GBA1

Summary

GBA1 (glucosylceramidase beta 1, HGNC:4177) is a protein-coding gene on chromosome 1q22, encoding Lysosomal acid glucosylceramidase (P04062). Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose.

This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2629 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 29
• Clinical variants (ClinVar): 689 total — 79 pathogenic, 214 likely-pathogenic
• Phenotypes (HPO): 251
• Druggable target: yes — 12 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000157

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4177
Approved symbol	GBA1
Name	glucosylceramidase beta 1
Location	1q22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000177628
Ensembl biotype	protein_coding
OMIM	606463
Entrez	2629

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 17 protein_coding, 10 protein_coding_CDS_not_defined

ENST00000327247, ENST00000368373, ENST00000427500, ENST00000428024, ENST00000460156, ENST00000464536, ENST00000467918, ENST00000470104, ENST00000473570, ENST00000478472, ENST00000484489, ENST00000491081, ENST00000493842, ENST00000497670, ENST00000852359, ENST00000852360, ENST00000852361, ENST00000852362, ENST00000852363, ENST00000852364, ENST00000852365, ENST00000852366, ENST00000852367, ENST00000852368, ENST00000948996, ENST00000948997, ENST00000948998

RefSeq mRNA: 5 — MANE Select: NM_000157 NM_000157, NM_001005741, NM_001005742, NM_001171811, NM_001171812

CCDS: CCDS1102, CCDS53373, CCDS53374

Canonical transcript exons

ENST00000368373 — 11 exons

Exon	Start	End
ENSE00001231060	155236245	155236469
ENSE00001890492	155241086	155241249
ENSE00001917720	155234452	155235100
ENSE00003469059	155240630	155240717
ENSE00003488376	155237341	155237578
ENSE00003499798	155239616	155239762
ENSE00003506590	155235681	155235844
ENSE00003562842	155238134	155238306
ENSE00003618264	155238517	155238650
ENSE00003644399	155235195	155235311
ENSE00003675620	155239886	155240077

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 70.1096 / max 415.0314, expressed in 1824 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14930	49.3329	1815
14933	9.3099	1656
14934	7.4439	1657
14932	1.6721	950
14931	0.9363	618
14935	0.6426	392
14928	0.4702	264
14929	0.2876	111
201748	0.0141	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	96.97	gold quality
islet of Langerhans	UBERON:0000006	96.42	gold quality
placenta	UBERON:0001987	95.44	gold quality
blood	UBERON:0000178	95.29	gold quality
pituitary gland	UBERON:0000007	95.08	gold quality
adenohypophysis	UBERON:0002196	94.70	gold quality
bone marrow cell	CL:0002092	94.48	gold quality
right adrenal gland	UBERON:0001233	94.26	gold quality
right adrenal gland cortex	UBERON:0035827	94.05	gold quality
left adrenal gland	UBERON:0001234	93.66	gold quality
granulocyte	CL:0000094	93.56	gold quality
rectum	UBERON:0001052	93.36	gold quality
mucosa of transverse colon	UBERON:0004991	93.32	gold quality
left adrenal gland cortex	UBERON:0035825	93.12	gold quality
gall bladder	UBERON:0002110	92.96	gold quality
adrenal gland	UBERON:0002369	92.87	gold quality
bone marrow	UBERON:0002371	92.81	gold quality
prefrontal cortex	UBERON:0000451	92.72	gold quality
smooth muscle tissue	UBERON:0001135	92.28	gold quality
leukocyte	CL:0000738	92.03	gold quality
superior frontal gyrus	UBERON:0002661	92.03	gold quality
pancreas	UBERON:0001264	91.97	gold quality
monocyte	CL:0000576	91.86	gold quality
descending thoracic aorta	UBERON:0002345	91.78	gold quality
cortex of kidney	UBERON:0001225	91.77	gold quality
vermiform appendix	UBERON:0001154	91.57	gold quality
right lobe of thyroid gland	UBERON:0001119	91.25	gold quality
thoracic aorta	UBERON:0001515	91.25	gold quality
frontal cortex	UBERON:0001870	91.24	gold quality
adult mammalian kidney	UBERON:0000082	91.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.68
E-MTAB-6386	no	329.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETV4

miRNA regulators (miRDB)

11 targeting GBA1, 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-3925-3P	100.00	69.95	1237
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-581	98.39	67.42	835
HSA-MIR-6784-3P	98.39	64.88	662
HSA-MIR-6862-3P	97.92	64.86	531
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-3085-5P	97.72	65.43	544
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-27A-5P	97.01	65.63	528

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• simple non-isotopic method to show pitfalls during mutation analysis of the glucocerebrosidase gene (PMID:11584048)
• A protocol is described for the isolation of genomic DNA from formalin-fixed bone marrow aspirate archival specimens. (PMID:11708865)
• seven novel missense mutations in the glucocerebrosidase gene (A136E, H162P, K198E, Y205C, F251L, Q350X and I402F) and a splice site mutation (IVS10+2T–>A) were identified by direct sequencing (PMID:11933202)
• In conclusion, 12% of Hypoalphalipoproteinemia subjects were found to carry mutations in apo A-I, LCAT, or GBA genes (PMID:12048121)
• PKLR- GBA region shows almost complete linkage disequilibrium over 70 kb in a set of worldwide populations. (PMID:12107439)
• incidence of the most common mutations and phenotypic manifestations in Romanian Gaucher disease patients (PMID:12173027)
• Review. Beta-glucosidase deficiency causes autosomal recessive Gaucher disease. Cloning of the gene has allowed the characterization of few common mutations. Some have a prognostic value, favoring either a non neurological form or more severe forms. (PMID:12360742)
• Review. 2-dimensional hydrophobic cluster analysis was used to make structure predictions for the catalytic domains of clan GH-A glycoside hydrolases. Glu 235 & Glu 340 do indeed play key roles in the active site of human glucocerebrosidase as predicted. (PMID:12360744)
• N-n-nonyl-deoxynojirimycin chaperones beta-Glu folding at neutral pH, thus allowing the stabilized enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome. (PMID:12434014)
• Reciprocal and nonreciprocal recombination at this region implies complexity in Gaucher disease. (PMID:12587096)
• substrate specificity of the cytosolic enzyme (PMID:12667141)
• X-ray structure of acid-beta-glucosidase at 2.0 A resolution (PMID:12792654)
• report a 36-year-old Turkish man with type I Gaucher’s disease with homozygous R463C mutation without neurological involvement (PMID:12803123)
• Glucosylceramidase mass and subcellular localization are modulated by cholesterol in Niemann-Pick disease type C (PMID:14757764)
• Mutations in Glucocerebrosidase is associated with Gaucher disease (PMID:14994233)
• a baculovirus-derived expression system to express cDNAs bearing several mutations found in Spanish Gaucher disease patients (PMID:15146461)
• Six of 16 haplotypes were found, and none was over- or underrepresented among patients with the severe Gaucher disease phenotypes compared with those from patients with mild phenotypes. (PMID:15322500)
• The N370S allele of glucosidase, beta (nt.1226 A>G) may be associated with Parkinson’s disease in patients of Jewish ethnicity. (PMID:15517591)
• Our results demonstrate a marginally significant association of GBA mutations with Parkinson’s disease and suggest that variations in the GBA gene may constitute a rare susceptibility factor for PD. (PMID:15517592)
• heterozygosity for a GBA mutation may predispose Ashkenazi Jews to Parkinson’s disease (PMID:15525722)
• mutant glucocerebrosidase, even in heterozygotes, may be a risk factor for the development of parkinsonism (PMID:15591280)
• alteration in water permeability barrier in lesional psoriatic skin can serve as a trigger for the upregulation of the expression of enzymes like GlcCer’ase with consequent stimulation of ceramide generation. (PMID:15610510)
• Expression of novel GBA mutations revealed that the enzyme defect could arise from one of two mechanisms: loss of catalytic activity (Y363C and M416V) or enzyme instability (P122L and N382K). (PMID:15954102)
• The high frequency of the E326K substitution observed in patients with GD type 2 suggests that this change may have a modulating negative effect on the clinical condition of these Gaucher disease patients when present in combination with mutation L444P. (PMID:15967693)
• Data describe the intracellular trafficking of glucocerebrosidase as an underlying mechanism for the expression of the clinical phenotype. (PMID:15982918)
• the glucocerebrosidase Gaucher mutation N188S associated with myoclonic epilepsy (PMID:16086325)
• The overall clinical manifestations and age at Parkinson disease onset of Ashkenazi Jews did not differ in patients with GBA mutations compared to patients without mutations. (PMID:16148263)
• Two novel disease-causing splicing mutations in the glucocerebrosidase gene, g.4252C>G and g.4426A>G, that have been found in two patients affected by Gaucher disease. (PMID:16329099)
• This study does not indicate increased susceptibility to Parkinson disease in glucocerebrosidase mutations carriers in Norway. (PMID:16476943)
• Mutations in glucocerebrosidase are identified at an increased frequency among Parkinson probands, including those of Ashkenazi Jewish ancestry. (PMID:16781064)
• Glucocerebrosidase mutations are an important risk factor for Lewy body disorders (PMID:16790605)
• the double D409H+H255Q allele may have a role in type II Gaucher disease within specific populations (PMID:16830265)
• Turning off hGCase expression led to storage cell reaccumulation of GC and macrophage activation in liver, lung, and spleen, demonstrating that conditionally expressed hGCase supplements mutant mouse GCase controlling visceral substrate accumulation (PMID:16861620)
• Isofagomine binds to the acid beta-glucosidase (GCase) active site, and both increases GCase activity in cell lysates and restores lysosomal trafficking in cells containing N370S mutant GCase. (PMID:17187079)
• identified 98.7% of mutated GBA alleles, finding 56 different mutations & 66 genotypes causing Gaucher disease in Spain: 47 previously described & 9 novel; findings indicate genotypic heterogeneity explaining phenotypic variation in Spanish GD patients (PMID:17427031)
• study demonstrates that GBA mutations are also encountered in Chinese subjects with sporadic Parkinson disease (PD) at higher frequency than many other PD genes & association of GBA mutations with development of PD is not related to ethnic origin (PMID:17462935)
• report from Lebanon describes a family with Gaucher disease caused by a heterozygous genotype of a rare mutation, R48W, and a common one, L444P (PMID:17574891)
• The L444P mutation is associated with an increased risk of PD anmong the Chinese population. (PMID:17620502)
• gene sequencing and mRNA analysis in four patients from three unrelated families with type 3 Gaucher disease (PMID:17689991)
• Mutations of the GBA gene may be associated with the development of EOPD in Taiwan. (PMID:17702778)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	gba1	ENSDARG00000076058
mus_musculus	Gba1	ENSMUSG00000028048
rattus_norvegicus	Gba1	ENSRNOG00000049281
drosophila_melanogaster	Gba1a	FBGN0051148
drosophila_melanogaster	Gba1b	FBGN0051414
caenorhabditis_elegans		WBGENE00008706
caenorhabditis_elegans		WBGENE00016335
caenorhabditis_elegans		WBGENE00016340
caenorhabditis_elegans		WBGENE00021160

Protein

Protein identifiers

Lysosomal acid glucosylceramidase — P04062 (reviewed: P04062)

Alternative names: Acid beta-glucosidase, Alglucerase, Beta-glucocerebrosidase, Beta-glucosylceramidase 1, Cholesterol glucosyltransferase, Cholesteryl-beta-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, Glucosylceramidase beta 1, Imiglucerase, Lysosomal cholesterol glycosyltransferase, Lysosomal galactosylceramidase, Lysosomal glycosylceramidase

All UniProt accessions (2): A0A068F658, P04062

UniProt curated annotations — full annotation on UniProt →

Function. Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose. Plays a central role in the degradation of complex lipids and the turnover of cellular membranes. Through the production of ceramides, participates in the PKC-activated salvage pathway of ceramide formation. Catalyzes the glucosylation of cholesterol, through a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol. GlcCer containing mono-unsaturated fatty acids (such as beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose donors for cholesterol glucosylation when compared with GlcCer containing same chain length of saturated fatty acids (such as beta-D-glucosyl-N-octadecanoyl-sphing-4-enine). Under specific conditions, may alternatively catalyze the reverse reaction, transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide. Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol. Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine), as well as the transfer of galactose between GalCers and cholesterol in vitro, but with lower activity than with GlcCers. Contrary to GlcCer and GalCer, xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1’)-N-acylsphing-4-enine) is not a good substrate for hydrolysis, however it is a good xylose donor for transxylosylation activity to form cholesteryl 3-beta-D-xyloside. Can also metabolize plant glycosyl phytosterols such as glucosylstigmasterol.

Subunit / interactions. Interacts with saposin-C. Interacts with SCARB2. Interacts with TCP1. May interacts with SNCA; this interaction may inhibit the glucosylceramidase activity. Interacts with GRN; this interaction prevents aggregation of GBA1-SCARB2 complex via interaction with HSPA1A upon stress.

Subcellular location. Lysosome membrane.

Disease relevance. Gaucher disease (GD) [MIM:230800] An autosomal recessive lysosomal storage disease due to deficient activity of lysosomal beta-glucocerebrosidase, and characterized by accumulation of glucosylceramide in the reticulo-endothelial system. GD is a multisystem disease historically divided into three main subtypes on the basis of the presence of neurologic involvement, age at onset and progression rate: type 1 is the non-neuropathic form, type 2 is the acute neuropathic form with early onset and rapid neurologic deterioration, type 3 is the chronic neuropathic form with slow progression of neurologic features. GD shows a marked phenotypic diversity ranging from adult asymptomatic forms, at the mild end, to perinatal lethal forms at the severe end of the disease spectrum. Formal diagnosis of Gaucher disease is based on the measurement of glucocerebrosidase levels in circulating leukocytes and molecular genetic analysis. The disease is caused by variants affecting the gene represented in this entry. Gaucher disease 1 (GD1) [MIM:230800] A form of Gaucher disease, an autosomal recessive lysosomal storage disease due to deficient activity of lysosomal beta-glucocerebrosidase, and characterized by accumulation of glucosylceramide in the reticulo-endothelial system. GD1 is characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved. The disease is caused by variants affecting the gene represented in this entry. Gaucher disease 2 (GD2) [MIM:230900] The most severe form of Gaucher disease, an autosomal recessive lysosomal storage disease due to deficient activity of lysosomal beta-glucocerebrosidase, and characterized by accumulation of glucosylceramide in the reticulo-endothelial system. GD2 is an acute neuronopathic form that manifests soon after birth, with death generally occurring before patients reach two years of age. Clinical features include hepatosplenomegaly, developmental regression, growth arrest, and rapidly progressing neurologic deterioration. The disease is caused by variants affecting the gene represented in this entry. Gaucher disease 3 (GD3) [MIM:231000] A form of Gaucher disease, an autosomal recessive lysosomal storage disease due to deficient activity of lysosomal beta-glucocerebrosidase, and characterized by accumulation of glucosylceramide in the reticulo-endothelial system. GD3 is a subacute neuronopathic form characterized by later onset and slower progression compared to Gaucher disease 2. The disease is caused by variants affecting the gene represented in this entry. Gaucher disease 3C (GD3C) [MIM:231005] A variant of subacute neuronopathic Gaucher disease 3 associated with cardiovascular calcifications. The disease is caused by variants affecting the gene represented in this entry. Gaucher disease perinatal lethal (GDPL) [MIM:608013] Distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry. Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Parkinson disease (PARK) [MIM:168600] A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Activity regulation. Synergistically activated by saposin-A and saposin-C, two saposin peptides produced by proteolytic processing of prosaposin/PSAP. Saposin-C activates GBA1 through its recruitment to membranes. The membrane structure and composition in anionic phospholipids are also important for the activation. Activated by PKC in the salvage pathway of ceramide formation. Inhibited by conduritol B epoxide/CBE.

Pathway. Steroid metabolism; cholesterol metabolism. Sphingolipid metabolism.

Miscellaneous. Major isoform. Produced by alternative initiation from a downstream AUG. Two to three times less protein is produced from this downstream AUG. Produced by alternative splicing.

Similarity. Belongs to the glycosyl hydrolase 30 family.

Isoforms (5)

UniProt ID	Names	Canonical?
P04062-1	Long	yes
P04062-2	Short
P04062-3	3
P04062-4	4
P04062-5	5

RefSeq proteins (5): NP_000148, NP_001005741, NP_001005742, NP_001165282, NP_001165283 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001139	Glyco_hydro_30	Family
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR033452	GH30_C	Domain
IPR033453	Glyco_hydro_30_TIM-barrel	Domain

Pfam: PF02055, PF17189

Enzyme classification (BRENDA):

• EC 3.2.1.45 — glucosylceramidase (BRENDA: 14 organisms, 148 substrates, 370 inhibitors, 77 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
4-METHYLUMBELLIFERYL-BETA-D-GLUCOPYRANOSIDE	0.0493–24	13
GLUCOSYLCERAMIDE	0.015–0.247	7
4-NITROPHENYL BETA-D-GLUCOSIDE	0.18–110	6
4-NITROPHENYL BETA-D-GLUCOPYRANOSIDE	2.331–12.6	5
2,4-DINITROPHENYL BETA-D-GLUCOPYRANOSIDE	0.0003–0.16	3
4-METHYLUMBELLIFERYL BETA-D-GLUCOPYRANOSIDE	1.06–1.127	3
4-NONYLUMBELLIFERYL-BETA-D-GLUCOPYRANOSIDE	0.026–0.17	3
BETA-D-GLUCOCEREBROSIDE	0.03–0.65	3
P-NITROPHENYL BETA-D-GLUCOPYRANOSIDE	0.018–0.33	3
P-NITROPHENYL-BETA-GLUCOPYRANOSIDE	0.593–1.35	2
(6-[N-(7-NITROBENZ-2-OXA-1,3 DIAZOL-4-YL)AMINO]H	0.002	1
(6-[N-(7-NITROBENZ-2-OXA-1,3 DIAZOL-4-YL)AMINO]H	0.0046	1
12(N-METHYL-N-(7-NITROBENZ-2-OXA-1,3-DIAZOL-4-YL	0.05	1
4-METHYLUMBELLIFERYL-BETA-D-GALACTOPYRANOSIDE	0.1445	1
4-NITROPHENYL BETA-D-GALACTOSIDE	16.3	1

Catalyzed reactions (Rhea), 12 shown:

• cholesteryl 3-beta-D-glucoside + H2O = cholesterol + D-glucose (RHEA:11956)
• a beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine + H2O = an N-acylsphing-4-enine + D-glucose (RHEA:13269)
• a beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine + H2O = an N-acylsphing-4-enine + D-galactose (RHEA:14297)
• a beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-glucoside + an N-acylsphing-4-enine (RHEA:58264)
• beta-D-glucosyl-(1<->1’)-N-hexadecanoylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-glucoside + N-hexadecanoylsphing-4-enine (RHEA:58316)
• beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4E-enine + cholesterol = N-(9Z-octadecenoyl)-sphing-4-enine + cholesteryl 3-beta-D-glucoside (RHEA:58324)
• stigmasteryl 3-beta-D-glucoside + H2O = stigmasterol + D-glucose (RHEA:62028)
• a beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-galactoside + an N-acylsphing-4-enine (RHEA:70235)
• a beta-D-xylosyl-(1<->1’)-N-acylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-xyloside + an N-acylsphing-4-enine (RHEA:70239)
• beta-D-xylosyl-(1<->1’)-N-(9Z-octadecenoyl)-sphing-4-enine + cholesterol = cholesteryl 3-beta-D-xyloside + N-(9Z-octadecenoyl)-sphing-4-enine (RHEA:70251)
• 1-(beta-D-galactosyl)-N-dodecanoylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-galactoside + N-dodecanoylsphing-4-enine (RHEA:70255)
• beta-D-glucosyl-N-octanoylsphing-4E-enine + cholesterol = N-octanoylsphing-4-enine + cholesteryl 3-beta-D-glucoside (RHEA:70303)

UniProt features (262 total): sequence variant 178, strand 33, helix 17, mutagenesis site 9, splice variant 6, glycosylation site 5, sequence conflict 4, turn 4, disulfide bond 2, active site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

58 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6TN1	X-RAY DIFFRACTION	0.98
9FB2	X-RAY DIFFRACTION	1.14
9FA3	X-RAY DIFFRACTION	1.36
9FAL	X-RAY DIFFRACTION	1.39
9FAY	X-RAY DIFFRACTION	1.4
6TJQ	X-RAY DIFFRACTION	1.41
9FDI	X-RAY DIFFRACTION	1.41
8AWR	X-RAY DIFFRACTION	1.49
9FA6	X-RAY DIFFRACTION	1.49
6TJK	X-RAY DIFFRACTION	1.56
8AWK	X-RAY DIFFRACTION	1.58
6TJJ	X-RAY DIFFRACTION	1.59
8AX3	X-RAY DIFFRACTION	1.59
6Q6N	X-RAY DIFFRACTION	1.63
9FAZ	X-RAY DIFFRACTION	1.63
6YTP	X-RAY DIFFRACTION	1.7
6YTR	X-RAY DIFFRACTION	1.7
6Z39	X-RAY DIFFRACTION	1.7
9ENA	X-RAY DIFFRACTION	1.7
8P3E	X-RAY DIFFRACTION	1.75
6YUT	X-RAY DIFFRACTION	1.76
2NT0	X-RAY DIFFRACTION	1.79
6YV3	X-RAY DIFFRACTION	1.8
6Z3I	X-RAY DIFFRACTION	1.8
9FAD	X-RAY DIFFRACTION	1.8
6Q6L	X-RAY DIFFRACTION	1.81
8P41	X-RAY DIFFRACTION	1.83
3GXI	X-RAY DIFFRACTION	1.84
6T13	X-RAY DIFFRACTION	1.85
7NWV	X-RAY DIFFRACTION	1.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04062-F1	93.46	0.89

Antibody-complex structures (SAbDab): 2 — 9ENA, 9FJF

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): 274 (proton donor); 379 (nucleophile)

Disulfide bonds (2): 57–62, 43–55

Glycosylation sites (5): 58, 98, 185, 309, 501

Mutagenesis-validated functional residues (9):

Position	Phenotype
43	loss of glucosylceramidase activity.
57	loss of glucosylceramidase activity.
62	loss of glucosylceramidase activity.
379	1000-fold decreases of glucosylceramidase activity.
482	loss of glucosylceramidase activity.
482	decreased glucosylceramidase activity.
482	severe decrease of glucosylceramidase activity.
501	loss of glucosylceramidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-9840310	Glycosphingolipid catabolism

MSigDB gene sets: 939 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_CERAMIDE_CATABOLIC_PROCESS, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_BEHAVIOR, GOBP_VACUOLE_ORGANIZATION, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GOCC_VACUOLAR_MEMBRANE

GO Biological Process (67): mitophagy (GO:0000423), glucosylceramide catabolic process (GO:0006680), autophagy (GO:0006914), immune response (GO:0006955), lysosome organization (GO:0007040), cholesterol metabolic process (GO:0008203), determination of adult lifespan (GO:0008340), glycolipid biosynthetic process (GO:0009247), cellular response to starvation (GO:0009267), response to pH (GO:0009268), microglia differentiation (GO:0014004), regulation of macroautophagy (GO:0016241), antigen processing and presentation (GO:0019882), lipid storage (GO:0019915), cerebellar Purkinje cell layer formation (GO:0021694), pyramidal neuron differentiation (GO:0021859), respiratory electron transport chain (GO:0022904), termination of signal transduction (GO:0023021), negative regulation of protein-containing complex assembly (GO:0031333), regulation of TOR signaling (GO:0032006), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of interleukin-6 production (GO:0032715), T cell differentiation in thymus (GO:0033077), response to testosterone (GO:0033574), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of MAPK cascade (GO:0043409), negative regulation of neuron apoptotic process (GO:0043524), response to estrogen (GO:0043627), sphingosine biosynthetic process (GO:0046512), ceramide biosynthetic process (GO:0046513), cell maturation (GO:0048469), thymus development (GO:0048538), brain morphogenesis (GO:0048854), homeostasis of number of cells (GO:0048872), negative regulation of inflammatory response (GO:0050728), neuromuscular process (GO:0050905), negative regulation of protein metabolic process (GO:0051248), neuron apoptotic process (GO:0051402), establishment of skin barrier (GO:0061436), microglial cell proliferation (GO:0061518)

GO Molecular Function (12): galactosylceramidase activity (GO:0004336), glucosylceramidase activity (GO:0004348), signaling receptor binding (GO:0005102), scavenger receptor binding (GO:0005124), beta-glucosidase activity (GO:0008422), glucosyltransferase activity (GO:0046527), steryl-beta-glucosidase activity (GO:0050295), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (9): lysosome (GO:0005764), lysosomal membrane (GO:0005765), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), obsolete extracellular space (GO:0005615), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
Glycosphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
macroautophagy	2
immune system process	2
glycosylceramidase activity	2
catalytic activity	2
lysosome	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
autophagy of mitochondrion	1
glucosylceramide metabolic process	1
glycosylceramide catabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
response to stimulus	1
lytic vacuole organization	1
sterol metabolic process	1
secondary alcohol metabolic process	1
multicellular organismal process	1
glycolipid metabolic process	1
lipid biosynthetic process	1
carbohydrate derivative biosynthetic process	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
response to abiotic stimulus	1
central nervous system development	1
glial cell differentiation	1
macrophage differentiation	1
regulation of autophagy	1
nutrient storage	1
cerebellar Purkinje cell layer morphogenesis	1
cerebellar cortex formation	1
anatomical structure formation involved in morphogenesis	1
central nervous system neuron differentiation	1
electron transport chain	1
cellular respiration	1
negative regulation of signal transduction	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1

Protein interactions and networks

STRING

2346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GBA1	SCARB2	Q14108	970
GBA1	SNCA	P37840	928
GBA1	UGCG	Q16739	928
GBA1	CHIT1	Q13231	924
GBA1	LRRK2	Q5S007	922
GBA1	PSAP	P07292	910
GBA1	GBA2	Q9HCG7	910
GBA1	PRKN	O60260	880
GBA1	ATP13A2	Q9NQ11	869
GBA1	MTX1	Q13505	818
GBA1	GLA	P06280	803
GBA1	GALC	P54803	796
GBA1	SFTA3	P0C7M3	790
GBA1	ASAH1	Q13510	788
GBA1	FBXO7	Q9Y3I1	785

IntAct

61 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
RAB27B	GBA1	psi-mi:“MI:0914”(association)	0.530
CGREF1	TNKS	psi-mi:“MI:0914”(association)	0.530
CNPY3	LRIG2	psi-mi:“MI:0914”(association)	0.530
GORASP1	PPP6R2	psi-mi:“MI:0914”(association)	0.530
PSG8	MGRN1	psi-mi:“MI:0914”(association)	0.530
Scarb2	GBA1	psi-mi:“MI:0915”(physical association)	0.400
GBA1	TCP1	psi-mi:“MI:0915”(physical association)	0.400
GBA1	CBL	psi-mi:“MI:0915”(physical association)	0.400
GBA1	SCAMP3	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
SCARB2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SPDYE4	RPS10-NUDT3	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350
ATP6V1A		psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
CEP135	WDR91	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
RAB27A	GTPBP1	psi-mi:“MI:0914”(association)	0.350
APOC3	EMC8	psi-mi:“MI:0914”(association)	0.350
GUCA1B	LYPLA1	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
LAIR2	AGRN	psi-mi:“MI:0914”(association)	0.350

BioGRID (161): ITCH (Affinity Capture-Western), SNCA (Reconstituted Complex), PCBP2 (Co-fractionation), GBA (Affinity Capture-MS), ATP5J (Affinity Capture-MS), CANX (Affinity Capture-MS), DHCR24 (Affinity Capture-MS), FMR1 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), HSP90B1 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), TOP3B (Affinity Capture-MS), SCAMP3 (Affinity Capture-MS), INADL (Affinity Capture-MS)

ESM2 similar proteins: A0JMP0, A7MBI7, D3YWP0, F1NZI4, G5E872, O09175, O88587, O97583, P04062, P17405, P21139, P21964, P22734, P25409, P52850, P55345, P58242, Q0V8G3, Q0VD19, Q14CH1, Q2KHZ8, Q2TBI8, Q32M88, Q5H879, Q5M868, Q5R6K5, Q5R8E3, Q69ZF3, Q6P9U1, Q6YGZ1, Q70KH2, Q71RP1, Q8BNV1, Q8BP56, Q8IZ69, Q8N371, Q8QZR5, Q8VCT3, Q91W89, Q920N2

Diamond homologs: G5ECR8, O16580, O16581, P04062, P17439, Q2KHZ8, Q5R8E3, Q70KH2, Q9BDT0, Q9UB00

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TFEB	“up-regulates quantity by expression”	GBA	“transcriptional regulation”
ACSS2	“up-regulates quantity by expression”	GBA	“transcriptional regulation”
TFE3	“up-regulates quantity by expression”	GBA	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	79
Likely pathogenic	214
Uncertain significance	232
Likely benign	46
Benign	7

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1321421	NM_000157.4(GBA1):c.256C>T (p.Arg86Ter)	Pathogenic
1321450	NM_000157.4(GBA1):c.203del (p.Pro68fs)	Pathogenic
1322984	NM_000157.4(GBA1):c.1388+1G>A	Pathogenic
1677224	NM_000157.4(GBA1):c.1439_1445del (p.Lys480fs)	Pathogenic
1698486	NM_000157.4(GBA1):c.898del (p.Ala300fs)	Pathogenic
1722541	NM_000157.4(GBA1):c.1361C>T (p.Pro454Leu)	Pathogenic
1799756	NM_000157.4(GBA1):c.236_237del (p.Arg78_Tyr79insTer)	Pathogenic
193611	NM_000157.4(GBA1):c.1265_1319del (p.Leu422fs)	Pathogenic
242383	NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)	Pathogenic
2436490	NM_000157.4(GBA1):c.1260G>A (p.Trp420Ter)	Pathogenic
2503944	NM_000157.4(GBA1):c.260G>A (p.Arg87Gln)	Pathogenic
2578609	GRCh37/hg19 1q22(chr1:155207925-155210903)x1	Pathogenic
2579610	NM_000157.4(GBA1):c.1505+2T>C	Pathogenic
2581173	NM_000157.4(GBA1):c.1054T>C (p.Tyr352His)	Pathogenic
281586	NM_000157.4(GBA1):c.580A>T (p.Lys194Ter)	Pathogenic
3064209	NM_000157.4(GBA1):c.820G>A (p.Glu274Lys)	Pathogenic
3257292	NM_000157.4(GBA1):c.1193G>T (p.Arg398Leu)	Pathogenic
3769167	NM_000157.4(GBA1):c.702dup (p.Ser235fs)	Pathogenic
4068448	NM_000157.4(GBA1):c.762-1G>T	Pathogenic
4295	NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)	Pathogenic
4302	NM_000157.4(GBA1):c.84dup (p.Leu29fs)	Pathogenic
4303	NM_000157.4(GBA1):c.1309G>T (p.Val437Phe)	Pathogenic
4305	NM_000157.4(GBA1):c.983C>T (p.Pro328Leu)	Pathogenic
4307	NM_000157.4(GBA1):c.73del (p.Leu25fs)	Pathogenic
4314	NM_000157.4(GBA1):c.680A>G (p.Asn227Ser)	Pathogenic
4321	NM_000157.4(GBA1):c.259C>T (p.Arg87Trp)	Pathogenic
4326	NM_000157.4(GBA1):c.1192C>T (p.Arg398Ter)	Pathogenic
4328	NM_000157.4(GBA1):c.887G>A (p.Arg296Gln)	Pathogenic
4331	NM_000157.4(GBA1):c.870C>A (p.Phe290Leu)	Pathogenic
4537286	NM_000157.4(GBA1):c.1389-2A>G	Pathogenic

SpliceAI

1337 predictions. Top by Δscore:

Variant	Effect	Δscore
1:155235308:CTTG:C	acceptor_gain	1.0000
1:155235309:TTG:T	acceptor_gain	1.0000
1:155235312:C:CC	acceptor_gain	1.0000
1:155235316:A:AC	acceptor_gain	1.0000
1:155235676:CTCA:C	donor_loss	1.0000
1:155235677:TCACC:T	donor_loss	1.0000
1:155235678:CA:C	donor_loss	1.0000
1:155235679:A:AT	donor_loss	1.0000
1:155235965:T:A	donor_gain	1.0000
1:155236243:A:AC	donor_gain	1.0000
1:155236244:C:CC	donor_gain	1.0000
1:155238132:A:AC	donor_gain	1.0000
1:155238133:C:CC	donor_gain	1.0000
1:155238512:CCTA:C	donor_loss	1.0000
1:155238513:CTACC:C	donor_loss	1.0000
1:155238514:TACC:T	donor_loss	1.0000
1:155238515:A:AC	donor_gain	1.0000
1:155238515:A:T	donor_loss	1.0000
1:155238516:C:CC	donor_gain	1.0000
1:155238533:T:TA	donor_gain	1.0000
1:155238647:ATTC:A	acceptor_gain	1.0000
1:155238648:TTC:T	acceptor_gain	1.0000
1:155238649:TC:T	acceptor_gain	1.0000
1:155238650:CC:C	acceptor_gain	1.0000
1:155238651:C:CC	acceptor_gain	1.0000
1:155238651:CT:C	acceptor_loss	1.0000
1:155238654:C:CT	acceptor_gain	1.0000
1:155238655:A:T	acceptor_gain	1.0000
1:155239883:TACCT:T	donor_loss	1.0000
1:155239885:C:A	donor_loss	1.0000

AlphaMissense

3497 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:155236260:G:C	S403R	0.999
1:155236260:G:T	S403R	0.999
1:155236262:T:G	S403R	0.999
1:155235820:A:G	W417R	0.998
1:155235820:A:T	W417R	0.998
1:155236281:C:A	W396C	0.998
1:155236281:C:G	W396C	0.998
1:155237521:A:C	N273K	0.998
1:155237521:A:T	N273K	0.998
1:155238243:A:G	W218R	0.998
1:155238243:A:T	W218R	0.998
1:155235752:A:C	S439R	0.997
1:155235752:A:T	S439R	0.997
1:155235754:T:G	S439R	0.997
1:155235806:G:C	N421K	0.997
1:155235806:G:T	N421K	0.997
1:155235811:A:G	W420R	0.997
1:155235811:A:T	W420R	0.997
1:155236283:A:G	W396R	0.997
1:155236283:A:T	W396R	0.997
1:155237375:T:A	D322V	0.997
1:155238247:G:C	S216R	0.997
1:155238247:G:T	S216R	0.997
1:155238249:T:G	S216R	0.997
1:155238604:G:C	F167L	0.997
1:155238604:G:T	F167L	0.997
1:155238606:A:G	F167L	0.997
1:155238608:T:A	D166V	0.997
1:155235713:T:A	K452N	0.996
1:155235713:T:G	K452N	0.996

dbSNP variants (sampled 300 via entrez): RS1000200049 (1:155240258 G>A,T), RS1000272750 (1:155246305 T>A), RS1000485283 (1:155246570 A>G), RS1000811839 (1:155244091 T>C), RS1000893098 (1:155244712 G>A,C), RS1001787113 (1:155238428 C>G,T), RS1001793998 (1:155244820 G>C), RS1001890512 (1:155243105 A>G), RS1002406253 (1:155237025 C>T), RS1002423696 (1:155243345 A>G), RS1002676919 (1:155237254 G>A,T), RS1002774030 (1:155246487 G>A), RS1002890652 (1:155241698 CTGAGA>C), RS1003268223 (1:155235957 G>A), RS1003425437 (1:155241998 G>A)

Disease associations

OMIM: gene MIM:606463 | disease phenotypes: MIM:608013, MIM:230800, MIM:127750, MIM:168600, MIM:230900, MIM:231000, MIM:231005, MIM:301040

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease	Definitive	Autosomal dominant
Gaucher disease perinatal lethal	Definitive	Autosomal recessive
Gaucher disease	Definitive	Autosomal recessive
late-onset Parkinson disease	Strong	Autosomal dominant
Gaucher disease type I	Strong	Autosomal recessive
Gaucher disease type II	Strong	Autosomal recessive
Gaucher disease type III	Strong	Autosomal recessive
Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Parkinson disease	Definitive	AD
Gaucher disease	Definitive	AR

Mondo (19): Gaucher disease perinatal lethal (MONDO:0011945), Gaucher disease type I (MONDO:0009265), Gaucher disease (MONDO:0018150), Lewy body dementia (MONDO:0007488), late-onset Parkinson disease (MONDO:0008199), Gaucher disease type II (MONDO:0009266), Gaucher disease type III (MONDO:0009267), Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome (MONDO:0009268), hepatoblastoma (MONDO:0018666), alpha thalassemia-X-linked intellectual disability syndrome (MONDO:0010519), dementia (MONDO:0001627), hypertensive disorder (MONDO:0005044), parkinsonian disorder (MONDO:0021095), hyperlipidemia (MONDO:0021187), movement disorder (MONDO:0005395)

Orphanet (13): Fetal Gaucher disease (Orphanet:85212), Gaucher disease (Orphanet:355), Gaucher disease type 1 (Orphanet:77259), Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome (Orphanet:2072), Hereditary late-onset Parkinson disease (Orphanet:411602), Gaucher disease type 2 (Orphanet:77260), Gaucher disease type 3 (Orphanet:77261), Hepatoblastoma (Orphanet:449), X-linked alpha-thalassemia-intellectual disability syndrome (Orphanet:847), Congenital portosystemic shunt (Orphanet:480531), Young-onset Parkinson disease (Orphanet:2828), NON RARE IN EUROPE: Dementia with Lewy body (Orphanet:1648), NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

251 total (30 of 251 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000027	Azoospermia
HP:0000093	Proteinuria
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000194	Open mouth
HP:0000211	Trismus
HP:0000218	High palate
HP:0000225	Gingival bleeding
HP:0000232	Everted lower lip vermilion
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000298	Mask-like facies
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000338	Hypomimic face
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000421	Epistaxis
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000565	Esotropia

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST001126_9	Parkinson’s disease	5.000000e-21
GCST001430_7	Parkinson’s disease	5.000000e-08
GCST001610_2	Renal function-related traits (BUN)	2.000000e-12
GCST002455_3	Parkinson’s disease	2.000000e-08
GCST002544_10	Parkinson’s disease	1.000000e-29
GCST003984_4	Parkinson’s disease	5.000000e-17
GCST004131_70	Inflammatory bowel disease	6.000000e-08
GCST004132_44	Crohn’s disease	2.000000e-07
GCST004902_39	Parkinson’s disease	3.000000e-35
GCST005276_3	Dementia with Lewy bodies	7.000000e-10
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST007354_21	Intracranial aneurysm	1.000000e-19
GCST007881_2	Dementia with Lewy bodies	1.000000e-09
GCST010696_19	Cortical thickness (min-P)	2.000000e-10
GCST010697_10	Cortical surface area (min-P)	3.000000e-10
GCST010698_59	Subcortical volume (min-P)	9.000000e-10
GCST010699_20	Brain morphology (min-P)	7.000000e-10
GCST010700_5	Cortical thickness (MOSTest)	8.000000e-17
GCST010701_66	Cortical surface area (MOSTest)	1.000000e-09
GCST010702_43	Subcortical volume (MOSTest)	3.000000e-10
GCST010703_253	Brain morphology (MOSTest)	4.000000e-14
GCST012431_11	Parkinson’s disease	5.000000e-11
GCST012489_71	Heel bone mineral density x serum urate levels interaction	3.000000e-09
GCST90020029_1228	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D003704	Dementia	C10.228.140.380; F03.615.400
D005776	Gaucher Disease	C10.228.140.163.100.435.825.400; C16.320.565.189.435.825.400; C16.320.565.398.641.803.441; C16.320.565.595.554.825.400; C18.452.132.100.435.825.400; C18.452.584.563.641.803.441; C18.452.648.189.435.825.400; C18.452.648.398.641.803.441; C18.452.648.595.554.825.400
D018197	Hepatoblastoma	C04.557.435.380
D006949	Hyperlipidemias	C18.452.584.500.500
D006973	Hypertension	C14.907.489
D009069	Movement Disorders	C10.228.662
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C538258	ATR-X syndrome (supp.)
C564306	Gaucher Disease, Perinatal Lethal (supp.)
C565553	Gaucher Disease, Type Iiic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2179 (SINGLE PROTEIN), CHEMBL4106172 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

12 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 455,486 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL110458	MIGALASTAT	4	430
CHEMBL1200829	GLUCONOLACTONE	4	24,595
CHEMBL1561	MIGLITOL	4	29,089
CHEMBL558	MEXILETINE	4	15,463
CHEMBL64894	GENTIAN VIOLET	4	111,449
CHEMBL790	CHLORHEXIDINE	4	85,053
CHEMBL83	TAMOXIFEN	4	171,635
CHEMBL153479	AMBROXOL	3	12,659
CHEMBL206468	AFEGOSTAT	2	334
CHEMBL2105671	AFEGOSTAT TARTRATE	2	33
CHEMBL307429	DUVOGLUSTAT	2	4,739
CHEMBL3354637	NIZUBAGLUSTAT	2	7

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 3.2.1.- Glycosidases

Binding affinities (BindingDB)

278 measured of 286 human assays (302 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Isofagomine derivative, 7	KI	0.07 nM
(3R,4R,5S)-5-(1-fluoroethyl)piperidine-3,4-diol	KI	0.9 nM	US-8604206: Compositions for preventing and/or treating degenerative disorders of the central nervous system
(1S,2R,3S,4R,5R,6R)-5-[[4-[4-(2,2-difluoro-4,6,10,12-tetramethyl-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-1(12),4,6,8,10-pentaen-8-yl)butyl]triazol-1-yl]methyl]-7-oxabicyclo[4.1.0]heptane-2,3,4-triol	KI	0.95 nM	US-9056847: Activity based probes (ABPs) interacting with glycosidases
CHEMBL3289676	KI	1 nM
CID46912122	IC50	1.24 nM
(1S,2R,3S,4R,5R,6R)-5-[[4-[4-[2,2-difluoro-4,12-bis(4-methoxyphenyl)-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-1(12),4,6,8,10-pentaen-8-yl]butyl]triazol-1-yl]methyl]-7-oxabicyclo[4.1.0]heptane-2,3,4-triol	KI	1.56 nM	US-9056847: Activity based probes (ABPs) interacting with glycosidases
CID46912120	IC50	1.94 nM
6-[3-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-N-[4-[4-(2,3-dihydro-1H-inden-2-ylamino)quinazolin-2-yl]phenyl]hexanamide	IC50	1.95 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8S)-8-(but-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	2.4 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-(4-fluorobut-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	2.5 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-methyl-4-azaspiro[2.5]octane-6,7-diol	IC50	3.7 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
N-(2,3-dihydro-1H-inden-2-yl)-2-thiophen-3-ylquinazolin-4-amine	IC50	5.2 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
tert-butyl N-[6-[4-[4-(2,3-dihydro-1H-inden-2-ylamino)quinazolin-2-yl]anilino]-6-oxohexyl]carbamate	IC50	5.6 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
2-pyridin-3-yl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)quinazolin-4-amine	IC50	6 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8S)-8-(fluoromethyl)-4-azaspiro[2.5]octane-6,7-diol	IC50	6.2 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-ethyl-4-azaspiro[2.5]octane-6,7-diol	IC50	6.3 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-(difluoromethyl)-4-azaspiro[2.5]octane-6,7-diol	IC50	6.5 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-(pent-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	6.7 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-vinyl-4-azaspiro[2.5]octane-6,7-diol	IC50	6.8 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
2-(4-aminophenyl)-N-(2,3-dihydro-1H-inden-2-yl)quinazolin-4-amine	IC50	7.1 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
[9-[4-[2-[2-[2-[2-[3-[[6-[4-[4-(2,3-dihydro-1H-inden-2-ylamino)quinazolin-2-yl]anilino]-6-oxohexyl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]-2-formyloxyphenyl]-6-(dimethylamino)xanthen-3-ylidene]-dimethylazanium	KD	7.1 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8S)-8-(chloromethyl)-4-azaspiro[2.5]octane-6,7-diol	IC50	7.4 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8R)-8-(methoxymethyl)-4-azaspiro[2.5]octane-6,7-diol	IC50	7.5 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
6-amino-N-[4-[4-(2,3-dihydro-1H-inden-2-ylamino)quinazolin-2-yl]phenyl]hexanamide	IC50	7.5 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8S)-8-(prop-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	9.7 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(3R,4R,5R)-5-(1-hydroxyethyl)piperidine-3,4-diol	KI	10 nM	US-8604206: Compositions for preventing and/or treating degenerative disorders of the central nervous system
2-pyridin-3-yl-N-[(2R)-1,2,3,4-tetrahydronaphthalen-2-yl]quinazolin-4-amine	IC50	10 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
N-(2,3-dihydro-1H-inden-2-yl)-2-phenylquinazolin-4-amine	IC50	10.5 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8S)-8-(4,4-difluorobut-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	11 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
N-(2,3-dihydro-1H-inden-2-yl)-2-(5-methyl-3-pyridinyl)quinazolin-4-amine	IC50	12.5 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
N-(2,3-dihydro-1H-inden-2-yl)-2-pyridin-3-ylquinazolin-4-amine	IC50	12.7 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
N-(2,3-dihydro-1H-inden-2-yl)-2-thiophen-2-ylquinazolin-4-amine	IC50	12.9 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8R)-8-(hydroxymethyl)-4-azaspiro[2.5]octane-6,7-diol	IC50	13 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-ethynyl-4-azaspiro[2.5]octane-6,7-diol	IC50	13 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(3R,4R,5S)-5-(difluoromethyl)piperidine-3,4-diol	KI	13.6 nM	US-8604206: Compositions for preventing and/or treating degenerative disorders of the central nervous system
(3R,4R,5S)-5-(2-hydroxypropan-2-yl)piperidine-3,4-diol	KI	15 nM	US-8604206: Compositions for preventing and/or treating degenerative disorders of the central nervous system
(6R,7R,8S)-8-propyl-4-azaspiro[2.5]octane-6,7-diol	IC50	15 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-(3-fluoroprop-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	16 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
2-pyridin-3-yl-N-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]quinazolin-4-amine	IC50	16.9 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8S)-8-(3-hydroxyprop-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	17 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
(6R,7R,8S)-8-((E)-2-fluorovinyl)-4-azaspiro[2.5]octane-6,7-diol	IC50	20 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
N-(4-methylcyclohexyl)-2-pyridin-3-ylquinazolin-4-amine	IC50	20 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
Aminoquinoline compound, 1	KI	21 nM
N-(2,3-dihydro-1H-inden-2-yl)-2-(furan-2-yl)quinazolin-4-amine	IC50	21.1 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
(6R,7R,8S)-8-(3,3-difluoroprop-1-yn-1-yl)-4-azaspiro[2.5]octane-6,7-diol	IC50	22 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
Isofagomine derivative, 3	KI	23 nM
(6R,7R,8S)-8-(2-fluoroethyl)-4-azaspiro[2.5]octane-6,7-diol	IC50	27 nM	US-9796680: Glucocerebrosidase modulators and uses thereof
N-cyclooctyl-2-pyridin-3-ylquinazolin-4-amine	IC50	27 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
N-(2,3-dihydro-1H-inden-2-yl)-2-(6-methyl-3-pyridinyl)quinazolin-4-amine	IC50	29.4 nM	US-10167270: Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity

ChEMBL bioactivities

1430 potent at pChembl≥5 of 1919 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.40	Ki	0.4	nM	CHEMBL2029773
9.22	IC50	0.6	nM	CHEMBL5192083
9.05	Ki	0.9	nM	CHEMBL3684925
9.02	Ki	0.95	nM	CHEMBL3692692
9.00	Ki	1	nM	CHEMBL2164231
9.00	Ki	1	nM	CHEMBL3289676
9.00	Ki	1	nM	CHEMBL4080589
8.92	Ki	1.2	nM	CHEMBL3350092
8.81	Ki	1.56	nM	CHEMBL3692694
8.77	Ki	1.7	nM	AFEGOSTAT
8.74	Ki	1.8	nM	CHEMBL2029772
8.71	IC50	1.95	nM	CHEMBL6017265
8.70	IC50	2	nM	CHEMBL3692692
8.68	Ki	2.1	nM	CHEMBL6059819
8.68	Ki	2.1	nM	CHEMBL3349997
8.66	Ki	2.2	nM	CHEMBL1091214
8.62	IC50	2.4	nM	CHEMBL6060394
8.62	Ki	2.4	nM	CHEMBL3349996
8.60	IC50	2.5	nM	CHEMBL5972882
8.60	Potency	2.5	nM	CHEMBL1523867
8.59	Ki	2.6	nM	CHEMBL5764654
8.52	Ki	3	nM	CHEMBL2029780
8.51	Ki	3.06	nM	CHEMBL3684924
8.43	IC50	3.7	nM	CHEMBL5277174
8.43	IC50	3.7	nM	CHEMBL5764654
8.40	Ki	4	nM	CHEMBL2029778
8.40	IC50	4	nM	CHEMBL2164231
8.40	Ki	4	nM	CHEMBL3684925
8.37	IC50	4.3	nM	CHEMBL2164231
8.36	Ki	4.4	nM	CHEMBL2029776
8.30	IC50	5	nM	CHEMBL2164231
8.28	IC50	5.2	nM	CHEMBL3976182
8.25	EC50	5.6	nM	CHEMBL5277174
8.25	IC50	5.6	nM	CHEMBL5969095
8.24	IC50	5.8	nM	CHEMBL3684924
8.22	Ki	6	nM	CHEMBL2029777
8.22	IC50	6	nM	CHEMBL5755815
8.22	IC50	6	nM	CHEMBL3950881
8.21	IC50	6.2	nM	CHEMBL6059819
8.20	IC50	6.3	nM	CHEMBL5817053
8.19	IC50	6.5	nM	CHEMBL3939100
8.19	IC50	6.5	nM	CHEMBL5285901
8.19	IC50	6.5	nM	CHEMBL5865000
8.18	IC50	6.6	nM	CHEMBL3976182
8.17	IC50	6.8	nM	CHEMBL5189151
8.17	IC50	6.8	nM	CHEMBL5759325
8.17	Ki	6.7	nM	CHEMBL5995977
8.17	IC50	6.7	nM	CHEMBL5912694
8.15	IC50	7	nM	CHEMBL3684925
8.15	Ki	7	nM	CHEMBL5953736

PubChem BioAssay actives

692 with measured affinity, of 2279 total; 50 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
5-(hydroxymethyl)-6-nonylpiperidine-3,4-diol	1799647: Fluorescene-based Assay from Article 10.1002/cbic.201100332: “Synthesis, kinetic evaluation and cell-based analysis of C-alkylated isofagomines as chaperones of β-glucocerebrosidase.”	ki	0.0001	uM
(2R,3S,4S,5R)-2-(2-octylsulfanylethyl)piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0004	uM
(3R,4R,5R,6S)-5-(hydroxymethyl)-6-nonylpiperidine-3,4-diol	1884452: Inhibition of human GCase assessed as reduction of 4-methylumbelliferone liberation using 4-methylumbelliferyl-beta-glucopyranoside as substrate incubated for 30 mins by fluorescence spectrophotometry	ic50	0.0006	uM
5-(dimethylamino)-N-[6-[methyl-[(1R,2S,3S,4S,5R)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclopentyl]amino]hexyl]naphthalene-1-sulfonamide	1454195: Competitive inhibition of recombinant beta-glucocerebrosidase (unknown origin) using 4-nitrophenyl beta-D-galactopyranoside as substrate pre-incubated for up to 5 mins before substrate addition	ki	0.0010	uM
(2R,3S,4S,5R)-2-[5-(1-adamantylmethoxy)pentyl]piperidine-3,4,5-triol	1152618: Inhibition of human lysosomal beta-glucocerebrosidase	ki	0.0010	uM
(1S,2R,3S,4R,5S,6S)-5-nonoxy-6-(nonylamino)cyclohexane-1,2,3,4-tetrol;hydrochloride	699345: Binding affinity to recombinant imiglucerase using 4-methylumbelliferyl-beta-D-glucopyranoside as substrate preincubated for 30 mins before substrate addition by Lineweaver-Burk plot assay	ki	0.0010	uM
7-(diethylamino)-N-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]methyl]-2-oxochromene-3-carboxamide	40289: Tested for inhibitory activity against Beta-glucosidase from Agrobacterium species	ki	0.0012	uM
5-(hydroxymethyl)-2-[3-(4-methoxyphenyl)propyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800219: GCase Ki Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ki	0.0012	uM
5-(hydroxymethyl)-2-[3-(4-methylphenyl)propyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800219: GCase Ki Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ki	0.0015	uM
(2R,3S,4S,5R)-2-(2-hexylsulfanylethyl)piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0018	uM
2-[3-(4-cyclohexylphenyl)propyl]-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800219: GCase Ki Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ki	0.0019	uM
5-(hydroxymethyl)-2-(2-phenylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800217: GCase IC50 Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ic50	0.0020	uM
N-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]methyl]-6-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]hexanamide	40287: Inhibitory activity against Agrobacterium sp. Beta-glucosidase employing fluorescence spectrometric method	ki	0.0021	uM
(2R,3S,4S,5R)-2-nonylpiperidine-3,4,5-triol	1152618: Inhibition of human lysosomal beta-glucocerebrosidase	ki	0.0022	uM
N-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]methyl]-5-(dimethylamino)naphthalene-1-sulfonamide	40287: Inhibitory activity against Agrobacterium sp. Beta-glucosidase employing fluorescence spectrometric method	ki	0.0024	uM
(2R,3S,4S,5R)-2-[2-(2-phenylethylsulfanyl)ethyl]piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0030	uM
2-[3-(4-fluorophenyl)propyl]-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800219: GCase Ki Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ki	0.0035	uM
5-(hydroxymethyl)-2-[3-(4-phenylphenyl)propyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800219: GCase Ki Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ki	0.0036	uM
(4-tert-butylphenyl)-[4-(2-pyrrolidin-1-yl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl]methanone	1937601: Inhibition of GCase in patient derived fibroblast cells using 5’pentafluorobenzoylaminofluorescein-di-beta-D-glucoside as substrate assessed as substrate hydrolysis by FACS analysis	ic50	0.0037	uM
(2R,3S,4S,5R)-2-(2-cyclohexylsulfanylethyl)piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0040	uM
N-phenyl-4-[6,7,8-trihydroxy-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]butanamide	1800219: GCase Ki Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ki	0.0042	uM
2-(3,3-dimethylbutyl)-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800217: GCase IC50 Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ic50	0.0043	uM
(2R,3S,4S,5R)-2-[2-(3-methylbutylsulfanyl)ethyl]piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0044	uM
5-(hydroxymethyl)piperidine-3,4-diol	1799647: Fluorescene-based Assay from Article 10.1002/cbic.201100332: “Synthesis, kinetic evaluation and cell-based analysis of C-alkylated isofagomines as chaperones of β-glucocerebrosidase.”	ki	0.0050	uM
5-(hydroxymethyl)-2-octyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol	1800217: GCase IC50 Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ic50	0.0050	uM
N-(2,3-dihydro-1H-inden-2-yl)-2-thiophen-3-ylquinazolin-4-amine	1321657: Inhibition of synthetic recombinant wild type GCase enzyme velaglucerase alfa (unknown origin) at pH 5.9 preincubated for 5 mins followed by addition of 4-Methylumbelliferyl beta-D-glucopyranoside as substrate measured after 30 mins by fluorescence analysis	ic50	0.0052	uM
(2R,3S,4S,5R)-2-(2-cyclopentylsulfanylethyl)piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0060	uM
N-(2,3-dihydro-1H-inden-2-yl)-2-phenylquinazolin-4-amine	1321657: Inhibition of synthetic recombinant wild type GCase enzyme velaglucerase alfa (unknown origin) at pH 5.9 preincubated for 5 mins followed by addition of 4-Methylumbelliferyl beta-D-glucopyranoside as substrate measured after 30 mins by fluorescence analysis	ic50	0.0065	uM
(4-tert-butylphenyl)-[4-(2-pyrrolidin-1-yl-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-1-yl]methanone	1937601: Inhibition of GCase in patient derived fibroblast cells using 5’pentafluorobenzoylaminofluorescein-di-beta-D-glucoside as substrate assessed as substrate hydrolysis by FACS analysis	ic50	0.0065	uM
(3S,4S,5R)-2-nonylpiperidine-3,4,5-triol	1884453: Inhibition of human GCase	ic50	0.0068	uM
(1S,2R,3S,4R,5R,6R)-5-[[4-[4-(2,2-difluoro-4,6,10,12-tetramethyl-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-1(12),4,6,8,10-pentaen-8-yl)butyl]triazol-1-yl]methyl]-7-oxabicyclo[4.1.0]heptane-2,3,4-triol	1799421: Enzymatic Activity Assay from Article 10.1038/nchembio.466: “Ultrasensitive in situ visualization of active glucocerebrosidase molecules.”	ki	0.0070	uM
5-(dimethylamino)-N-[[(2R,3S,4S,5R)-3,4,5-trihydroxypiperidin-2-yl]methyl]naphthalene-1-sulfonamide	1152619: Inhibition of human lysosomal beta-glucocerebrosidase using 2,4-dinitrophenyl-beta-D-glucopyranoside as substrate by UV spectrophotometric analysis	ki	0.0075	uM
(1S,2R,3S,4R,5R,6R)-5-[[4-[4-[2,2-difluoro-4,12-bis(4-methoxyphenyl)-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-1(12),4,6,8,10-pentaen-8-yl]butyl]triazol-1-yl]methyl]-7-oxabicyclo[4.1.0]heptane-2,3,4-triol	1799421: Enzymatic Activity Assay from Article 10.1038/nchembio.466: “Ultrasensitive in situ visualization of active glucocerebrosidase molecules.”	ki	0.0080	uM
N-(2,3-dihydro-1H-inden-2-yl)-2-thiophen-2-ylquinazolin-4-amine	1321657: Inhibition of synthetic recombinant wild type GCase enzyme velaglucerase alfa (unknown origin) at pH 5.9 preincubated for 5 mins followed by addition of 4-Methylumbelliferyl beta-D-glucopyranoside as substrate measured after 30 mins by fluorescence analysis	ic50	0.0082	uM
N-(2,3-dihydro-1H-inden-2-yl)-2-pyridin-3-ylquinazolin-4-amine	1321657: Inhibition of synthetic recombinant wild type GCase enzyme velaglucerase alfa (unknown origin) at pH 5.9 preincubated for 5 mins followed by addition of 4-Methylumbelliferyl beta-D-glucopyranoside as substrate measured after 30 mins by fluorescence analysis	ic50	0.0083	uM
2-pyridin-3-yl-N-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]quinazolin-4-amine	1321657: Inhibition of synthetic recombinant wild type GCase enzyme velaglucerase alfa (unknown origin) at pH 5.9 preincubated for 5 mins followed by addition of 4-Methylumbelliferyl beta-D-glucopyranoside as substrate measured after 30 mins by fluorescence analysis	ic50	0.0087	uM
(3R,4S,5S)-5-hexoxypiperidine-3,4-diol	1884453: Inhibition of human GCase	ic50	0.0090	uM
(4-tert-butylphenyl)-[4-(6-methyl-2-pyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]methanone	1937595: Chaperone activity at GCase N370S GBA mutant in patient derived fibroblast cell using 4-methylumbelliferyl-beta-D-glucopyranoside as substrate assessed as substrate cleavage by measuring concentration required for maximal response incubated for 5 days by fluorescence based assay	ec50	0.0096	uM
2-pyridin-3-yl-N-[(2R)-1,2,3,4-tetrahydronaphthalen-2-yl]quinazolin-4-amine	1321657: Inhibition of synthetic recombinant wild type GCase enzyme velaglucerase alfa (unknown origin) at pH 5.9 preincubated for 5 mins followed by addition of 4-Methylumbelliferyl beta-D-glucopyranoside as substrate measured after 30 mins by fluorescence analysis	ic50	0.0099	uM
2,2-dimethyl-N-phenyl-5-[6,7,8-trihydroxy-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl]pentanamide	1800217: GCase IC50 Assay from Article 10.1002/cbic.201300197: “New insights into the pharmacological chaperone activity of c2-substituted glucoimidazoles for the treatment of Gaucher disease.”	ic50	0.0115	uM
1-phenyl-3-[2-[2-[(2R,3S,4S,5R)-3,4,5-trihydroxypiperidin-2-yl]ethylsulfanyl]ethyl]urea;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0120	uM
N-(2,3-dihydro-1H-inden-2-yl)-2-(5-methyl-3-pyridinyl)quinazolin-4-amine	1321657: Inhibition of synthetic recombinant wild type GCase enzyme velaglucerase alfa (unknown origin) at pH 5.9 preincubated for 5 mins followed by addition of 4-Methylumbelliferyl beta-D-glucopyranoside as substrate measured after 30 mins by fluorescence analysis	ic50	0.0125	uM
N-[(2S)-2-amino-2-[3-(dimethylamino)phenyl]ethyl]-3-fluoro-N-methyl-5-propoxybenzenesulfonamide	2085396: Binding affinity to human Avi/10-his tagged GCase (40 to 536 residues) expressed baculovirus expression system in Sf9 cells in assessed as dissociation constant by isothermal titration calorimetry analysis	kd	0.0180	uM
(2R,3S,4S,5R)-2-(2-butylsulfanylethyl)piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0180	uM
5-(dimethylamino)-N-[6-[[(1R,2S,3S,4S,5R)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclopentyl]amino]hexyl]naphthalene-1-sulfonamide	1454195: Competitive inhibition of recombinant beta-glucocerebrosidase (unknown origin) using 4-nitrophenyl beta-D-galactopyranoside as substrate pre-incubated for up to 5 mins before substrate addition	ki	0.0190	uM
N-[(2S)-2-amino-2-[3-(dimethylamino)phenyl]ethyl]-3,5-difluoro-N-methylbenzenesulfonamide	2085396: Binding affinity to human Avi/10-his tagged GCase (40 to 536 residues) expressed baculovirus expression system in Sf9 cells in assessed as dissociation constant by isothermal titration calorimetry analysis	kd	0.0190	uM
(2R,3S,4S,5R)-2-hexylpiperidine-3,4,5-triol	474612: Inhibition of human recombinant beta-glucocerebrosidase assessed as p-nitrophenolate accumulation preincubated for 10 mins before p-nitrophenyl-beta-d-glucopyranoside addition measured after 10 mins by fluorescence spectrophotometry	ic50	0.0190	uM
(2R,3S,4S,5R)-2-(2-benzylsulfanylethyl)piperidine-3,4,5-triol;hydrochloride	662915: Competitive inhibition of wild type human glucocerebrosidase using 4-methylumbelliferyl beta-D-glucopyranoside as substrate after 15 mins by Dixon and Line-Weaver Burk plot analysis at pH 5	ki	0.0190	uM
(1S,2R,3S,4R,5S,6S)-5-methoxy-6-(nonylamino)cyclohexane-1,2,3,4-tetrol;hydrochloride	699342: Competitive inhibition of recombinant Imiglucerase using 4-methylumbelliferyl-beta-D-glucopyranoside as substrate preincubated for 30 mins before substrate addition at pH 7.0 Lineweaver-Burk plot assay	ic50	0.0190	uM
2,3-dihydroxybutanedioic acid;(3R,4R,5R)-5-(hydroxymethyl)piperidine-3,4-diol	702056: Inhibition of glucocerebrosidase N370S mutant using 4-methylumbelliferone-beta-Glc as substrate incubated for 5 mins prior to substrate addition measured after 30 to 45 mins by HPLC analysis	ic50	0.0190	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression, affects expression, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
intybin	decreases reaction, increases expression, affects cotreatment, increases abundance	1
4-oxoretinoic acid	decreases expression	1
bisphenol A	increases expression	1
conduritol epoxide	affects binding, decreases activity, increases expression	1
tanshinone	increases expression	1
leucyl-leucine-methyl ester	increases expression	1
isofagomine	decreases activity	1
bisphenol B	increases expression	1
eliglustat	affects localization, decreases activity	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	decreases expression, decreases reaction, increases cleavage, increases expression	1
Arsenic Trioxide	increases expression	1
Alitretinoin	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Fatty Acids, Nonesterified	increases expression, decreases reaction, affects cotreatment, increases abundance	1
Ivermectin	decreases expression	1
Smoke	decreases expression, increases abundance	1
Sulindac	decreases reaction, increases expression	1
Tetradecanoylphorbol Acetate	increases expression, increases reaction	1
Vitallium	increases expression	1
Isotretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

436 unique, capped per target: 403 binding, 33 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1007618	Binding	Inhibition of human placental beta-glucocerebrosidase by spectrophotometry	Glycosidase-inhibiting pyrrolidines and pyrrolizidines with a long side chain in Scilla peruviana. — J Nat Prod
CHEMBL1613812	Functional	PUBCHEM_BIOASSAY: qHTS Assay for Inhibitors and Activators of N370S glucocerebrosidase as a Potential Chaperone Treatment of Gaucher Disease: Activity in Non-Mutant Spleen Homogenate Using a Red Fluorescent Substrate. (Class of assay: confi	PubChem BioAssay data set

Cellosaurus cell lines

275 cell lines: 202 induced pluripotent stem cell, 35 finite cell line, 15 transformed cell line, 11 cancer cell line, 11 embryonic stem cell, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0R27	GM00877	Finite cell line	Male
CVCL_0R28	GM00878	Finite cell line	Female
CVCL_0R29	GM01030	Transformed cell line	Female
CVCL_0R30	GM01031	Transformed cell line	Male
CVCL_0R31	GM01260	Finite cell line	Female
CVCL_0R32	GM02627	Finite cell line	Female
CVCL_0R33	GM04394	Finite cell line	Male
CVCL_0R34	GM07968	Finite cell line	Male
CVCL_0R36	GM10870	Transformed cell line	Female
CVCL_0R37	GM10871	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients
NCT00642356	PHASE4	TERMINATED	Carbidopa/Levodopa/Entacapone Versus Immediate Release (IR) Carbidopa/Levodopa on Non-motor Symptoms in Patients With Idiopathic Parkinson’s Disease and Demonstrating Non-motor Symptoms of Wearing Off