such as the brain, gills, heart,
not been characterized (Roysommuti & Wyss 2015). kidney, spleen, liver, intestine, muscle, adipose tissue,
The distribution of taurine endogenously synthesized or ovary, and testis (Haga et al. 2015, Betancor et al. 2019,
acquired from food is mainly regulated by the taurine Poppi et al. 2019). In fish, species of the family
Labridae, Scombridae, Soleidae, and Rajidae have been
transporter (taut; Wang et al. 2017, Xiong et al. 2020)
reported to lack the activity of CSAD (Salze & Davis
2015). Some studies on the silencing or elimination of
Cysteine dioxygenase (cdo)
the gene suggest that mortality and cardiac abnorma-
Cysteine dioxygenase (cdo) is a gene that codes for the lities may be the effects that organisms suffer when this
CDO protein (EC 1.13.11.20) and is one of the main occurs (Chang et al. 2013) and that, in turn, they can be
enzymes in the formation of taurine and sulfate (2:1 recovered through taurine supplementation in the diet
ratio). It is found at high levels in the liver, while low (Park et al. 2014). Among the works carried out in fish,
levels predominate in the kidney, brain, and lungs which allow us to observe what happens when one of
(Stipanuk 2004). This iron metalloenzyme catalyzes the the genes involved in the biosynthesis of taurine is
addition of molecular oxygen to the thiol group of silenced or eliminated, is that carried out by Chang et
cysteine, producing cysteine sulfinic acid, thus playing al. (2013) in zebrafish. In this work, the researchers
an important role in the catabolism of cysteine mutated a part of the csad gene, presumed to be the
(Stipanuk et al. 2006). In mammals, it has extensively limiting enzyme in endogenous taurine production. In
been studied (Driggers et al. 2015, Stipanuk et al. 2015, this work, they found that by mutating the gene and
Dawson et al. 2020), and among these works, it has therefore not producing the CSAD protein, there was a
been shown that the deletion or silencing of cdo can reduction in taurine levels in embryos, early mortality
produce abnormalities in organisms. For example, in increased, and cardiac abnormalities were found
rodents, Ueki et al. (2011) observed the differences in (pericardial edema, cardiac tube malformation).
the physiological function of CDO and what happened Therefore, to test whether taurine supplementation
after the loss of its activity. To achieve this, they could influence embryos with the phenotype of cardiac
crossed mice carrying a CDO null allele (CDO +/-) to abnormalities, they supplemented taurine in the environ-
16 Latin American Journal of Aquatic Research

Figure 1. Pathways of taurine biosynthesis (adapted from Salze & Davis 2015). Pathway I, cysteine sulfinate-dependent
pathway; Pathway II, cysteine acid; Pathway III, cysteamine.

ment in which the embryos were and managed to rescue years. Therefore, with the advances in sequencing
these embryos. Nevertheless, most works on fish technology and bioinformatics, it would be interesting
species have been conducted to identify their punctual to study the regulation of the gene and its mechanism
identification and expression (Huang et al. 2014, Haga in fish.
et al. 2015, Betancor et al. 2019, Poppi et al. 2020, Ma
et al. 2021). 2-aminoethanethiol dioxygenase (ado)
The 2-aminoethanethiol dioxygenase (ado) gene, also
Glutamate decarboxylase (gad) known as cysteamine dioxygenase (cao), encodes the
Glutamate decarboxylase (gad), also known as cysteic ADO protein (EC 1.13.11.19) and participates in the
acid decarboxylase (cad), is a gene that codes for the alternate route of taurine biosynthesis by oxidizing
GAD/CAD protein (EC 4.1.1.15) and is synthesized cysteamine to form hypotaurine, which subsequently
and expressed mainly in the brain (Wu et al. 1979). This action of hypotaurine dehydrogenase to produce taurine
enzyme participates in an alternative route to the main (Stipanuk et al. 2015). Although it is the least studied
one for the formation of taurine, where cysteine is gene of those involved in taurine biosynthesis, its
oxidized to cysteine sulfinic acid by the action of CDO, expression in fishes may have been studied in different
and later, instead of being decarboxylated, cysteine tissues and organs such as the hepatopancreas, brain,
sulfinic acid is metabolized to cysteic acid which gills, intestine, muscles, eye, heart, spleen, kidney, and
GAD/CAD decarboxylates to become taurine (Salze & gallbladder of Atlantic bluefin tuna Thunnus thynnus
Davis 2015). (Watson et al. 2014, Betancor et al. 2019). Hence,
It is known that there are three different isoforms of Gonzales-Plasus et al. (2019) characterized the
the gene in vertebrates (Grone & Maruska 2016). In nucleotide and amino acid sequence in common carp
fishes, some studies have been directed at the deep sea Cyprinus carpio and quantified its expression in
armed grenadier Coryphaenoides (Nematonurus) different tissues.
armatus (Trudeau et al. 2000), goldfish (Lariviere et al.
2002), zebrafish (Mueller & Guo 2009), and detected Taurine transporter
by RNAseq in gulf pipefish Syngnathus scovelli (Beal Taurine is distributed across the plasma membrane by
et al. 2018). Hence, in zebrafish, Cocco et al. (2017) taurine transporters (Mezzomo et al. 2018). These
studied gad localization in different brain regions and taurine transporters are the proton/amino acid
found three different paralogs, of which two resemble symporter (PAT1) encoded by the solute carrier family
the gad1 paralog of mammals and the third one the 36 member 1 (slc36a1) and taurine transporter (TAUT)
gad2. However, it has yet to be studied in fish in recent encoded by solute carrier family 6 membrane 6 (slc6a6)
 Taurine biosynthesis in fish 17

being this last one the most studied (Lambert et al. (Gearing et al. 2019) using the Jaspar 2020 core
2015, Chen et al. 2019, Seidel et al. 2019). Hence, it is vertebrate sequences. Because TFBS varies and rarely
known that the adaptive response of taut to changes in matches the model perfectly, a default deficit score of
the availability of taurine, when there are reduced levels 0.05 was used, where a deficit score of 0 represents a
of dietary taurine, elevated the expression of the gene perfect match. Once the software was run, results were
(Han et al. 2006). In fishes, this regulation of taut obtained in .csv format, converted to .xls format, and
availability can be observed in the distribution of used to calculate TFBS frequency to construct
different tissues of fishes like turbot Scophthalmus heatmaps using GraphPad Prism version 9.3.0 (San
maximus (Wang et al. 2017, Wei et al. 2019), Atlantic Diego, CA, USA).
bluefin tuna (Betancor et al. 2019), grass carp Identification of TFs share among the promoter
Ctenopharyngodon idella (Yan et al. 2019) and region of genes in the study was obtained using the
goldfish (Xiong et al. 2020). Kozlowski et al. (2008) http://bioinformatics.psb.ugent.be/webtools/Venn/
characterized taut in zebrafish and observed its webtool of the Van de Peer Lab.
expression during embryogenesis.
Additionally, to understand the role of taut, they
RESULTS
investigated the effect that a knockdown of the gene
could have on these embryos. The results they found
Complete raw results from the program CiiiDER can be
were a) the expression of taut is present from the very
early stages of embryonic development in all tissues found in Supplementary Material 1. The CiiiDER
where taurine is known to be essential (retina, heart, program predicted the presence of several TFs and
brain, kidney, and blood vessels) and b) taut TFBS on the promoter regions of all species in the study
knockdown caused its low expression and results in a (Table 2). Identification of putative TFs exclusive of
phenotype that involves cell apoptosis in the brain and the promoter zone of the genes in each species is shown
spinal cord. These results determine the importance of (Table 3).
taut during embryogenesis.
Cysteine dioxygenase (cdo)
Therefore, further work regarding the use of
different tools in molecular biology, such as site- The promoter sequences of different fish species were
directed mutagenesis or bioinformatics, to identify used to identify the putative TFs and TFBS in cdo. Our
transcription factors that regulate taurine biosynthesis finding shows that Arid3a, Arid3b, BARX1, BSX,
genes and the transportation of taurine should be Foxf, FOXL1, GATA3, GATA5, GSX1, GSX2, HLTF,
accomplished for a better understanding of the HOXA7, HOXB3, HOXB6, LHX1, MEIS1, MEIS3,
physiological roles played by taurine. NFATC1, NFATC3, NFATC4, NKX6-2, RHOXF1,
SOX15, Sox17, ZNF354C were present in all species
while Alx3, Dlx1, Dlx2, Dlx3, DRGX, HOXB2 and
METHODOLOGY
HOXB8 were present in all except zebrafish. A
Retrieval of promoters, nucleotide, and amino acid representation of the comparison among the promoter
sequences of organisms can be obtained from different zone of some of the species in the study can be observed
public databases such as Ensembl, NCBI, and Uniprot (Fig. 2). The frequency of the TFBS of the TFs present
(Yates et al. 2020, Madeira et al. 2022 Martin et al. in all species was also identified (Fig. 3). Moreover, the
2023). For the present study, the Ensembl database frequency of the TFBS for BSX, HLTF, and HOXB3 is
(https://www.ensembl.org/index.html) was accessed to constant among species. In addition, it can also be
retrieve sequences for promoter analysis. observed that LHX1 frequency in zebrafish is higher
than in the rest of the species.
Promoter analysis of TFBS involved in taurine
biosynthesis and transportation Cysteine sulfonate decarboxylase (csad)
Promoter regions spanning +2000 to -1 bp for cdo, Four hundred eighty-six putative TFs were found in the
csad, gad, ado, and taut of different species were promoter region of csad of different fish species (Suppl.
retrieved from Ensembl (https://www.ensembl.org/) Mat. 1). We also found that Arid3b, BARX1, BSX,
and converted to FASTA files. Species and their gene EVX1, EVX2, GSX1, HLTF, HOXA7, HOXB2,
identifiers used for the analysis can be found in Table 1. HOXB3, HOXB6, MEIS1, MEIS3, NFATC1,
The retrieved sequences were used to identify the TFs NFATC3, NKX6-2, PDX1, and RHOXF1 are present
and TFBS using the software CiiiDER, version 0.9 in all the species in study. The frequency of the TFBS
 18
18 Latin American
Latin American Journal of Aquatic ResearchJournal of Aquatic Research

Table 1. Species and accession number of the genes in Ensembl used for the in silico approach to determine transcription factors (TFs) and transcription factor binding sites
(TFBS) using CiiiDER software version 0.9 (Gearing et al. 2019).

Species Common name cdo csad gad ado taut

Poecilia formosa Amazon molly ENSPFOG00000002497 ENSPFOG00000001389 ENSPFOG00000011193 ENSPFOG00000020791 ENSPFOG00000008415
Salmo salar Atlantic salmon ENSSSAG00000045718 ENSSSAG00000077542 ENSSSAG00000081646 ENSSSAG00000071248 ENSSSAG00000068263
Salmo trutta Brown trout ENSSTUG00000030331 ENSSTUG00000049081 ENSSTUG00000030337 ENSSTUG00000021119 ENSSTUG00000013971
Ictalurus punctatus Channel catfish ENSIPUG00000025116 ENSIPUG00000022545 ENSIPUG00000020814 ENSIPUG00000023869 ENSIPUG00000009147
Cyprinus carpio Common carp ENSCCRG00000019916 ENSCCRG00000050160 ENSCCRG00000009363 ENSCCRG00000009651 ENSCCRG00000028865
Electrophorus electricus Electric eel ENSEEEG00000007791 ENSEEEG00000020397 ENSEEEG00000004961 ENSEEEG00000006255 ENSEEEG00000023351
Dicentrarchus labrax European seabass ENSDLAG00005030923 ENSDLAG00005001675 ENSDLAG00005000274 ENSDLAG00005020461 ENSDLAG00005010961
Takifugu rubripes Fugu ENSTRUG00000020607 ENSTRUG00000001632 ENSTRUG00000017805 ENSTRUG00000012216 ENSTRUG00000009909
Sparus aurata Gilthead seabream ENSSAUG00010005231 ENSSAUG00010018857 ENSSAUG00010026343 ENSSAUG00010014882 ENSSAUG00010000496
Carassius auratus Goldfish ENSCARG00000068233 ENSCARG00000017734 ENSCARG00000023792 ENSCARG00000047487 ENSCARG00000058589
Poecilia reticulata Guppy ENSPREG00000013161 ENSPREG00000020183 ENSPREG00000004050 ENSPREG00000012002 ENSPREG00000017002
Oryzias latipes Japanese medaka ENSORLG00000003390 ENSORLG00000008058 ENSORLG00000017268 ENSORLG00000027492 ENSORLG00000010119
Cyclopterus lumpus Lumpfish ENSCLMG00005007809 ENSCLMG00005009685 ENSCLMG00005021952 ENSCLMG00005021103 ENSCLMG00005002451
Oreochromis niloticus Nile tilapia ENSONIG00000014479 ENSONIG00000012260 ENSONIG00000008762 ENSONIG00000021007 ENSONIG00000000371
Esox lucius Northern pike ENSELUG00000018836 ENSELUG00000018621 ENSELUG00000021349 ENSELUG00000005239 ENSELUG00000018892
Oncorhynchus mykiss Rainbow trout ENSOMYG00000029549 ENSOMYG00000024325 ENSOMYG00000008187 ENSOMYG00000041907 ENSOMYG00000033005
Pygocentrus nattereri Red-bellied piranha ENSPNAG00000002994 ENSPNAG00000021775 ENSPNAG00000019728 ENSPNAG00000014619 ENSPNAG00000024574
Lepisosteus oculatus Spotted gar ENSLOCG00000008927 ENSLOCG00000006576 ENSLOCG00000007840 ENSLOCG00000018234 ENSLOCG00000013551
Seriola lalandi dorsalis Yellowtail amberjack ENSSLDG00000009729 ENSSLDG00000003612 ENSSLDG00000002119 ENSSLDG00000024277 ENSSLDG00000006439
Danio rerio Zebrafish ENSDARG00000099389 ENSDARG00000026348 ENSDARG00000093411 ENSDARG00000053571 ENSDARG00000098438
 Taurine biosynthesis in fish 19

Table 2. Total transcription factor (TF) and transcription factor binding sites (TFBS) found in the fish under study.

cdo csad gad ado taut

Species Common name
TF TFBS TF TFBS TF TFBS TF TFBS TF TFBS
Poecilia formosa Amazon molly 222 743 188 1135 233 919 137 404 179 472
Salmo salar Atlantic salmon 184 965 198 533 173 526 201 746 189 441
Salmo trutta Brown trout 201 649 191 502 189 606 216 643 190 541
Ictalurus punctatus Channel catfish 164 385 214 795 211 685 228 723 219 1052
Cyprinus carpio Common carp 262 968 224 783 198 618 213 937 213 545
Electrophorus electricus Electric eel 227 963 179 778 132 309 203 624 212 729
Dicentrarchus labrax European seabass 198 658 147 385 201 797 187 526 210 678
Takifugu rubripes Fugu 222 652 183 544 223 494 259 956 222 506
Sparus aurata Gilthead seabream 233 651 220 840 225 725 244 919 195 605
Carassius auratus Goldfish 242 717 177 525 192 442 206 586 210 1064
Poecilia reticulata Guppy 221 720 186 704 170 809 135 408 180 516
Oryzias latipes Japanese medaka 211 1526 197 567 160 554 184 474 203 718
Cyclopterus lumpus Lumpfish 189 458 204 754 223 854 251 1366 222 921
Oreochromis niloticus Nile tilapia 226 953 220 472 198 736 285 688 202 675
Esox lucius Northern pike 155 374 199 571 205 987 184 781 193 485
Oncorhynchus mykiss Rainbow trout 186 557 241 951 197 631 217 651 199 508
Pygocentrus nattereri Red-bellied piranha 189 494 230 680 211 904 206 505 225 652
Lepisosteus oculatus Spotted gar 185 828 88 125 196 978 246 1048 189 543
Seriola lalandi dorsalis Yellowtail amberjack 245 709 223 774 203 755 238 740 216 585
Danio rerio Zebrafish 150 490 184 648 199 1064 196 866 219 815

of the TFs present in all species was also identified (Fig. found the following TFs to be present in all species:
4). It can be observed that the frequencies of HLTF and ALX3, Arid3a, ARNT::HIF1A, BARHL2, BARX1,
HOXB3 in most of the species are higher than in the BSX, Dlx1, Dlx2, Dlx3, DLX6, DRGX, ESX1, EVX1,
rest of the TFs. However, the frequency of the TFBS EVX2, GATA3, GSX1, HESX1, HLTF, HOXA7,
for spotted gar is really low. HOXB3, HOXB6, LHX1, MEIS1, MEIS3, MIXL1,
NFATC1, NFIX, NKX6-2, OTX1, PRRX1, RAX,
Glutamate decarboxylase (gad) RAX2, SHOX, Shox2, SOX15, Sox17, TBX3, TLX2,
The promoter region of gad was revised among 20 fish UNCX, ZNF384. The frequency of the TFs can be
species, and 488 putative TFBS were found (Suppl. observed in Figure 6. The frequency of HOXB3 in the
Mat. 1). The search retrieved that ALX3, Arid3a, promoter region of all species in the study was
BARHL2, BARX1, BSX, Dlx1, Dlx2, DRGX, EVX1, considerably higher than in the rest of the TFs.
EVX2, GATA3, GATA5, HESX1, HLTF, HOXA6, However, in species like seabass Dicentrarchus labrax,
HOXA7, HOXB3, HOXB6, HOXB8, LHX1, MEIS1, Japanese medaka Oryzias latipes, and red-bellied
MEIS3, MIXL1, NFATC1, NFATC3, NFIX, NKX6-2, piranha Pygocentrus nattereri, the frequency of HLTF
PRRX1, RAX, RAX2, RHOXF1, SHOX, Shox2, was higher than in HOXB3. Meanwhile, the frequency
SOX15, Sox17, SRY, TLX2, UNCX, and ZNF354C of ZNF384 TFBS for electric eel was higher than in the
were present in all studied species. Moreover, the TFBS rest of the TFs.
frequency of these TFs is described in Figure 5, where
it can be observed that HOXB3 in the studied promoter Taurine transporter
regions in the different fish species appears more The identification of TFBS among promoters'
frequently. In addition, Nile tilapia Oreochromis sequences of the gene taut for fish species gave back a
niloticus also presents high frequencies for EVX1, total of 506 putative TFs (Suppl. Mat. 1). A total of at
EVX2, and NKX6-2. least 45 TFs are present in all fish species. These TFs
are: ALX3, Arid3a, BARX1, BSX, Dlx1, Dlx2, Dlx3,
2-aminoethanethiol dioxygenase (ado) DLX6, DRGX, ESX1, GATA3, GATA5, GSX1,
In silico search for TFBS among 20 fish species, we GSX2, HESX1, HLTF, HOXA7, HOXB2, HOXB3,
retrieved 508 putative TFs (Suppl. Mat. 1). Our search HOXB6, ISX, LBX2, LHX1, MEIS1, MEIS3, MIXL1,
20 Latin
Latin American Journal of Aquatic American Journal of Aquatic Research
Research

Table 3. Putative transcription factors identified to appear only in each species of fish for the promoter sequence of cysteine dioxygenase (cdo), cysteine sulfonate
decarboxylase (csad), glutamate decarboxylase (gad), 2-amino ethanethiol dioxygenase (ado), and taurine transporter (taut).

Species Common name cdo csad gad ado taut

Poecilia formosa Amazon molly ZBTB7C SMAD3, SMAD5, POU4F3 ATF4, IRF2, JUN, SOX14,
TGIF2LY, Zic2, STAT1::STAT2,
JUND(var.2) TAL1::TCF3
Salmo salar Atlantic salmon DUX4 HNF4A, HNF4G, HOXA13, CEBPA, MAX::MYC
MEF2A, OSR1, Znf423
Salmo trutta Brown trout ELK1, ELK3, ERF, ERG, ATF6, CREB3, CREB3L1, RORA(var.2), RORC CREB1, Hmx1, HSF1,
ETS1, ETV3, FEV, FLI1, KLF15, XBP1, ZBTB18 HSF4, Klf1
ZBTB33
Ictalurus punctatus Channel catfish FOXH1, HNF1A, HNF1B, Prdm15, ZNF148 TFAP2B(var.2), CEBPG, Ebf2, JDP2,
MEF2C, Sox3, ZBTB6, TFAP2E, YY1 JUNB, Mecom, PHOX2B,
ZNF148 TBX2, TBX4, TBX5
Cyprinus carpio Common carp ATOH7, BHLHE23, POU4F1, Pou5f1::Sox2 TBX1, TBX15, TBX18, HOXA13, HOXD10, ESR2, ESRRA, ESRRB,
OLIG1, PBX3, Zic2 TBX20 ZBTB18 Nr5a2, POU3F3,
RORA(var.2)
Electrophorus electricus Electric eel SREBF1 Crx, NFIC(var.2), NHLH1, NR1I2 DPRX, NR6A1, Plagl1, NRF1, OSR1, TEAD1,
NFIX(var.2), PBX1 SOX21, ZNF740 TEAD4, ZFP57
Dicentrarchus labrax European seabass ESRRA, ESRRB, Esrrg, DBP, FOXE1 Ebf2, EBF3, EGR1, Gfi1b, PROX1, ZNF274
Nr5a2 HOXA13, HOXD13, PBX3, SREBF1(var.2)
PKNOX1, SP1, SP2, SP4,
SP9
Takifugu rubripes Fugu MAFF, NR4A1, NRL, USF1, USF2 CTCFL, ELF1, ELF5, ETS2, FOXN3, HES2, Creb3l2, ELK1, ELK4,
POU4F1, POU4F3, ETV1, ETV5,,FOXC2, NR2C2, PBX3, ETS2, ETV3, HES2, HEY2,
Rhox11, SOX12, ZFP57 FOXD2, GABPA, HEY2, TFAP2A, KLF11, SPDEF, TFEB,
IKZF1, POU2F1, POU3F2, TFAP2C(var.2), THRB TFEC, ZBTB7A
POU3F3, SCRT1, SCRT2,
SPIB, SREBF1(var.2),
TFEC
Sparus aurata Gilthead seabream CTCFL, IRF2, NR1I2, ETS2, RXRA::VDR, CEBPG, GCM1, GCM2, CREM, MYBL1, RFX1
SOHLH2 SPDEF, TFAP2B, TFAP2C, Wt1 ZBTB7C
TFAP2C(var.2), TFAP2E,
TFCP2
Carassius auratus Goldfish ATF7, CEBPG, Creb5, ETV5, ETV6, ONECUT3 Crx, CUX2, ESR1, ESR2, CEBPG(var.2), PROP1, MEF2A, RELB
FOS::JUN(var.2), PHOX2A, PHOX2B, SMAD3, SMAD5
FOSB::JUN, PROP1, RELA, TFDP1
FOSL1::JUN(var.2),
JDP2(var.2), JUNB(var.2),
STAT1, Stat4,
Stat5a::Stat5b
Poecilia reticulata Guppy E2F6, E2F7, E2F8, GRHL2 SOX9 POU3F2 PBX3, PKNOX1, TCF7L1
Oryzias latipes Japanese medaka GFI1, Gfi1b, Hmx2, Hmx3, KLF4, Sox1 CEBPD, CEBPG(var.2), SP1, TFAP2A(var.2), Wt1
NR3C1, NR3C2, SP8 Sox3, TEF
 Taurine biosynthesis in fish Taurine biosynthesis in fish 21
21

Continuation

Species Common name cdo csad gad ado taut

Cyclopterus lumpus Lumpfish SMAD2::SMAD3::SMAD4 PKNOX1, POU3F1, Dmrt1, MYC, Lhx3, Nr2f6(var.2), HOXD10, KLF4, NR2C2,
POU4F3, Pparg::Rxra TFAP2B(var.2), TFAP2E, ONECUT1, ONECUT2, NR2F1(var.2),,Pparg::Rxra,
TFCP2 PAX5, Rarg, RFX1, SP8, THRB
ZBTB6
Oreochromis niloticus Nile tilapia GATA1::TAL1, POU3F1, EHF, ELF1, ETV1, GFI1, KLF4 BACH2(var.2), Crx, RELA, ZNF341
Pou5f1::Sox2, POU5F1B, FOXC2, GABPA, GCM2, Mecom, TBX1, TBX15,
TEAD1, TEAD4 GFI1, KLF9, MEF2B, TBX18, TBX20,
MEF2D, NKX2-2, SP8, TBX21, TCFL5, USF2,
STAT1, Stat4, ZNF143
Stat5a::Stat5b, Stat5b
Esox lucius Northern pike CTCF, DMRTC2, Klf1 PAX3 DUXA, FOXN3 ONECUT2, ONECUT3,
PBX1, TCF21(var.2)
Oncorhynchus mykiss Rainbow trout FOS::JUN, FOS::JUNB, BACH2, RFX1, RFX3, JUN ATOH1(var.2)
FOS::JUND, FOSL1, ZBTB7C
FOSL1::JUN, IRF7, JUNB,
JUND, TFAP2B(var.2)
Pygocentrus nattereri Red-bellied piranha HOXB9, HOXC12, STAT1::STAT2 FOSL1::JUND(var.2), BACH2, BHLHE22, DBP
HOXC9, HOXD12, TEAD1, TEAD4, TFAP2A ELF1, ETV1, GABPA,
KLF15, IKZF1, OLIG3, SIX1
KLF16
Lepisosteus oculatus Spotted gar RUNX2, ZBTB32 CTCF, CTCFL, Plagl1 OVOL2, TFAP2B(var.3) CEBPA, CEBPB, FOSB::JUN,
CEBPD, CEBPE, FOSB::JUNB(var.2),
CEBPG, FOXB1, FOSL1::JUN(var.2),
MAX::MYC, FOSL1::JUND(var.2),
ORA(var.2), RORC, FOSL2::JUN(var.2),
SCRT1, SCRT2, FOSL2::JUND(var.2),
ZNF449 JUND(var.2)
Seriola lalandi dorsalis Yellowtail amberjack IRF6, KLF11, KLF6, ONECUT2, ONECUT3, HOXD13, MAFF,
SCRT1, TCF21(var.2), PLAGL2 MAFG, NKX2-2,
ZNF449 PLAGL2, Stat5a
Danio rerio Zebrafish CREM, HES2, MYF6, PROP1, YY2 BHLHE23, GATA1, POU2F2, POU2F3,
TEF, TFEC OLIG1, OLIG2, Prdm15
SMAD2::SMAD3::SMAD4,
TCF21(var.2)
22 Latin American Journal of Aquatic Research

Figure 2. Top 15 putative transcription factors found in the promoter regions of cdo among some of the fish studied in the
present review.

Figure 3. Frequency of transcription factors binding sites (TFBS) of transcription factors (TFs) found in the promoter region
of cdo from fish species examined in the present study. Each column represents one species in study. The color of each cell
is determined by the frequency of the TFBS in the promoter zone. Darker blue represents higher frequency within the
promoter region of a TFBS of each TF and lighter blue represents low to absence of the TFBS.

NFATC1, NFATC3, NFATC4, NFIX, NKX6-2, observed that TFBS for HOXB3 is the most frequent
NR2C1, PDX1, PRRX1, RAX, RAX2, SHOX, Shox2, for almost all species. However, ZNF384 in fugu
Sox17, SRY, TLX2, UNCX, ZNF354C, ZNF384. The presents higher frequencies in its promoter region.
frequency of these TFs is graphed (Fig. 7). It can be
 Taurine biosynthesis in fish 23

Figure 4. Frequency of transcription factors binding sites (TFBS) of transcription factors (TFs) found in the promoter region
of csad from fish species examined in the present study. Each column represents one species in study. The color of each
cell is determined by the frequency of the TFBS in the promoter zone. Darker blue represents higher frequency within the
promoter region of a TFBS of each TF and lighter blue represents low to absence of the TFBS.

Identification of transcription factors among taurine can occur when this capacity is limited, or taurine is not
biosynthesis and transport being acquired from food sources (Li et al. 2022). This
In addition to identifying TFBS among species, the limited capacity has been identified in some species of
identification of putative transcription factors was the family Labridae, Scombridae, Soleidae, and Rajidae
compared among the genes involved in taurine because of CSAD's lack of activity (Salze & Davis
biosynthesis. We found that binding sites for homeobox 2015). Meanwhile, the disruption of csad and taut has
protein BarH-like 1 (BARX1), brain-specific homeobox identified cardiac anomalies in zebrafish (Kozlowski et
protein homolog (BSX), helicase-like transcription al. 2008, Chang et al. 2013, Park et al. 2014) as has been
factor (HLTF), homeobox protein Hox-A7 (HOXA7), observed in other vertebrates such as mice, when
homeobox protein Hox-B3 (HOXB3), homeobox elimination of cdo has been accomplished (Ueki et al.
protein Hox-B6 (HOXB6), homeobox protein Meis1 2011).
(MEIS1), homeobox protein Meis3 (MEIS3), nuclear Additionally, the identification of TFs and TFBS in
factor of activated T cells 1 (NFATC1), and homeobox the promoter regions of different fish species was also
protein Nkx-6.2 (NKX6-2) were commonly found in investigated to have a first look into the identification
the promoter regions of genes involved in taurine of putative TFs that might be regulating genes involved
transportation and biosynthesis. in the biosynthesis and transport of taurine due to the
lack of information regarding this issue. Regulatory
DISCUSSION elements, such as TFs, play a key role in the regulation
of genes, inducing or repressing their expression
In the present study, a literature review was conducted (Tellechea-Luzardo et al. 2023), while the combination
to identify the major physiological roles played by of the TFBS with the promoter determines the
genes involved in taurine transportation and condition of the gene expression (Lu & Rogan 2018).
biosynthesis in fishes. Taurine biosynthesis depends on Therefore, our results showed that a wide distribution
each species' production capacity (Sampath et al. 2020). of TFs and TFBS are present in the promoter zone of
Thus, it has been reported that physiological damage the different fish studied. It was observed that a set of
24 Latin American Journal of Aquatic Research

Figure 5. Frequency of transcription factors binding sites Figure 6. Frequency of transcription factors binding
(TFBS) of transcription factors (TFs) found in the promoter sites (TFBS) of transcription factors (TFs) found in the
region of gad from fish species examined in the present promoter region of ado from fish species examined in
study. Each column represents one species in study. The the present study. Each column represents one species
color of each cell is determined by the frequency of the in study. The color of each cell is determined by the
TFBS in the promoter zone. Darker blue represents higher frequency of the TFBS in the promoter zone. Darker
frequency within the promoter region of a TFBS of each TF blue represents higher frequency within the promoter
and lighter blue represents low to absence of the TFBS. region of a TFBS of each TF and lighter blue represents
low to absence of the TFBS.

TFs is shared among species depending on the gene in There were the following shared set of TFs present
the study. Nonetheless, it was also observed that in the in the promoter zone of the genes cdo, csad, gad¸ ado,
case of zebrafish, some TFs are not shared with the and taut of all the fish analyzed: homeobox protein
other species for the promoter region of cdo. It was also BarH-like 1 (BARX1), brain-specific homeobox
noted that the promoter region of spotted gar for the protein homolog (BSX), helicase-like transcription
gene csad was not completed as the rest of the species factor (HLTF), homeobox protein Hox-A7 (HOXA7),
in the database Ensembl, limiting the recognition of homeob ox protein Hox-B3 (HOXB3), homeobox
TFs for this species. protein Hox-B6 (HOXB6), homeobox protein Meis1
(MEIS1), homeobox protein Meis3 (MEIS3), nuclear
factor of activated T cells 1 (NFATC1), and homeobox
 Taurine biosynthesis in fish 25

Figure 7. Frequency of transcription factors binding sites (TFBS) of transcription factors (TFs) found in the promoter region
of taut from fish species examined in the present study. Each column represents one species in study. The color of each cell
is determined by the frequency of the TFBS in the promoter zone. Purple represents higher frequency within the promoter
region of a TFBS of each TF and red represents low to absence of the TFBS.

protein Nkx-6.2 (NKX6-2). These TFs have been of resources for the free use of different databases (i.e.
described to play an important role in normal NCBI, Ensembl), seems to be the following path to
development, immunity, and the regulation of finding more about the mechanism and regulation of
transcription by RNA polymerase II (Guner & taurine biosynthesis. Furthermore, using bioinformatic
Karlstrom 2007, Lyon et al. 2013, Uribe & Bronner and molecular tools to measure and analyze the
2015, Lu et al. 2019, Rittgers et al. 2021, Torres et al. expression levels of RNA should also be applied.
2023, Wan et al. 2023)
As mentioned in the introduction, other factors can CONCLUSIONS
affect the biosynthesis of taurine in fishes, such as
species, type of tissue, stage of development, eating Taurine biosynthesis and taurine transportation genes
habits, and the environment in which they live (Haga et regulate endogenous taurine availability in fish species.
al. 2015, Salze & Davis 2015, Sampath et al. 2020), Our literature review suggests that the lack or null
thus also affecting the regulation of the TFs that bind to expression of the main key genes in the synthesis or
the DNA sequence of different promoters zone. In this transportation of taurine could affect fish physio-
sense, the recent advantages in the sequencing of logically, particularly when a disruption, silencing, or
genomes and transcriptomes, as well as the availability elimination of cdo or taut occurs. Additionally, our in
26 Latin American Journal of Aquatic Research

silico approach to determining putative TFs suggests Chang, Y.C., Ding, S.T., Lee, Y.H., Wang, Y.C., Huang,
that the following are shared among the promoter M.F. & Liu, I.H. 2013. Taurine homeostasis requires
region of all study species in genes implicated in taurine de novo synthesis via cysteine sulfinic acid
transportation and biosynthesis: homeobox protein decarboxylase during zebrafish early embryogenesis.
BarH-like 1 (BARX1), brain-specific homeobox Amino Acids, 44: 615-629. doi: 10.1007/s00726-012-
protein homolog (BSX), helicase-like transcription 1386-8
factor (HLTF), homeobox protein Hox-A7 (HOXA7), Chatterjee, S. & Ahituv, N. 2017. Gene regulatory
homeobox protein Hox-B3 (HOXB3), homeobox elements, major drivers of human disease. Annual
protein Hox-B6 (HOXB6), homeobox protein Meis1 Review of Genomics and Human Genetics, 18: 45-63.
(MEIS1), homeobox protein Meis3 (MEIS3), nuclear doi: 10.1146/annurev-genom-091416-035537
factor of activated T cells 1 (NFATC1), and homeobox Chen, C., Xia, S.F., He, J., Lu, G., Xie, Z. & Han, H. 2019.
protein Nkx-6.2 (NKX6-2). However, it is necessary to Roles of taurine in cognitive function of physiology,
recall that it has also been found that each species has pathologies and toxication. Life Sciences, 231:
its regulatory elements and that further work regarding 116584. doi: 10.1016/j.lfs.2019.116584
how these TFs regulated taurine synthesis needs to be
Cocco, A., Rönnberg, A.M.C., Jin, Z., André, G.I.,
further investigated.
Vossen, L.E., Bhandage, A.K., et al. 2017.
Characterization of the γ-aminobutyric acid signaling
ACKNOWLEDGMENTS system in the zebrafish (Danio rerio Hamilton) central
nervous system by reverse transcription-quantitative
The author thanks the National Council of Humanities, polymerase chain reaction. Neuroscience, 343: 321.
Sciences and Technology of Mexico for the grant N° doi: 10.1016/j.neuroscience.2016.07.018
712313 and the project CB-2016-01-282775 for the Dawson, P.A., Weerasekera, S.J., Atcheson, R.J.,
financial support. Twomey, S.A. & Simmons, D.G. 2020. Molecular
analysis of the human placental cysteine dioxygenase
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Received: March 21, 2023; Accepted: October 30, 2023

 Taurine biosynthesis in fish 31

SUPPLEMENTARY MATERIAL
Supplementary Material 1. Complete CiiiDER analysis results of transcription factors and transcription factor binding
sites in promoter region of the genes cysteine dioxygenase (cdo), cysteine sulfonate decarboxylase (csad) promoters,
glutamate decarboxylase (gad), 2-amino ethanethiol dioxygenase (ado), taurine transporter (taut) of different fish species.