SEPHS2

Summary

SEPHS2 (selenophosphate synthetase 2, HGNC:19686) is a protein-coding gene on chromosome 16p11.2, encoding Selenide, water dikinase 2 (Q99611). Selenophosphate synthase that generates the selenium donor for selenocysteine biosynthesis by catalyzing formation of selenophosphate from selenide and ATP. It is a selective cancer dependency (DepMap: 66.1% of cell lines).

This gene encodes an enzyme that catalyzes the production of monoselenophosphate (MSP) from selenide and ATP. MSP is the selenium donor required for synthesis of selenocysteine (Sec), which is co-translationally incorporated into selenoproteins at in-frame UGA codons that normally signal translation termination. The 3’ UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. This protein is itself a selenoprotein containing a Sec residue at its active site, suggesting the existence of an autoregulatory mechanism. It is preferentially expressed in tissues implicated in the synthesis of selenoproteins and in sites of blood cell development. A pseudogene for this locus has been identified on chromosome 5.

Source: NCBI Gene 22928 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 56 total
• Cancer dependency (DepMap): dependent in 66.1% of screened cell lines
• MANE Select transcript: NM_012248

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19686
Approved symbol	SEPHS2
Name	selenophosphate synthetase 2
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	SPS2, SPS2b
Ensembl gene	ENSG00000179918
Ensembl biotype	protein_coding
OMIM	606218
Entrez	22928

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000478753

RefSeq mRNA: 1 — MANE Select: NM_012248 NM_012248

CCDS: CCDS42150

Canonical transcript exons

ENST00000478753 — 1 exons

Exon	Start	End
ENSE00001219630	30443631	30445874

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.3875 / max 451.1032, expressed in 1813 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157055	35.3875	1813

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.30	gold quality
nephron tubule	UBERON:0001231	98.85	gold quality
right lobe of liver	UBERON:0001114	98.83	gold quality
liver	UBERON:0002107	98.41	gold quality
renal medulla	UBERON:0000362	98.04	gold quality
duodenum	UBERON:0002114	98.01	gold quality
kidney epithelium	UBERON:0004819	97.54	gold quality
adult mammalian kidney	UBERON:0000082	97.38	gold quality
colonic mucosa	UBERON:0000317	97.37	gold quality
renal glomerulus	UBERON:0000074	96.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.98	gold quality
secondary oocyte	CL:0000655	96.76	gold quality
jejunum	UBERON:0002115	96.76	gold quality
palpebral conjunctiva	UBERON:0001812	96.67	gold quality
metanephric glomerulus	UBERON:0004736	96.52	gold quality
germinal epithelium of ovary	UBERON:0001304	96.30	gold quality
esophagus squamous epithelium	UBERON:0006920	96.30	gold quality
adult organism	UBERON:0007023	96.27	gold quality
amniotic fluid	UBERON:0000173	96.17	gold quality
rectum	UBERON:0001052	96.17	gold quality
kidney	UBERON:0002113	96.17	gold quality
mucosa of transverse colon	UBERON:0004991	96.12	gold quality
pylorus	UBERON:0001166	95.89	gold quality
cortex of kidney	UBERON:0001225	95.82	gold quality
visceral pleura	UBERON:0002401	95.80	gold quality
metanephros	UBERON:0000081	95.61	gold quality
ileal mucosa	UBERON:0000331	95.30	gold quality
epithelium of nasopharynx	UBERON:0001951	95.28	gold quality
islet of Langerhans	UBERON:0000006	95.19	gold quality
epithelial cell of pancreas	CL:0000083	95.11	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	122.35
E-HCAD-10	yes	25.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting SEPHS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-6760-5P	98.87	66.73	1515

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 66.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• the Sps1-encoded enzyme depends on a selenium salvage system that recycles l-selenocysteine, whereas the Sps2 enzyme can function with a selenite assimilation system (PMID:15534230)
• miR-185 plays a role in up-regulation of GPX2 and SEPHS2 expression.In the case of SEPHS2 this may contribute to maintaining selenoprotein synthesis. (PMID:23934683)
• Data confirm interactions among components of the early steps of the selenocysteine biosynthesis pathway (SEPSECS, SECP43, SEPHS1, and SEPHS2); SECP43, which interacts with SEPSECS and SEPHS1, is a globular protein that forms oligomers in vivo. (PMID:28414460)
• Structural analysis of human SEPHS2 protein, a selenocysteine machinery component, over-expressed in triple negative breast cancer. (PMID:31695102)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sephs3	ENSDARG00000017659
mus_musculus	Sephs2	ENSMUSG00000049091
drosophila_melanogaster	Sps2	FBGN0032224
drosophila_melanogaster	Sps1	FBGN0261270
caenorhabditis_elegans		WBGENE00012867

Paralogs (1): SEPHS1 (ENSG00000086475)

Protein

Protein identifiers

Selenide, water dikinase 2 — Q99611 (reviewed: Q99611)

Alternative names: Selenium donor protein 2, Selenophosphate synthase 2

All UniProt accessions (1): Q99611

UniProt curated annotations — full annotation on UniProt →

Function. Selenophosphate synthase that generates the selenium donor for selenocysteine biosynthesis by catalyzing formation of selenophosphate from selenide and ATP.

Subunit / interactions. Homodimer. Component of a complex composed of SEPHS1, SEPHS2, SEPSECS and TRNAU1AP.

Subcellular location. Cytoplasm.

Post-translational modifications. Truncated SEPHS2 proteins produced by failed UGA/Sec decoding are ubiquitinated by the CRL2(KLHDC3) complex, which recognizes the glycine (Gly) at the C-terminus of truncated SEPHS2 proteins.

Cofactor. Binds 1 Mg(2+) ion per monomer.

Similarity. Belongs to the selenophosphate synthase 1 family. Class I subfamily.

RefSeq proteins (1): NP_036380* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004536	SPS/SelD	Family
IPR010918	PurM-like_C_dom	Domain
IPR016188	PurM-like_N	Domain
IPR036676	PurM-like_C_sf	Homologous_superfamily
IPR036921	PurM-like_N_sf	Homologous_superfamily

Pfam: PF00586, PF02769

Enzyme classification (BRENDA):

• EC 2.7.9.3 — selenide, water dikinase (BRENDA: 41 organisms, 55 substrates, 16 inhibitors, 18 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.026–10.3	14
SELENIDE	0.02–0.046	3

Catalyzed reactions (Rhea), 1 shown:

• hydrogenselenide + ATP + H2O = selenophosphate + AMP + phosphate + 2 H(+) (RHEA:18737)

UniProt features (19 total): binding site 8, modified residue 3, initiator methionine 1, chain 1, site 1, non-standard amino acid 1, sequence variant 1, mutagenesis site 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q99611 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 63 (important for catalytic activity); 60

Ligand- & substrate-binding residues (8): 212–215; 316; 63 (in other chain); 118–120 (in other chain); 120; 138 (in other chain); 161 (in other chain); 161

Post-translational modifications (3): 2, 46, 97

Mutagenesis-validated functional residues (1):

Position	Phenotype
60	does not affect the selenophosphate synthase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2408557	Selenocysteine synthesis
R-HSA-1430728	Metabolism
R-HSA-2408522	Selenoamino acid metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 235 (showing top): BECKER_TAMOXIFEN_RESISTANCE_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, KENNY_CTNNB1_TARGETS_UP, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, MARTINEZ_RB1_TARGETS_DN, MORF_ATOX1, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_CDC25_UP, chr16p11, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_DN

GO Biological Process (3): selenium compound metabolic process (GO:0001887), obsolete selenocysteine metabolic process (GO:0016259), L-selenocysteine biosynthetic process (GO:0016260)

GO Molecular Function (7): selenide, water dikinase activity (GO:0004756), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Selenoamino acid metabolism	1
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
metabolic process	1
modified amino acid biosynthetic process	1
L-amino acid biosynthetic process	1
proteinogenic amino acid biosynthetic process	1
kinase activity	1
phosphotransferase activity, paired acceptors	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEPHS2	PSTK	Q8IV42	916
SEPHS2	SEPSECS	Q9HD40	902
SEPHS2	SELENOT	P62341	874
SEPHS2	DIO1	P49895	860
SEPHS2	SELENOO	Q9BVL4	859
SEPHS2	TRNAU1AP	Q9NX07	858
SEPHS2	EEFSEC	P57772	845
SEPHS2	SELENOK	Q9Y6D0	844
SEPHS2	SELENOF	O60613	828
SEPHS2	SELENOH	Q8IZQ5	821
SEPHS2	SELENOS	Q9BQE4	815
SEPHS2	SELENOI	Q9C0D9	809
SEPHS2	MSRB1	Q9NZV6	808
SEPHS2	SELENON	Q9NZV5	804
SEPHS2	TXNRD3	Q86VQ6	795

IntAct

17 interactions, top by confidence:

A	B	Type	Score
SEPHS1	QRICH1	psi-mi:“MI:0914”(association)	0.780
LOXL4	CCT6A	psi-mi:“MI:0914”(association)	0.530
CCL22	PLXNA2	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
SEPHS1	SEPHS2	psi-mi:“MI:0915”(physical association)	0.500
ARHGEF5	SEPHS2	psi-mi:“MI:0915”(physical association)	0.370
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
ENDOV	VWA8	psi-mi:“MI:0914”(association)	0.350
ZNF408		psi-mi:“MI:0914”(association)	0.350
CCL22	HSPA12A	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
FAM86C1P	ZBTB39	psi-mi:“MI:0914”(association)	0.350
TNNC2	ECI2	psi-mi:“MI:0914”(association)	0.350
CDPF1	USP4	psi-mi:“MI:0914”(association)	0.350

BioGRID (47): SEPHS2 (Affinity Capture-RNA), SEPHS2 (Affinity Capture-RNA), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS), SEPHS2 (Co-fractionation), SEPHS2 (Co-fractionation), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-RNA), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS), SEPHS2 (Affinity Capture-MS)

ESM2 similar proteins: A1YIZ1, A2ARP1, A7Z050, B5DFG1, E1BPN0, E7FCP8, O14976, O18373, O35385, P0C644, P33402, P46489, P49903, P57075, P97364, P97874, Q05145, Q0VC82, Q38A34, Q3V3E1, Q42713, Q43307, Q4Q0M0, Q5R4H0, Q5RDF1, Q5RF87, Q66I14, Q6ESZ9, Q6GL12, Q6PF47, Q6PFW1, Q7Z3D6, Q7ZW38, Q80V31, Q84MA1, Q8BGG7, Q8BH69, Q8BH86, Q8C0D5, Q8H1E2

Diamond homologs: A0KKE7, A0KRK1, A1APP9, A1RP94, A1VE87, A1YIZ1, A3DA84, A3MZ45, A4SMM1, A4W9I2, A4YBB9, A5UG02, A6QBB7, A6WHQ5, A7MNU8, A7ZMN3, A8A0V7, A8EUZ4, A8MHJ6, A9KPW1, A9KW79, B1K568, B1Z181, B2RLG7, B2TKP6, B2V0F0, B3E7F7, B4EJQ7, B5EBG1, B8DNL1, B8EBM9, B8ES21, B8FWU2, C4ZDB0, C6E5Z5, O18373, O62461, O67139, P16456, P43911

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

56 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

88 predictions. Top by Δscore:

Variant	Effect	Δscore
16:30445871:T:TA	donor_gain	0.9400
16:30445841:AAG:A	donor_gain	0.8100
16:30445739:G:T	acceptor_gain	0.6200
16:30445300:A:T	acceptor_gain	0.5900
16:30445299:C:CT	acceptor_gain	0.5600
16:30445808:TATTA:T	donor_loss	0.5400
16:30445809:ATTAC:A	donor_loss	0.5400
16:30445810:TTAC:T	donor_loss	0.5400
16:30445811:TACC:T	donor_loss	0.5400
16:30445812:ACCTG:A	donor_loss	0.5400
16:30445813:CC:C	donor_loss	0.5400
16:30445807:ATATT:A	donor_loss	0.5300
16:30445814:C:A	donor_loss	0.5300
16:30445827:C:CA	donor_gain	0.5200
16:30444689:T:TC	acceptor_gain	0.4700
16:30444700:T:TC	acceptor_gain	0.4400
16:30445815:T:A	donor_loss	0.4100
16:30445806:AATAT:A	donor_loss	0.3700
16:30445816:G:A	donor_loss	0.3600
16:30445841:AAGC:A	donor_gain	0.3600
16:30445738:C:T	acceptor_gain	0.3400
16:30444692:T:TC	acceptor_gain	0.3300
16:30444696:CAGAT:C	acceptor_gain	0.3000
16:30444702:A:C	acceptor_gain	0.3000
16:30445735:GCC:G	acceptor_gain	0.3000
16:30445736:CCC:C	acceptor_gain	0.3000
16:30445749:C:A	acceptor_gain	0.3000
16:30445797:CAAAA:C	donor_loss	0.3000
16:30444654:T:TA	donor_gain	0.2900
16:30445731:G:GA	acceptor_gain	0.2800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000619174 (16:30443678 T>C), RS1000736086 (16:30446886 G>A,C,T), RS1001377947 (16:30447062 T>C), RS1001913764 (16:30444161 A>C), RS1001986190 (16:30447679 A>G), RS1002094176 (16:30447323 G>A,T), RS1002733310 (16:30443409 T>G), RS1003317957 (16:30445877 T>TA), RS1003381934 (16:30443825 G>T), RS1003968393 (16:30444859 T>C), RS1005163462 (16:30446241 G>GA), RS1005639832 (16:30446007 C>G), RS1005755374 (16:30447847 G>C), RS1005775548 (16:30445835 C>A,T), RS1006888866 (16:30446862 G>A,C,T)

Disease associations

OMIM: gene MIM:606218 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002381_85	Eosinophil count	6.000000e-18

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	4
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	4
Cisplatin	affects expression, affects cotreatment, increases expression	3
Tetrachlorodibenzodioxin	increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	2
Aflatoxin B1	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	affects expression	1
tanshinone	increases expression	1
nickel chloride	decreases expression	1
avobenzone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
thifluzamide	increases expression	1
jinfukang	increases expression, affects cotreatment	1
Resveratrol	increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases response to substance	1
Air Pollutants	increases abundance, increases expression	1
Antimony	decreases expression	1
Antimony Potassium Tartrate	decreases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Caffeine	decreases phosphorylation	1
Fluorouracil	affects response to substance	1
Hydrogen Peroxide	affects expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.