PGLS

Summary

PGLS (6-phosphogluconolactonase, HGNC:8903) is a protein-coding gene on chromosome 19p13.11, encoding 6-phosphogluconolactonase (O95336). Hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate.

Enables 6-phosphogluconolactonase activity. Involved in pentose-phosphate shunt. Located in extracellular exosome.

Source: NCBI Gene 25796 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 70 total
• Druggable target: yes
• MANE Select transcript: NM_012088

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8903
Approved symbol	PGLS
Name	6-phosphogluconolactonase
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	6PGL
Ensembl gene	ENSG00000130313
Ensembl biotype	protein_coding
OMIM	604951
Entrez	25796

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000252603, ENST00000594761, ENST00000595782, ENST00000596799, ENST00000598811, ENST00000600923, ENST00000879052, ENST00000879053, ENST00000930485, ENST00000960963

RefSeq mRNA: 1 — MANE Select: NM_012088 NM_012088

CCDS: CCDS12361

Canonical transcript exons

ENST00000252603 — 5 exons

Exon	Start	End
ENSE00000895565	17516173	17516280
ENSE00000895568	17520944	17521288
ENSE00001236496	17511649	17511960
ENSE00003624521	17517710	17517850
ENSE00003624869	17517288	17517389

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 97.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.2440 / max 423.1610, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174522	81.7059	1823
174523	0.5381	295

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.82	gold quality
lower esophagus mucosa	UBERON:0035834	97.34	gold quality
mucosa of transverse colon	UBERON:0004991	97.04	gold quality
monocyte	CL:0000576	96.60	gold quality
right adrenal gland	UBERON:0001233	96.55	gold quality
right adrenal gland cortex	UBERON:0035827	96.48	gold quality
leukocyte	CL:0000738	96.47	gold quality
mononuclear cell	CL:0000842	96.44	gold quality
esophagus mucosa	UBERON:0002469	96.11	gold quality
left adrenal gland cortex	UBERON:0035825	96.07	gold quality
stromal cell of endometrium	CL:0002255	96.05	gold quality
left adrenal gland	UBERON:0001234	96.05	gold quality
skin of abdomen	UBERON:0001416	95.99	gold quality
skin of leg	UBERON:0001511	95.74	gold quality
blood	UBERON:0000178	95.63	gold quality
body of pancreas	UBERON:0001150	95.61	gold quality
adrenal cortex	UBERON:0001235	95.54	gold quality
minor salivary gland	UBERON:0001830	95.43	gold quality
right uterine tube	UBERON:0001302	95.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.19	gold quality
spleen	UBERON:0002106	95.13	gold quality
mouth mucosa	UBERON:0003729	95.13	gold quality
right ovary	UBERON:0002118	95.02	gold quality
left ovary	UBERON:0002119	94.91	gold quality
omental fat pad	UBERON:0010414	94.85	gold quality
zone of skin	UBERON:0000014	94.82	gold quality
peritoneum	UBERON:0002358	94.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.73	gold quality
right lobe of thyroid gland	UBERON:0001119	94.67	gold quality
ectocervix	UBERON:0012249	94.60	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	21.14
E-ANND-3	yes	8.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

4 targeting PGLS, 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-3119	99.92	71.34	2390
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1225-3P	97.29	64.60	876

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pgls	ENSDARG00000021233
mus_musculus	Pgls	ENSMUSG00000031807
rattus_norvegicus	Pgls	ENSRNOG00000018326
drosophila_melanogaster	Pgls	FBGN0030239
caenorhabditis_elegans		WBGENE00013301

Protein

Protein identifiers

6-phosphogluconolactonase — O95336 (reviewed: O95336)

All UniProt accessions (5): O95336, A0A0K0K1K7, M0R0U3, M0R1L2, M0R261

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate.

Subcellular location. Cytoplasm.

Pathway. Carbohydrate degradation; pentose phosphate pathway; D-ribulose 5-phosphate from D-glucose 6-phosphate (oxidative stage): step 2/3.

Similarity. Belongs to the glucosamine/galactosamine-6-phosphate isomerase family. 6-phosphogluconolactonase subfamily.

RefSeq proteins (1): NP_036220* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005900	6-phosphogluconolactonase_DevB	Domain
IPR006148	Glc/Gal-6P_isomerase	Domain
IPR037171	NagB/RpiA_transferase-like	Homologous_superfamily
IPR039104	6PGL	Family

Pfam: PF01182

Enzyme classification (BRENDA):

• EC 3.1.1.31 — 6-phosphogluconolactonase (BRENDA: 18 organisms, 21 substrates, 9 inhibitors, 7 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
6-PHOSPHO-D-GLUCONO-1,5-LACTONE	0.0515–0.83	5

Catalyzed reactions (Rhea), 1 shown:

• 6-phospho-D-glucono-1,5-lactone + H2O = 6-phospho-D-gluconate + H(+) (RHEA:12556)

UniProt features (5 total): modified residue 3, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95336-F1	95.09	0.93

Functional residue map

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

Post-translational modifications (3): 2, 49, 180

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-71336	Pentose phosphate pathway
R-HSA-1430728	Metabolism
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives

MSigDB gene sets: 130 (showing top): GOBP_NADPPLUS_METABOLIC_PROCESS, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_GLUCOSE_6_PHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, KEGG_PENTOSE_PHOSPHATE_PATHWAY, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, RICKMAN_TUMOR_DIFFERENTIATED_MODERATELY_VS_POORLY_UP, GOBP_PURINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, MORI_MATURE_B_LYMPHOCYTE_DN

GO Biological Process (3): carbohydrate metabolic process (GO:0005975), pentose-phosphate shunt (GO:0006098), pentose-phosphate shunt, oxidative branch (GO:0009051)

GO Molecular Function (3): 6-phosphogluconolactonase activity (GO:0017057), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of carbohydrates and carbohydrate derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
NADPH regeneration	2
cellular anatomical structure	2
primary metabolic process	1
pentose-phosphate shunt, oxidative branch	1
pentose-phosphate shunt, non-oxidative branch	1
glucose 6-phosphate metabolic process	1
glucose-6-phosphate dehydrogenase activity	1
phosphogluconate dehydrogenase (decarboxylating) activity	1
pentose-phosphate shunt	1
6-phosphogluconolactonase activity	1
carbohydrate derivative metabolic process	1
carboxylic ester hydrolase activity	1
binding	1
catalytic activity	1
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PGLS	PGD	P52209	795
PGLS	RPIA	P49247	743
PGLS	TALDO1	P37837	733
PGLS	TKT	P29401	701
PGLS	RPE	Q96AT9	686
PGLS	RPEL1	Q2QD12	667
PGLS	GPI	P06744	664
PGLS	TKTL1	P51854	661
PGLS	TKTL2	Q9H0I9	636
PGLS	G6PD	P11413	623
PGLS	TPI1	P00938	615
PGLS	XYLB	O75191	563
PGLS	IDNK	Q5T6J7	540
PGLS	CS	O75390	528
PGLS	FH	P07954	511

IntAct

24 interactions, top by confidence:

A	B	Type	Score
PGLS	BLMH	psi-mi:“MI:0915”(physical association)	0.560
PGLS	TERF2IP	psi-mi:“MI:0915”(physical association)	0.510
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
TERF1	PGLS	psi-mi:“MI:0915”(physical association)	0.370
POT1	PGLS	psi-mi:“MI:0915”(physical association)	0.370
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
KSR1	DDX39A	psi-mi:“MI:0914”(association)	0.350
MAGI1	CIT	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
HRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
GPKOW	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
LARP7	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
TERF2IP	PGLS	psi-mi:“MI:0915”(physical association)	0.000
PGLS	BLMH	psi-mi:“MI:0915”(physical association)	0.000
BLMH	PGLS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (83): PGLS (Two-hybrid), PGLS (Two-hybrid), PGLS (Two-hybrid), PGLS (Two-hybrid), RCHY1 (Two-hybrid), KRTAP4-2 (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-9 (Two-hybrid), KRTAP10-8 (Two-hybrid), KRTAP10-3 (Two-hybrid), NOTCH2NL (Two-hybrid), PGLS (Two-hybrid), PGLS (Two-hybrid), PGLS (Two-hybrid), PGLS (Affinity Capture-Western)

ESM2 similar proteins: A0JNU3, A1A4L8, A2BDX3, A5GFZ6, A6NK58, A6QQ74, O19179, O43542, O60294, O95336, O95396, P19971, P85971, Q02846, Q05922, Q08DH8, Q0VFH3, Q28F19, Q29R99, Q2TBQ8, Q2V057, Q3SZ07, Q3UQ84, Q561R2, Q5ZKI2, Q68FW7, Q6PAT0, Q6QHF9, Q86U10, Q86WU2, Q86Y79, Q8BW00, Q8IVS8, Q8N8Q3, Q8R123, Q8VCZ9, Q8VDG5, Q8WV74, Q8WVB3, Q8WZ82

Diamond homologs: A2XI04, A2YNH4, A2YXS5, A2Z3C4, C4L2C5, O74455, O84189, O95336, P37262, P46016, P50278, P56201, P74618, P85971, Q2TBQ8, Q54CJ3, Q69NG5, Q6Z4H0, Q6Z9C3, Q75IV7, Q7UVM5, Q84WW2, Q8IKU0, Q8LEV7, Q8LG70, Q9A6N1, Q9CQ60, Q9FIN1, Q9LMX8, Q9PKK7, Q9VZ64, Q9XAB7, O83490, O95479, P53315, P63339, P9WQP4, P9WQP5, Q8CFX1, A6ZT71

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PGLS	“down-regulates quantity”	6-O-phosphono-D-glucono-1,5-lactone	“chemical modification”
PGLS	“up-regulates quantity”	6-phospho-D-gluconate	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	4
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

772 predictions. Top by Δscore:

Variant	Effect	Δscore
19:17516172:GACGC:G	acceptor_gain	1.0000
19:17517281:C:CA	acceptor_gain	1.0000
19:17517688:A:AG	acceptor_gain	1.0000
19:17517689:T:G	acceptor_gain	1.0000
19:17517693:T:TA	acceptor_gain	1.0000
19:17517694:G:A	acceptor_gain	1.0000
19:17517848:AAGG:A	donor_loss	1.0000
19:17517849:AGGT:A	donor_loss	1.0000
19:17517850:GG:G	donor_loss	1.0000
19:17517851:GTAAC:G	donor_loss	1.0000
19:17517852:T:A	donor_loss	1.0000
19:17520942:A:AG	acceptor_gain	1.0000
19:17520943:G:GG	acceptor_gain	1.0000
19:17520943:GCGC:G	acceptor_gain	1.0000
19:17516164:T:A	acceptor_gain	0.9900
19:17516168:TGCAG:T	acceptor_loss	0.9900
19:17516169:GCAGA:G	acceptor_loss	0.9900
19:17516170:CAG:C	acceptor_loss	0.9900
19:17516171:A:AG	acceptor_gain	0.9900
19:17516172:G:GG	acceptor_gain	0.9900
19:17516172:GAC:G	acceptor_gain	0.9900
19:17517281:C:G	acceptor_gain	0.9900
19:17517385:TACAG:T	donor_loss	0.9900
19:17517386:ACAG:A	donor_loss	0.9900
19:17517387:CAG:C	donor_loss	0.9900
19:17517388:AG:A	donor_loss	0.9900
19:17517389:GG:G	donor_loss	0.9900
19:17517390:G:GA	donor_loss	0.9900
19:17517391:T:A	donor_loss	0.9900
19:17517681:T:TA	acceptor_gain	0.9900

AlphaMissense

1633 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:17517359:C:G	C156W	0.999
19:17517366:T:C	F159L	0.999
19:17517368:C:A	F159L	0.999
19:17517368:C:G	F159L	0.999
19:17511905:G:A	C78Y	0.998
19:17511908:A:T	D79V	0.998
19:17517367:T:G	F159C	0.998
19:17511906:C:G	C78W	0.997
19:17517322:T:C	L144P	0.997
19:17517349:G:A	G153D	0.997
19:17517351:C:G	H154D	0.997
19:17517358:G:A	C156Y	0.997
19:17511889:T:A	W73R	0.996
19:17511889:T:C	W73R	0.996
19:17517349:G:T	G153V	0.996
19:17517353:C:A	H154Q	0.996
19:17517353:C:G	H154Q	0.996
19:17517366:T:G	F159V	0.996
19:17517367:T:C	F159S	0.996
19:17517764:C:A	R185S	0.996
19:17517835:G:C	K208N	0.996
19:17517835:G:T	K208N	0.996
19:17520990:T:A	V229D	0.996
19:17517319:A:T	D143V	0.995
19:17511812:G:A	G47D	0.994
19:17511902:T:C	F77S	0.994
19:17511904:T:C	C78R	0.994
19:17511908:A:C	D79A	0.994
19:17511911:A:T	E80V	0.994
19:17511955:T:G	Y95D	0.994

dbSNP variants (sampled 300 via entrez): RS1000048095 (19:17511895 C>A,G,T), RS1000251487 (19:17510935 T>C), RS1000584236 (19:17515836 C>A,T), RS1000655653 (19:17517614 T>C), RS1000716747 (19:17521138 C>T), RS1000756937 (19:17520650 G>T), RS1000778783 (19:17521373 G>T), RS1000956483 (19:17515585 C>A,T), RS1001046 (19:17515548 G>A), RS1001092385 (19:17515802 C>A,G), RS1001148702 (19:17515259 C>G), RS1001358977 (19:17516558 T>C,G), RS1001455787 (19:17511326 G>A), RS1001695318 (19:17511624 T>C,G), RS1001926971 (19:17521084 G>A)

Disease associations

OMIM: gene MIM:604951 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724745 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.02	Kd	9.535	nM	CHEMBL5653589
8.02	ED50	9.535	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148989: Binding affinity to human PGLS incubated for 45 mins by Kinobead based pull down assay	kd	0.0095	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	4
bisphenol A	increases expression	3
bisphenol F	increases expression	2
bisphenol S	increases expression	2
Ethanol	increases expression, affects cotreatment, increases abundance	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	decreases expression, increases methylation	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
hydroquinone	affects expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
quinocetone	increases expression	1
jinfukang	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cisplatin	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652031	Binding	Binding affinity to human PGLS incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0K2	Ubigene HeLa PGLS KO	Cancer cell line	Female
CVCL_TD02	HAP1 PGLS (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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