ENGASE

Summary

ENGASE (endo-beta-N-acetylglucosaminidase, HGNC:24622) is a protein-coding gene on chromosome 17q25.3, encoding Cytosolic endo-beta-N-acetylglucosaminidase (Q8NFI3). Endoglycosidase that releases N-glycans from glycoproteins by cleaving the beta-1,4-glycosidic bond in the N,N’-diacetylchitobiose core.

This gene encodes a cytosolic enzyme which catalyzes the hydrolysis of peptides and proteins with mannose modifications to produce free oligosaccharides.

Source: NCBI Gene 64772 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 172 total
• GTEx eGene: eQTL in 47 tissues, sQTL in 43 (q < 0.05)
• ChEMBL bioactivity: 5 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.02 (unconstrained)
• MANE Select transcript: NM_001042573
• Notable: 172 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24622
Approved symbol	ENGASE
Name	endo-beta-N-acetylglucosaminidase
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21865
Ensembl gene	ENSG00000167280
Ensembl biotype	protein_coding
OMIM	611898
Entrez	64772

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 10 nonsense_mediated_decay, 8 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000579016

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 4, TSL 3: 1, TSL 5: 3

ENST00000579016, ENST00000300682, ENST00000311595, ENST00000577783, ENST00000578419, ENST00000579809, ENST00000583041, ENST00000583646, ENST00000584568, ENST00000585160, ENST00000903610, ENST00000903611, ENST00000903612, ENST00000945017, ENST00000945018, ENST00001000946, ENST00001009136, ENST00001009137, ENST00001009138, ENST00001009139, ENST00001009140, ENST00001058371, ENST00001058372, ENST00001122271

RefSeq mRNA: 5 — MANE Select: NM_001042573 NM_001042573, NM_001396052, NM_001396053, NM_001396054, NM_001396055

CCDS: CCDS42394

Canonical transcript exons

ENST00000579016 — 14 exons

Exon	Start	End
ENSE00001111713	79079489	79079637
ENSE00001111730	79081898	79082063
ENSE00003475281	79077663	79077864
ENSE00003496822	79085234	79085342
ENSE00003536864	79083020	79083123
ENSE00003597902	79083761	79083951
ENSE00003603548	79085933	79088599
ENSE00003607773	79080925	79081073
ENSE00003622219	79085620	79085734
ENSE00003646266	79083482	79083590
ENSE00003651250	79080207	79080364
ENSE00003658448	79084538	79084686
ENSE00003672628	79077430	79077497
ENSE00003902292	79074824	79075090

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 95.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9937 / max 885.0759, expressed in 1803 samples.

Highest expression (Bgee): mucosa of transverse colon, spleen, transverse colon, small intestine Peyer’s patch, granulocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ENGASE is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 47 tissues and its splicing (sQTL) in 43 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 90 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.5e-90	-1.07	17:79082873:T:C
Thyroid	eqtl	1.5e-87	-0.94	17:79082873:T:C
Skin Sun Exposed Lower leg	eqtl	1.2e-81	-0.91	17:79082873:T:C
Adipose Subcutaneous	eqtl	2.1e-80	-1.17	17:79082873:T:C
Esophagus Mucosa	eqtl	6.4e-76	-0.87	17:79082873:T:C
Artery Tibial	sqtl	5.9e-74	+1.61	17:79082873:T:C
Adipose Visceral Omentum	eqtl	1.7e-68	-1.00	17:79082873:T:C
Muscle Skeletal	sqtl	6.1e-68	+1.60	17:79082873:T:C
Thyroid	sqtl	6.6e-68	+1.75	17:79082873:T:C
Lung	eqtl	5.3e-64	-0.86	17:79082873:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.8e-61	-0.88	17:79082873:T:C
Adipose Subcutaneous	sqtl	6.4e-61	+1.55	17:79082873:T:C
Whole Blood	eqtl	8.7e-59	-0.65	17:79082873:T:C
Nerve Tibial	sqtl	2.1e-57	+1.52	17:79082873:T:C
Colon Transverse	sqtl	2.8e-55	+1.67	17:79082873:T:C
Breast Mammary Tissue	eqtl	4.6e-55	-1.26	17:79082873:T:C
Lung	sqtl	6.8e-55	+1.51	17:79082873:T:C
Esophagus Muscularis	eqtl	1.4e-54	-0.64	17:79082873:T:C
Esophagus Muscularis	sqtl	7.2e-51	+1.73	17:79082873:T:C
Artery Aorta	sqtl	3.9e-48	+1.71	17:79082873:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
163171	21.7566	1803
163170	1.9611	562
163172	0.2760	79

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.77	gold quality
spleen	UBERON:0002106	95.41	gold quality
transverse colon	UBERON:0001157	95.13	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.09	gold quality
granulocyte	CL:0000094	94.85	gold quality
pancreatic ductal cell	CL:0002079	94.55	silver quality
tendon of biceps brachii	UBERON:0008188	94.11	gold quality
sural nerve	UBERON:0015488	94.11	gold quality
small intestine	UBERON:0002108	94.09	gold quality
right lobe of thyroid gland	UBERON:0001119	93.56	gold quality
left ovary	UBERON:0002119	93.54	gold quality
right ovary	UBERON:0002118	93.45	gold quality
body of stomach	UBERON:0001161	93.37	gold quality
apex of heart	UBERON:0002098	93.29	gold quality
right uterine tube	UBERON:0001302	93.09	gold quality
endocervix	UBERON:0000458	92.94	gold quality
right adrenal gland	UBERON:0001233	92.94	gold quality
left uterine tube	UBERON:0001303	92.77	gold quality
right adrenal gland cortex	UBERON:0035827	92.65	gold quality
left adrenal gland cortex	UBERON:0035825	92.51	gold quality
gastrocnemius	UBERON:0001388	92.50	gold quality
left lobe of thyroid gland	UBERON:0001120	92.38	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.28	gold quality
muscle of leg	UBERON:0001383	92.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.24	gold quality
body of uterus	UBERON:0009853	92.23	gold quality
right atrium auricular region	UBERON:0006631	92.22	gold quality
metanephros cortex	UBERON:0010533	92.22	gold quality
thyroid gland	UBERON:0002046	92.16	gold quality
left adrenal gland	UBERON:0001234	92.13	gold quality
tibial nerve	UBERON:0001323	92.12	gold quality
adrenal cortex	UBERON:0001235	92.10	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.09	gold quality
lower esophagus	UBERON:0013473	92.07	gold quality
fundus of stomach	UBERON:0001160	91.79	gold quality
ileal mucosa	UBERON:0000331	91.71	gold quality
intestine	UBERON:0000160	91.67	gold quality
colon	UBERON:0001155	91.61	gold quality
ascending aorta	UBERON:0001496	91.55	gold quality
thoracic aorta	UBERON:0001515	91.47	gold quality
mucosa of stomach	UBERON:0001199	91.41	gold quality
minor salivary gland	UBERON:0001830	91.38	gold quality
right lobe of liver	UBERON:0001114	91.36	gold quality
vagina	UBERON:0000996	91.32	gold quality
descending thoracic aorta	UBERON:0002345	91.32	gold quality
stomach	UBERON:0000945	91.29	gold quality
large intestine	UBERON:0000059	91.26	gold quality
tibialis anterior	UBERON:0001385	91.23	gold quality
left coronary artery	UBERON:0001626	91.19	gold quality
omental fat pad	UBERON:0010414	91.16	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.15	gold quality
peritoneum	UBERON:0002358	91.13	gold quality
right coronary artery	UBERON:0001625	91.06	gold quality
aorta	UBERON:0000947	91.04	gold quality
prostate gland	UBERON:0002367	91.03	gold quality
cardiac atrium	UBERON:0002081	90.96	gold quality
vermiform appendix	UBERON:0001154	90.91	gold quality
coronary artery	UBERON:0001621	90.85	gold quality
popliteal artery	UBERON:0002250	90.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.79	gold quality
tibial artery	UBERON:0007610	90.78	gold quality
muscle organ	UBERON:0001630	90.77	gold quality
skeletal muscle organ	UBERON:0014892	90.77	gold quality
duodenum	UBERON:0002114	90.71	gold quality
ectocervix	UBERON:0012249	90.68	gold quality
adrenal gland	UBERON:0002369	90.63	gold quality
skin of abdomen	UBERON:0001416	90.57	gold quality
saliva-secreting gland	UBERON:0001044	90.56	gold quality
tibia	UBERON:0000979	90.47	gold quality
body of pancreas	UBERON:0001150	90.46	gold quality
upper lobe of left lung	UBERON:0008952	90.44	gold quality
pituitary gland	UBERON:0000007	90.39	gold quality
ovary	UBERON:0000992	90.38	gold quality
heart left ventricle	UBERON:0002084	90.37	gold quality
mouth mucosa	UBERON:0003729	90.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.25	gold quality
diaphragm	UBERON:0001103	90.22	gold quality
caecum	UBERON:0001153	90.21	gold quality
cardiac ventricle	UBERON:0002082	90.17	gold quality
monocyte	CL:0000576	89.90	gold quality
adenohypophysis	UBERON:0002196	89.89	gold quality
urinary bladder	UBERON:0001255	89.86	gold quality
right lung	UBERON:0002167	89.86	gold quality
mononuclear cell	CL:0000842	89.85	gold quality
triceps brachii	UBERON:0001509	89.72	silver quality
heart	UBERON:0000948	89.64	gold quality
lymph node	UBERON:0000029	89.62	gold quality
lower esophagus mucosa	UBERON:0035834	89.47	gold quality
rectum	UBERON:0001052	89.46	gold quality
skin of leg	UBERON:0001511	89.43	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	89.32	gold quality
esophagus	UBERON:0001043	89.30	gold quality
upper lobe of lung	UBERON:0008948	89.23	gold quality
gall bladder	UBERON:0002110	89.19	gold quality
leukocyte	CL:0000738	89.15	gold quality
gluteal muscle	UBERON:0002000	88.83	gold quality
adipose tissue	UBERON:0001013	88.75	gold quality
zone of skin	UBERON:0000014	88.53	gold quality
blood	UBERON:0000178	88.48	gold quality
connective tissue	UBERON:0002384	88.48	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.98
E-MTAB-6386	no	789.75

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	22.4	medium
Spleen	tissue	18.9	low
Choroid plexus	tissue	17.2
Locus coeruleus	tissue	15.7
Duodenum	tissue	13.4	medium
Hippocampus	tissue	12.7	low
Small intestine	tissue	12.4	medium
Postcentral gyrus	tissue	11.5
Vagina	tissue	10.6	medium
Nucleus accumbens	tissue	10.4
Tongue	tissue	9.7
Cerebellum	tissue	9.5	not detected
Pituitary gland	tissue	8.8
Skin 1	tissue	8.7	medium
Lymph node	tissue	8.6	medium
Salivary gland	tissue	8.6	low
Rectum	tissue	8.6	medium
Stomach 1	tissue	7.9	medium
Heart muscle	tissue	7.8	medium
Appendix	tissue	7.7	medium
Ovary	tissue	7.3	not detected
Colon	tissue	7.3	medium
Pancreas	tissue	6.8	medium
Endometrium 1	tissue	6.8	medium
Bone marrow	tissue	6.8	medium
Thymus	tissue	6.7	medium
Olfactory bulb	tissue	6.7
Parathyroid gland	tissue	6.3	not detected
Prostate	tissue	6.2	medium
Adipose tissue	tissue	5.9	not detected
Cerebral cortex	tissue	5.8	low
Amygdala	tissue	5.8
Insular cortex	tissue	5.8
Retina	tissue	5.7
Adrenal gland	tissue	5.6	low
Temporal cortex	tissue	5.6
Gallbladder	tissue	5.5	medium
Retrosplenial cortex	tissue	5.5
Tonsil	tissue	5.4	medium
Hippocampal formation	tissue	5.3
Entorhinal cortex	tissue	5.3
Retrosplenial and cingulate cortex	tissue	5.3
Fallopian tube	tissue	5.3	medium
Placenta	tissue	5.2	low
Thyroid gland	tissue	5.2	medium
Lung	tissue	5.2	low
Prefrontal cortex	tissue	5.1
Basal ganglia	tissue	5.0	not detected
Corpus callosum	tissue	5.0
Somatosensory cortex	tissue	5.0
Motor cortex	tissue	4.9
Smooth muscle	tissue	4.8	not detected
Hypothalamus	tissue	4.8
Ventral forebrain	tissue	4.8
Occipital cortex	tissue	4.8
Periaqueductal gray	tissue	4.7
Urinary bladder	tissue	4.6	low
Putamen	tissue	4.6
Septum	tissue	4.6
Substantia nigra	tissue	4.4

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Temporal white matter (21.1), Piriform cortex (21.0), Parieto-temporal junction (white matter) (19.7), Nucleus rhomboideus (18.9), Median raphe nucleus (18.3).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 2.61e-19, LOEUF 1.02, missense Z 0.633 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000579016 — one region, missense o/e 0.95.

Literature-anchored findings (GeneRIF, showing 10)

• involved in processing of free oligosaccharides in the cytosol; identification of the gene encoding human cytosolic ENGase (PMID:12114544)
• endo-beta-n-acetylglucosaminidase present in the synovial fluid of rheumatoid arthritis patients, may contribute to the depletion of glycosaminoglycans from cartilage allowing the invasion of synovial cells (PMID:12905469)
• identification of O-GlcNAcase as a caspase-3 substrate with a novel caspase-3 cleavage site and provide insight about O-GlcNAcase regulation during apoptosis. (PMID:18586680)
• Data show that kinetic and X-ray crystallographic analyses of the binding modes with human/bacterial O-GlcNAcases identify some of these as competitive inhibitors. (PMID:20026047)
• O-GlcNAcase expression is increased in erythrocytes from both individuals with pre-diabetes and individuals with less well-controlled diabetes. (PMID:20413512)
• As the generation of the bulk of fOS is unaffected by co-down regulation of Ngly1p and Engase1p, alternative quantitatively important mechanisms must underlie the liberation of these fOS from either LLO or glycoproteins during protein N-glycosylation. (PMID:20668520)
• Serological N-acetyl-glucosaminidase, telomere length, and the UCP2-886G>A variant are independent risk factors for type 2 diabetes. (PMID:21873561)
• In patients with autosomal dominant polycystic kidney disease, urinary NAGase was correlated with urinary ET-1 which was inversely associated with eGFR and positively correlated with total kidney volume. (PMID:26923419)
• Transcriptome-wide association study reveals two genes that influence mismatch negativity. (PMID:33730571)
• N-acetyl-ss-D-glucosaminidase is predictive of mortality in chronic heart failure: a 10-year follow-up. (PMID:34397265)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	engase	ENSDARG00000010035
mus_musculus	Engase	ENSMUSG00000033857
rattus_norvegicus	Engase	ENSRNOG00000027498
drosophila_melanogaster	ENGase	FBGN0030839
caenorhabditis_elegans		WBGENE00017164

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	P0C7A1	81.1%	Diamond
Arabidopsis thaliana	F4JZC2	71.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
C1QTNF1	protein-coding	114897
CANT1	protein-coding	124583
RBFOX3	protein-coding	146713
LGALS3BP	protein-coding	3959
LINC02078	ncRNA	100652929
C1QTNF1-AS1	ncRNA	100507410
MIR4739	ncRNA	100616170
CEP295NL	protein-coding	100653515
TIMP2	protein-coding	7077
ENPP7	protein-coding	339221

Protein

Protein identifiers

Cytosolic endo-beta-N-acetylglucosaminidase — Q8NFI3 (reviewed: Q8NFI3)

All UniProt accessions (4): F8W925, Q8NFI3, J3QLG5, J9JID0

UniProt curated annotations — full annotation on UniProt →

Function. Endoglycosidase that releases N-glycans from glycoproteins by cleaving the beta-1,4-glycosidic bond in the N,N’-diacetylchitobiose core. Involved in the processing of free oligosaccharides in the cytosol.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed. Expressed at higher level in thymus and spleen.

Similarity. Belongs to the glycosyl hydrolase 85 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NFI3-1	1	yes
Q8NFI3-2	2
Q8NFI3-3	3

RefSeq proteins (5): NP_001036038, NP_001382981, NP_001382982, NP_001382983, NP_001382984 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001357	BRCT_dom	Domain
IPR005201	TIM_ENGase	Domain
IPR032979	ENGase	Family
IPR057882	ENGase_C	Domain

Pfam: PF03644, PF25529

Enzyme classification (BRENDA)

• EC 3.2.1.96 — mannosyl-glycoprotein endo-beta-N-acetylglucosaminidase (BRENDA: 59 organisms, 331 substrates, 58 inhibitors, 37 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

25 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-NITROPHENYL-BETA-D-N-ACETYLGLUCOSAMINE	3.5–77.4	5
DANSYL ASIALOTRANSFERRIN GLYCOPEPTIDE	0.68–2	2
DANSYL-ASN-(GLCNAC)2(MAN)5	0.207–0.876	2
FMOC-ASN(FUCALPHA(1->6)GLCNAC)-OH	8.51–18.51	2
FMOC-ASN(GLCNAC)-OH	0.73–5.22	2
MAN3GLCNAC-OXAZOLINE	0.5–0.67	2
(MAN)5(GLCNAC)2-PYRIDYLAMINO	0.4	1
(MAN)5(GLCNAC)2ASN-ACETYL	0.2	1
(MAN)6(GLCNAC)2-PYRIDYLAMIDATED	0.025	1
(MAN)6(GLCNAC)2-PYRIDYLAMINO	0.25	1
(MAN)9(GLCNAC)2-PYRIDYLAMINO	0.32	1
4-METHYLUMBELLIFERYL DI-N-ACETYL-BETA-CHITOBIOSI	0.0063	1
4-METHYLUMBELLIFERYL N,N’,N’’-TRIACETYL-BETA-D-G	0.0204	1
9-FLUORENYLMETHYLOXYCARBONYL-LABELED ASPARAGINE-	5.54	1
ASN(GLCNAC)2-(MAN)5	0.25	1

Catalyzed reactions (Rhea)

• an N(4)-(oligosaccharide-(1->3)-[oligosaccharide-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc)-L-asparaginyl-[protein] + H2O = an oligosaccharide-(1->3)-[oligosaccharide-(1->6)]-beta-D-Man-(1->4)-D-GlcNAc + N(4)-(N-acetyl-beta-D-glucosaminyl)-L-asparaginyl-[protein] (RHEA:73067)

UniProt features (14 total): splice variant 4, sequence variant 2, sequence conflict 2, modified residue 2, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFI3-F1	86.41	0.71

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; centrosome

Antibody reliability (HPA): IH approved · IF approved

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 (2)

Type	Positions
N-acetylmethionine	1
Phosphoserine	66

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle	curated
R-HSA-446203	Asparagine N-linked glycosylation	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 94 (showing top): GOBP_N_GLYCAN_PROCESSING, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_PROTEIN_FOLDING, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, PARENT_MTOR_SIGNALING_DN, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS, OSMAN_BLADDER_CANCER_DN, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, LAIHO_COLORECTAL_CANCER_SERRATED_DN, KEGG_OTHER_GLYCAN_DEGRADATION

GO Biological Process (2): protein folding (GO:0006457), N-glycan processing (GO:0006491)

GO Molecular Function (4): mannosyl-glycoprotein endo-beta-N-acetylglucosaminidase activity (GO:0033925), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

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

Reactome top-level categories

3 top-level categories:

Category	Pathways
Asparagine N-linked glycosylation	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

11 GO namespaces:

Category	Terms
cellular anatomical structure	2
cellular process	1
protein maturation	1
protein N-linked glycosylation	1
glycoprotein biosynthetic process	1
hydrolase activity, hydrolyzing O-glycosyl compounds	1
hydrolase activity, acting on glycosyl bonds	1
catalytic activity	1
hydrolase activity	1
cytoplasm	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 8 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
mannosyl-glycoprotein endo-beta-N-acetylglucosaminidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 480 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENGASE	NGLY1	Q96IV0	829
ENGASE	MAN2C1	Q9NTJ4	595
ENGASE	NFE2L1	Q14494	529
ENGASE	FBXO6	Q9NRD1	527
ENGASE	FAM89A	Q96GI7	511
ENGASE	GYG1	P46976	494
ENGASE	MAN1A1	P33908	470
ENGASE	FUCA2	Q9BTY2	437
ENGASE	FUT8	Q9BYC5	431
ENGASE	FUCA1	P04066	411
ENGASE	EPYC	Q99645	404
ENGASE	SPATA20	Q8TB22	396
ENGASE	MGAT1	P26572	389
ENGASE	RNASE9	P60153	367
ENGASE	B7Z1P2	B7Z1P2	366

IntAct

BioGRID (10 interactions; top human partners by supporting records): GNS (Affinity Capture-MS; 2 records), DDX58 (Affinity Capture-RNA), NUDT21 (Affinity Capture-RNA), PEMT (Affinity Capture-MS), PLD5 (Affinity Capture-MS), RPA1 (Proximity Label-MS), RPA3 (Proximity Label-MS), TOP3B (Affinity Capture-RNA)

Disease & clinical

Genetic variants

Variant evidence for ENGASE: 172 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	133
Likely benign	10
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 21 predictions of 1,283):

Position(s)	Effect	Δscore	Sites
17:79075084	donor_gain	1.0000
17:79077405–79077407	acceptor_gain	1.0000	2
17:79077655–79077656	acceptor_gain	1.0000	2
17:79077717	acceptor_gain	1.0000
17:79077865	donor_loss	1.0000	2
17:79080198	acceptor_gain	1.0000
17:79080204–79080206	acceptor_gain	1.0000	2
17:79080205–79080206	acceptor_loss	1.0000	5
17:79080359	donor_gain	1.0000
17:79080923–79080924	acceptor_loss	1.0000	4

AlphaMissense

1,088 missense substitutions predicted likely pathogenic (of 4,797 scored), across 307 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F361	8	0.959	0.994
F164	8	0.950	0.995
D330	8	0.948	0.974
D130	8	0.935	0.975
D272	8	0.931	0.977
F161	8	0.913	0.967
H166	8	0.908	0.980
D159	8	0.898	0.976
F251	8	0.898	0.975
F404	8	0.893	0.975
H129	8	0.890	0.967
D138	8	0.855	0.937
F597	8	0.836	0.966
F229	8	0.826	0.955
F332	7	0.968	0.993
W306	7	0.962	0.988
W383	7	0.954	0.988
W176	7	0.941	0.992
W365	7	0.940	0.989
N235	7	0.938	0.986

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (TCGA)	favorable	2.94e-05
Rectum Adenocarcinoma (TCGA)	favorable	6.34e-05

Disease associations

OMIM: gene MIM:611898 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST009391_1944	Metabolite levels	2e-6
GCST009391_339	Metabolite levels	6e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0010511	niacinamide measurement
EFO:0010430	triacylglycerol 56:3 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5172 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 93,623 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

5 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1201863	DEXLANSOPRAZOLE	4	1,639
CHEMBL480	LANSOPRAZOLE	4	24,499
CHEMBL1503	OMEPRAZOLE	4	52,666
CHEMBL1219	RABEPRAZOLE	4	12,552
CHEMBL1475252	TENATOPRAZOLE	2	2,267

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

6 measured of 9 human assays (9 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-((5R,6S,7R,8S)-8-acetamido-6,7-dihydroxy-5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)acetic acid	IC50	1.83 nM
(1R*, 3S*, 5S*, 6S*, 7R*, 7a S*)-5-acetamidomethyl-3-hydroxymethyl-1,6,7-trihydroxypyrrolizidine	IC50	2.39 nM
CHEMBL259756	IC50	420 nM
CHEBI:8768	IC50	8500 nM
TENATOPRAZOLE	IC50	20000 nM
(2S,3S)-3-Hydroxybaikiain	IC50	750000 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
9.03	Ki	0.925	nM	NAGSTATIN
8.90	Ki	1.25	nM	POCHONICINE
8.74	IC50	1.83	nM	NAGSTATIN
8.62	IC50	2.39	nM	POCHONICINE
6.38	IC50	420	nM	CHEMBL259756
5.35	IC50	4470	nM	RABEPRAZOLE

PubChem BioAssay actives

6 with measured affinity, of 63 total; 4 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
2-[(5R,6S,7R,8S)-8-acetamido-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]acetic acid	453057: Competitive inhibition of human placenta beta-N-acetylglucosaminidase by pNP-GlcNAc substrate hydrolysis assay	ki	0.0009	uM
N-[[(1R,2S,3S,5S,7R,8S)-1,2,7-trihydroxy-5-(hydroxymethyl)-2,3,5,6,7,8-hexahydro-1H-pyrrolizin-3-yl]methyl]acetamide	453052: Mixed type inhibition of human placenta beta-N-acetylglucosaminidase by pNP-GlcNAc substrate hydrolysis assay	ki	0.0013	uM
(2S,3S,4S,5S,6R)-2-[[(2R,3S,4S,5S,6S)-6-[[(2R,3R,4S,5S,6S)-6-[[(2R,3R,4S,5S,6S)-6-[[(3aS,5R,6S,7R,7aR)-7-hydroxy-5-(hydroxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-6-yl]oxy]-4-[(2S,3S,4S,5S,6R)-3-[(2S,3S,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxyoxan-2-yl]methoxy]-4-[(2S,3S,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxyoxan-2-yl]methoxy]-3,4,5-trihydroxyoxan-2-yl]methoxy]-6-(hydroxymethyl)oxane-3,4,5-triol	318993: Inhibition of human endo-beta-N-acetylglucosaminidase expressed in Hek293 cells after 3 mins	ic50	0.4200	uM
Rabeprazole	1453445: Inhibition of recombinant human C-MYC/DDK-tagged ENGase expressed in HEK293T cells using heat inactivated bovine ribonuclease B as substrate pretreated for 15 mins followed by substrate addition after 90 mins by SDS-PAGE analysis	ic50	4.4700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
sodium arsenite	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
deoxynivalenol	increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Zinc	increases expression, affects cotreatment	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1041612	Binding	Inhibition of human placenta beta-N-acetylglucosaminidase by pNP-GlcNAc substrate hydrolysis assay	Pochonicine, a polyhydroxylated pyrrolizidine alkaloid from fungus Pochonia suchlasporia var. suchlasporia TAMA 87 as a potent beta-N-acetylglucosaminidase inhibitor. — *Bioorg Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ENGASE across ~30M SureChEMBL compounds — explore on Sugi Predict.