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Information on EC 2.9.1.2 - O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase and Organism(s) Homo sapiens and UniProt Accession Q9HD40
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2.9.1.2 O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthaseIUBMB Comments
A pyridoxal-phosphate protein . In archaea and eukarya selenocysteine formation is achieved by a two-step process: EC 2.7.1.164 (O-phosphoseryl-tRNASec kinase) phosphorylates the endogenous L-seryl-tRNASec to O-phospho-L-seryl-tRNASec, and then this misacylated amino acid-tRNA species is converted to L-selenocysteinyl-tRNASec by Sep-tRNA:Sec-tRNA synthase.
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Word Map
- 2.9.1.2
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selenoproteins
- autoantibodies
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sec-trnasec
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ama-m2
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cerebello-cerebral
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sep-trna:sec-trna
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trna-dependent
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anti-soluble
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trnasersec
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secisbp2
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selenoproteome
-
efsec
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anti-smooth
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anti-liver
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selenoenzymes
- sephs2
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Reaction Schemes
Synonyms
sepsecs, sla/lp, o-phosphoseryl-trna:selenocysteinyl-trna synthase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
O-phospho-L-seryl-tRNASec + selenophosphate + H2O = L-selenocysteinyl-tRNASec + 2 phosphate
proposed pyridoxal 5'-phosphate mechanism of L-phosphoseryl-tRNA to L-selenocysteinyl-tRNA conversion: the reaction begins by the covalently attached O-phospho-L-serine being brought into the proximity of the Schiff base when L-phosphoseryl-tRNASec binds to the enzyme. The amino group of O-phospho-L-serine can then attack the Schiff base formed between Lys284 and pyridoxal 5'-phosphate, which yields an external aldimine. The reoriented side chain of Lys284 abstracts the Calpha proton from O-phospho-L-serine, and the electron delocalization by the pyridine ring assists in rapid beta-elimination of the phosphate group, which produces an intermediate dehydroalanyl-tRNASec. After phosphate dissociation and binding of selenophosphate, the concomitant attack of water on the selenophosphate group and of the nucleophilic selenium onto the highly reactive dehydroalanyl moiety yield an oxidized form of L-phosphoseryl-tRNASec. The protonated Lys284, returns the proton to the Calpha carbon and then attacks pyridoxal 5'-phosphate to form an internal aldimine. Finally, Sec-tRNASec is released from the active site
PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
selenophosphate:O-phospho-L-seryl-tRNASec selenium transferase
A pyridoxal-phosphate protein [4]. In archaea and eukarya selenocysteine formation is achieved by a two-step process: EC 2.7.1.164 (O-phosphoseryl-tRNASec kinase) phosphorylates the endogenous L-seryl-tRNASec to O-phospho-L-seryl-tRNASec, and then this misacylated amino acid-tRNA species is converted to L-selenocysteinyl-tRNASec by Sep-tRNA:Sec-tRNA synthase.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-phosphoseryl-tRNASec + selenophosphate
L-selenocysteinyl-tRNASec + phosphate
selenocysteine is the only genetically encoded amino acid in humans whose biosynthesis occurs on its cognate transfer RNA (tRNA). O-Phosphoseryl-tRNA:selenocysteinyl-tRNA synthase catalyzes the final step of selenocysteine formation by a tRNA-dependent mechanism
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-
?
O-phospho-L-seryl-tRNASec + selenophosphate
L-selenocysteinyl-tRNASec + phosphate
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-
?
O-phospho-L-seryl-tRNASec + selenophosphate
L-selenocysteinyl-tRNASec + phosphate
L-phosphoseryl-tRNA is the crucial precursor for L-selenocysteinyl-tRNA formation in archaea and eukarya. Selenocysteine formation is achieved by a two-step process: O-phosphoseryl-tRNASec kinase phosphorylates the endogenous L-seryl-tRNASec to O-phospho-L-seryl-tRNASec, and then this misacylated amino acid-tRNA species is converted to L-selenocysteinyl-tRNASec by Sep-tRNA:Sec-tRNA synthase
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-
?
O-phospho-L-seryl-tRNASec + selenophosphate
L-selenocysteinyl-tRNASec + phosphate
proposed pyridoxal 5'-phosphate mechanism of L-phosphoseryl-tRNA to L-selenocysteinyl-tRNA conversion: the reaction begins by the covalently attached O-phospho-L-serine being brought into the proximity of the Schiff base when L-phosphoseryl-tRNASec binds to the enzyme. The amino group of O-phospho-L-serine can then attack the Schiff base formed between Lys284 and pyridoxal 5'-phosphate, which yields an external aldimine. The reoriented side chain of Lys284 abstracts the Calpha proton from O-phospho-L-serine, and the electron delocalization by the pyridine ring assists in rapid beta-elimination of the phosphate group, which produces an intermediate dehydroalanyl-tRNASec. After phosphate dissociation and binding of selenophosphate, the concomitant attack of water on the selenophosphate group and of the nucleophilic selenium onto the highly reactive dehydroalanyl moiety yield an oxidized form of L-phosphoseryl-tRNASec. The protonated Lys284, returns the proton to the Calpha carbon and then attacks pyridoxal 5'-phosphate to form an internal aldimine. Finally, Sec-tRNASec is released from the active site
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-
?
O-phospho-L-seryl-tRNASec + selenophosphate + H2O
L-selenocysteinyl-tRNASec + 2 phosphate
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?
O-phospho-L-seryl-tRNASec + selenophosphate + H2O
L-selenocysteinyl-tRNASec + 2 phosphate
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-
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?
additional information
?
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SepSecS binds unacylated tRNASec equally well as Sep-tRNASec 1
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additional information
?
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SepSecS binds unacylated tRNASec equally well as Sep-tRNASec 1
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-phosphoseryl-tRNASec + selenophosphate
L-selenocysteinyl-tRNASec + phosphate
selenocysteine is the only genetically encoded amino acid in humans whose biosynthesis occurs on its cognate transfer RNA (tRNA). O-Phosphoseryl-tRNA:selenocysteinyl-tRNA synthase catalyzes the final step of selenocysteine formation by a tRNA-dependent mechanism
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-
?
O-phospho-L-seryl-tRNASec + selenophosphate
L-selenocysteinyl-tRNASec + phosphate
L-phosphoseryl-tRNA is the crucial precursor for L-selenocysteinyl-tRNA formation in archaea and eukarya. Selenocysteine formation is achieved by a two-step process: O-phosphoseryl-tRNASec kinase phosphorylates the endogenous L-seryl-tRNASec to O-phospho-L-seryl-tRNASec, and then this misacylated amino acid-tRNA species is converted to L-selenocysteinyl-tRNASec by Sep-tRNA:Sec-tRNA synthase
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-
?
O-phospho-L-seryl-tRNASec + selenophosphate + H2O
L-selenocysteinyl-tRNASec + 2 phosphate
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-
-
?
O-phospho-L-seryl-tRNASec + selenophosphate + H2O
L-selenocysteinyl-tRNASec + 2 phosphate
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pyridoxal 5'-phosphate
pyridoxal 5'-phosphatedependent mechanism of Sec-tRNASec formation. Each SepSecS monomer has a pyridoxal 5'-phosphate cofactor covalently linked to the Nepsilon-amino group of the conserved Lys284 by means of formation of a Schiff base
pyridoxal 5'-phosphate
the enzyme needs pyridoxal 5'-phosphate to carry out the conversion of O-phosphoserine to selenocysteine
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
four distinct mutations (A239T, Y334C, T325S and nonsense Y429*) in human gene SEPSECS cause congenital cerebellar atrophy termed pontocerebellar hypoplasia type 2D (PCH2D). Pontocerebellar hypoplasia (PCH) is a group of autosomal recessive disorders affecting different cerebral structures, particularly the brainstem and cerebellum. Most PCH types result from mutations in genes important for tRNA splicing and aminoacylation and RNA transport. The PCH2D patients similarly suffer from progressive cerebellar and cerebral atrophy, neonatal irritability, and debilitating spasticity. Neuropathological analysis reveals severe atrophy of the brainstem and cerebellar cortex with loss of both white and gray matter. This subset of patients also exhibits a slight reduction in selenoprotein levels, suggesting that SepSecS catalysis is impaired. Pathogenic variants are less soluble than wild-type SepSecS. Mutations Thr325Ser and Tyr334Cys do not affect the binding affinity of the SepSecS-tRNA complex
metabolism
in mammalian cells, the incorporation of the 21st amino acid, selenocysteine, into proteins is guided by the Sec machinery. The function of this protein complex requires several protein?protein and protein?RNA interactions, leading to the incorporation of selenocysteine at UGA codons. It is guided by stem?loop structures localized in the 3? untranslated regions of the selenoprotein-encoding genes
physiological function
the enzyme is responsible for the formation of only 25 human proteins, but the human selenoproteome is pivotal for the maintenance of the cellular redox potential (e.g. thioredoxin reductases), regulation of the overall metabolic rate (e.g. iodothyronine deiodinases), removal of reactive oxygen species and prevention of oxidative damage (e.g. glutathione peroxidases, and methionine sulfoxide reductases), and selenium homeostasis (e.g. selenoprotein P)
malfunction
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enzyme silencing clearly inhibits proliferation of JEG-3 cells, significantly induces cell apoptosis and reduces the production of progesterone and human chorionic gonadotropin
physiological function
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the enzyme significantly affects proliferation, apoptosis and hormone secretion of human trophoblast cells
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SPCS_HUMAN
501
0
55726
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
two SepSecS monomers form a homodimer, and two active sites are formed at the dimer interface. The two homodimers associate into a tetramer through interactions between the N-terminal alpha1-loop-alpha2 motifs
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of the quaternary complex between human SepSecS, unacylated tRNASec, and a mixture of O-phosphoserine and thiophosphate to 2.8 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A239T
naturally occurring mutation and site-directed mutagenesis. The mutant forms a stable complex with GroEL. Residue Ala239 is located in helix alpha8 near the site that interacts with the variable arm of tRNASec, and is distant from the active site. The A239T variant binds tRNASec with less affinity compared to wild-type SepSecS, but its catalytic function is unaffected
K173A
in vivo activity of the mutant is indistinguishable from that of the wild-type enzyme
K173M
in vivo activity of the mutant is indistinguishable from that of the wild-type enzyme
R97A
in vivo activity of the mutant is indistinguishable from that of the wild-type enzyme
R97Q
in vivo activity of the mutant is indistinguishable from that of the wild-type enzyme
T325S
naturally occurring mutation and site-directed mutagenesis, the mutation does not affect the binding affinity of the SepSecS-tRNA complex. The mutant does not form a complex with GroEL. Residue Thr325 is located in helix alpha12 and about 15 A away from the active site. The Thr325 to Ser replacement does not cause any changes in the tetrameric structure of SepSecS. Tetramers of T325S adopt the same structure as wild-type SepSecS. The pathogenic mutation Thr325Ser does not alter the three-dimensional structure of the SepSecS tetramer
Y334C
naturally occurring mutation and site-directed mutagenesis, the mutation does not affect the binding affinity of the SepSecS-tRNA complex. The mutant forms a stable complex with GroEL. The side chain of Tyr334 is in helix alpha13 near the active-site pocket. Its hydroxyl group forms a hydrogen bond with the backbone carbonyl of Asn285, and this interaction may help stabilize a loop that carries Lys284 and the covalently attached PLP cofactor. In the Y334C crystal, the side chain of Cys334 coordinates two water molecules, which interact with the backbone carbonyl of Asn285 in the same fashion as the Tyr side chain in the wild-type enzyme. Tetramers of Y334C adopt the same structure as wild-type SepSecS. The pathogenic mutation Tyr334Cys does not alter the three-dimensional structure of the SepSecS tetramer
Y429*
naturally occurring nonsense mutation and site-directed mutagenesis. Y429* expresses at low levels and as insoluble protein regardless of the incubation temperature, induction point, or the growth media used. Tyr429 is located before strand beta14. Premature abortion of protein synthesis yields a truncated enzyme devoid of strand beta14, loop beta14-alpha15, and the C-terminal helix alpha15. Loop beta14-alpha15 establishes a side of the catalytic groove, and helix alpha15 provides residues that bind the 5'-end of tRNASec. The Y429* variant is not be capable of promoting selenocysteine synthesis
additional information
additional information
mapping pathogenic mutations onto the tetrameric human SepSecS-tRNASec complex, overview
additional information
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mapping pathogenic mutations onto the tetrameric human SepSecS-tRNASec complex, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged enzyme mutants from Escherichia coli strain BL21(DE3) and SoluBL21(DE3) by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene SEPSECS, recombinant expression of His6-tagged enzyme mutants in Escherichia coli strain BL21(DE3) and SoluBL21(DE3) (a bacterial strain engineered to increase solubility of recombinant proteins)
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Yuan, J.; Palioura, S.; Salazar, J.C.; Su, D.; O'Donoghue, P.; Hohn, M.J.; Cardoso, A.M.; Whitman, W.B.; Sll, D.
RNA-dependent conversion of phosphoserine forms selenocysteine in eukaryotes and archaea
Proc. Natl. Acad. Sci. USA
103
18923-18927
2006
Methanocaldococcus jannaschii (Q58027), Methanococcus maripaludis (Q6LZM9), Homo sapiens (Q9HD40), Homo sapiens
Palioura, S.; Sherrer, R.L.; Steitz, T.A.; Sll, D.; Simonovic, M.
The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation
Science
325
321-325
2009
Homo sapiens (Q9HD40), Homo sapiens
Zhao, H.D.; Zhang, W.G.; Sun, M.N.; Duan, Q.F.; Li, F.L.; Li, H.
The role of Sep (O-phosphoserine) tRNA: Sec (selenocysteine) synthase (SEPSECS) in proliferation, apoptosis and hormone secretion of trophoblast cells
Placenta
34
967-972
2013
Homo sapiens
Oudouhou, F.; Casu, B.; Dopgwa Puemi, A.S.; Sygusch, J.; Baron, C.
Analysis of Novel interactions between components of the selenocysteine biosynthesis pathway, SEPHS1, SEPHS2, SEPSECS, and SECp43
Biochemistry
56
2261-2270
2017
Homo sapiens (Q9HD40)
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