TGM6

Summary

TGM6 (transglutaminase 6, HGNC:16255) is a protein-coding gene on chromosome 20p13, encoding Protein-glutamine gamma-glutamyltransferase 6 (O95932). Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

The protein encoded by this gene belongs to the transglutaminase superfamily. It catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Mutations in this gene are associated with spinocerebellar ataxia type 35 (SCA35). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 343641 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 35 (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 555 total — 4 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• MANE Select transcript: NM_198994

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16255
Approved symbol	TGM6
Name	transglutaminase 6
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	dJ734P14.3, TGY, SCA35
Ensembl gene	ENSG00000166948
Ensembl biotype	protein_coding
OMIM	613900
Entrez	343641

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000202625, ENST00000381423, ENST00000477505

RefSeq mRNA: 2 — MANE Select: NM_198994 NM_001254734, NM_198994

CCDS: CCDS13025, CCDS58761

Canonical transcript exons

ENST00000202625 — 13 exons

Exon	Start	End
ENSE00000655903	2403397	2403500
ENSE00000655922	2403581	2403823
ENSE00000656030	2417232	2417573
ENSE00000656034	2430446	2430600
ENSE00000656037	2430894	2431027
ENSE00000858631	2395194	2395436
ENSE00000858632	2396506	2396624
ENSE00003459427	2397918	2398046
ENSE00003482779	2432490	2432753
ENSE00003507324	2399561	2399738
ENSE00003654227	2394452	2394625
ENSE00003660212	2400306	2400444
ENSE00003888863	2380901	2380975

Expression profiles

Bgee: expression breadth broad, 39 present calls, max score 99.02.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0102 / max 7.6230, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183163	0.0102	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	99.02	gold quality
bone marrow cell	CL:0002092	97.12	gold quality
kidney epithelium	UBERON:0004819	80.61	gold quality
myocardium	UBERON:0002349	73.00	gold quality
left ventricle myocardium	UBERON:0006566	72.36	gold quality
cardiac muscle of right atrium	UBERON:0003379	72.32	gold quality
nasal cavity epithelium	UBERON:0005384	71.16	gold quality
upper arm skin	UBERON:0004263	70.47	gold quality
deltoid	UBERON:0001476	69.62	gold quality
esophagus squamous epithelium	UBERON:0006920	68.72	gold quality
gingival epithelium	UBERON:0001949	67.83	gold quality
parotid gland	UBERON:0001831	67.77	gold quality
quadriceps femoris	UBERON:0001377	67.59	gold quality
gingiva	UBERON:0001828	67.33	gold quality
vastus lateralis	UBERON:0001379	67.03	gold quality
secondary oocyte	CL:0000655	66.20	gold quality
epithelial cell of pancreas	CL:0000083	65.37	gold quality
oral cavity	UBERON:0000167	65.25	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.12	gold quality
vena cava	UBERON:0004087	64.87	gold quality
tonsil	UBERON:0002372	64.76	gold quality
lateral globus pallidus	UBERON:0002476	64.52	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	64.23	gold quality
layer of synovial tissue	UBERON:0007616	64.07	gold quality
substantia nigra pars reticulata	UBERON:0001966	63.81	gold quality
heart right ventricle	UBERON:0002080	63.61	gold quality
tibialis anterior	UBERON:0001385	63.52	silver quality
skeletal muscle tissue	UBERON:0001134	63.18	gold quality
cartilage tissue	UBERON:0002418	63.16	gold quality
biceps brachii	UBERON:0001507	63.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting TGM6, 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-6077	99.99	68.04	2299
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-10398-5P	97.12	64.94	1051

Literature-anchored findings (GeneRIF, showing 19)

• Antibodies against transglutaminase 6 can serve as marker antibodies to identify a subgroup of patients with gluten sensitivity who may be at risk for development of neurological disease. (PMID:18825674)
• findings lend credence to the notion that TG3 and TG6 are involved in the gluten-induced autoimmune responses of dermatitis herpetiformis and gluten ataxia (PMID:20300788)
• The finding of TGM6 as a novel causative gene of spinocerebellar ataxia illustrates whole-exome sequencing of affected individuals from one family (PMID:21106500)
• TG6 autoantibodies are not gluten-dependent (PMID:21453693)
• Human inter-alpha-inhibitor is a substrate for factor XIIIa and tissue transglutaminase. (PMID:21939789)
• New DNA sequencing technologies are enabling us to investigate the whole or large targeted proportions of the genome in a rapid, affordable, and comprehensive way. Exome and targeted sequencing TMG6 genes causing ataxia. (PMID:22527681)
• Results indicate a mutation in the transglutaminase 6 (TGM6) gene (c.1528G>C) which showed co-segregation with disease phenotype in all nine members of this family. (PMID:22554020)
• this study analyzed the subcellular distribution, expression and in vitro activity of two missense mutations of TG6 (D327G, L517W) and found that both mutants exhibited decreased transglutaminase activity and stability. (PMID:23206699)
• Antibodies against TG6 are gluten-dependent and appear to be a sensitive and specific marker of glten ataxia. (PMID:23576621)
• transglutaminase 6 could be involved in polyQ diseases. (PMID:23800413)
• Whole-exome and targeted sequencing have defined the genetic basis of dizziness including new genes causing ataxia: GBA2, TGM6, ANO10 and SYT14 (PMID:24275721)
• TGM6 missense mutation cosegregated with AML in a large family. (PMID:24755948)
• Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified in Spinocerebellar ataxia 35. (PMID:25253745)
• Importance of TGM6 mutations in Chinese cerebellar ataxia patients, not only in SCA families, but also in individuals with sporadic cerebellar ataxia. (PMID:28927799)
• Results indicate that mutations differently impacting on TG6 function cause neuronal dysfunction and death through diverse mechanisms. (PMID:28934387)
• rs6114027 risk allele related to decreased transcripts in peripheral blood mononuclear cells from pulmonary tuberculosis patients (PMID:30287856)
• we identified 8 families with reported TGM6 variants sharing no features of Spinocerebellar ataxia 35 (PMID:30670339)
• TGM6 variants in Parkinson’s disease: clinical findings and functional evidence. (PMID:32259886)
• TGM6 might not be a specific causative gene for spinocerebellar ataxia resulting from genetic analysis and functional study. (PMID:33588035)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgm8	ENSDARG00000097651
danio_rerio	tgm5l	ENSDARG00000098837
mus_musculus	Tgm6	ENSMUSG00000027403
rattus_norvegicus	Tgm6	ENSRNOG00000006830

Paralogs (8): TGM1 (ENSG00000092295), TGM5 (ENSG00000104055), F13A1 (ENSG00000124491), TGM3 (ENSG00000125780), TGM7 (ENSG00000159495), TGM4 (ENSG00000163810), EPB42 (ENSG00000166947), TGM2 (ENSG00000198959)

Protein

Protein identifiers

Protein-glutamine gamma-glutamyltransferase 6 — O95932 (reviewed: O95932)

Alternative names: Transglutaminase Y, Transglutaminase-3-like, Transglutaminase-6

All UniProt accessions (1): O95932

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

Subcellular location. Cytoplasm.

Disease relevance. Spinocerebellar ataxia 35 (SCA35) [MIM:613908] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA35 patients commonly show upper limb involvement and torticollis. There is no cognitive impairment. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds up to 3 Ca(2+) cations per subunit.

Similarity. Belongs to the transglutaminase superfamily. Transglutaminase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95932-1	1, Long	yes
O95932-2	2, Short

RefSeq proteins (2): NP_001241663, NP_945345* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001102	Transglutaminase_N	Domain
IPR002931	Transglutaminase-like	Domain
IPR008958	Transglutaminase_C	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR013808	Transglutaminase_AS	Active_site
IPR014756	Ig_E-set	Homologous_superfamily
IPR023608	Transglutaminase_animal	Family
IPR036238	Transglutaminase_C_sf	Homologous_superfamily
IPR036985	Transglutaminase-like_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050779	Transglutaminase	Family

Pfam: PF00868, PF00927, PF01841

Enzyme classification (BRENDA):

• EC 2.3.2.13 — protein-glutamine gamma-glutamyltransferase (BRENDA: 68 organisms, 476 substrates, 772 inhibitors, 122 Km, 49 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PUTRESCINE	0.035–9.63	13
L-LYSINE	2.9–15.8	6
N-CBZ-GLN-GLY	12.83–59.5	5
HYDROXYLAMINE	1.37–61.9	4
NALPHA-BENZYLOXYCARBONYL-L-GLN-GLY	11.2–30	4
CASEIN	0.006–0.012	3
CBZ-GLN-GLY	0.0169–5.9	3
CBZ-GLN-GLY-OH	3.53–8.55	3
METHYLAMINE	0.024–0.061	3
MONODANSYLCADAVERINE	0.01–0.034	3
N-CARBOXYBENZOYL-L-GLUTAMINYL-GLYCINE	0.0547–69.4	3
PENTYLAMINE	0.0029–0.0203	3
Z-GLN-GLY	1.8–11.6	3
ACETYL-ALPHAS1-CASEIN	0.0029–0.0032	2
GTP	0.0044–0.01	2

Catalyzed reactions (Rhea), 1 shown:

• L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N(6)-5-L-glutamyl-[protein] + NH4(+) (RHEA:54816)

UniProt features (25 total): binding site 12, sequence variant 7, active site 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95932-F1	90.95	0.77

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 (3): 274; 333; 356

Ligand- & substrate-binding residues (12): 309; 327; 396; 417; 445; 450; 223; 226; 228; 303; 305; 307

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 83 (showing top): GOBP_PEPTIDE_CROSS_LINKING, TGACCTY_ERR1_Q2, TAATTA_CHX10_01, GOMF_ACYLTRANSFERASE_ACTIVITY, GOMF_AMINOACYLTRANSFERASE_ACTIVITY, MZF1_01, ERR1_Q2, GOMF_PROTEIN_GLUTAMINE_GAMMA_GLUTAMYLTRANSFERASE_ACTIVITY, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, MIR6721_5P, MIR6077, MIR4701_5P, MIR588, MIR3190_3P, GSE11924_TH1_VS_TH2_CD4_TCELL_UP

GO Biological Process (1): peptide cross-linking (GO:0018149)

GO Molecular Function (4): protein-glutamine gamma-glutamyltransferase activity (GO:0003810), metal ion binding (GO:0046872), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification process	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
cation binding	1
catalytic activity	1
transferase activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGM6	ASB17	Q8WXJ9	771
TGM6	ATXN10	Q9UBB4	604
TGM6	ASB2	Q96Q27	583
TGM6	ADAM8	P78325	552
TGM6	ATN1	P54259	542
TGM6	ATXN7	O15265	498
TGM6	PRRT2	Q7Z6L0	482
TGM6	TOR1A	O14656	476
TGM6	EPO	P01588	447
TGM6	SPTBN2	O15020	433
TGM6	AFG3L2	Q9Y4W6	431
TGM6	CACNA1A	P78510	429
TGM6	PPP2R2B	Q00005	424
TGM6	KCNC3	Q14003	414
TGM6	ATXN1	P54253	394
TGM6	TTBK2	Q6IQ55	394

IntAct

2 interactions, top by confidence:

A	B	Type	Score
TGM6	MRPS9	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (1): MRPS9 (Proximity Label-MS)

ESM2 similar proteins: A0A1W2PQ27, A0A1W2PQ64, A0A1W2PQC6, A0A1W2PQD8, A0A1W2PQJ5, A0A1W2PR75, A2AV36, A4QN59, A6QQV6, D4A1F2, F1RA39, G5E8F4, J9SQF3, O00142, O42868, O55239, O95050, O95932, O97972, P0CR76, P0CR77, P10938, P40261, P40936, P53538, Q01841, Q22453, Q32LP9, Q4R7D0, Q566Y1, Q5M9G7, Q5RFR7, Q5U4E8, Q5XG58, Q62160, Q6C195, Q6CQ61, Q6DE00, Q6FMU7, Q6PCI6

Diamond homologs: A6QP57, D4A5U3, O08619, O43548, O46510, O95932, P00488, P08587, P16452, P21980, P21981, P22735, P22758, P23606, P49221, P51176, P52181, P52183, Q01841, Q05187, Q08188, Q08189, Q8BH61, Q8BZH1, Q96PF1, Q99041, Q9D7I9, Q9GLK0, Q9JLF6, Q9WVJ6, P49222, P12260

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	6
Uncertain significance	275
Likely benign	107
Benign	76

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1298293	NM_198994.3(TGM6):c.1429_1430insTCTCT (p.Gly477fs)	Pathogenic
1299628	NM_198994.3(TGM6):c.1336+1G>T	Pathogenic
190253	NM_198994.3(TGM6):c.331C>T (p.Arg111Cys)	Pathogenic
190254	NM_198994.3(TGM6):c.1719AGA[1] (p.Glu574del)	Pathogenic
1027361	NM_198994.3(TGM6):c.1005G>A (p.Trp335Ter)	Likely pathogenic
2636053	NM_198994.3(TGM6):c.673-1G>A	Likely pathogenic
3256544	NM_198994.3(TGM6):c.850+1G>A	Likely pathogenic
3256788	NM_198994.3(TGM6):c.110C>A (p.Ser37Ter)	Likely pathogenic
4077695	NM_198994.3(TGM6):c.416G>A (p.Trp139Ter)	Likely pathogenic
809215	NM_198994.3(TGM6):c.1093+1G>A	Likely pathogenic

SpliceAI

2291 predictions. Top by Δscore:

Variant	Effect	Δscore
20:2380971:GGCAG:G	donor_gain	1.0000
20:2380972:GCAGG:G	donor_gain	1.0000
20:2380973:CAGGT:C	donor_loss	1.0000
20:2380975:GGTA:G	donor_loss	1.0000
20:2380976:G:GG	donor_gain	1.0000
20:2394446:A:AG	acceptor_gain	1.0000
20:2394447:C:G	acceptor_gain	1.0000
20:2394448:CCAG:C	acceptor_loss	1.0000
20:2394449:CAG:C	acceptor_loss	1.0000
20:2394450:A:AG	acceptor_gain	1.0000
20:2394450:A:T	acceptor_loss	1.0000
20:2394450:AG:A	acceptor_gain	1.0000
20:2394450:AGG:A	acceptor_gain	1.0000
20:2394451:G:GA	acceptor_loss	1.0000
20:2394451:G:GG	acceptor_gain	1.0000
20:2394451:GG:G	acceptor_gain	1.0000
20:2394451:GGG:G	acceptor_gain	1.0000
20:2394621:GACAG:G	donor_gain	1.0000
20:2394624:AGGT:A	donor_loss	1.0000
20:2394625:GGTAA:G	donor_loss	1.0000
20:2394626:GTA:G	donor_loss	1.0000
20:2394627:T:A	donor_loss	1.0000
20:2396651:G:GT	donor_gain	1.0000
20:2397916:A:AG	acceptor_gain	1.0000
20:2397917:G:GG	acceptor_gain	1.0000
20:2403665:C:CA	acceptor_gain	1.0000
20:2403819:GGAAG:G	donor_gain	1.0000
20:2403820:GAAG:G	donor_gain	1.0000
20:2403820:GAAGG:G	donor_gain	1.0000
20:2403821:A:T	donor_gain	1.0000

AlphaMissense

4627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:2403401:T:C	F332L	0.998
20:2403403:C:A	F332L	0.998
20:2403403:C:G	F332L	0.998
20:2396610:T:A	W177R	0.997
20:2396610:T:C	W177R	0.997
20:2399648:A:C	S254R	0.997
20:2399650:C:A	S254R	0.997
20:2399650:C:G	S254R	0.997
20:2400347:T:C	F298L	0.997
20:2400349:C:A	F298L	0.997
20:2400349:C:G	F298L	0.997
20:2399710:C:G	C274W	0.996
20:2399717:T:C	F277L	0.996
20:2399719:C:A	F277L	0.996
20:2399719:C:G	F277L	0.996
20:2400443:T:A	W330R	0.996
20:2400443:T:C	W330R	0.996
20:2403410:T:A	W335R	0.996
20:2403410:T:C	W335R	0.996
20:2403760:A:C	S425R	0.996
20:2403762:C:A	S425R	0.996
20:2403762:C:G	S425R	0.996
20:2396612:G:C	W177C	0.995
20:2396612:G:T	W177C	0.995
20:2400312:G:T	R286M	0.995
20:2403397:G:C	W330C	0.995
20:2403397:G:T	W330C	0.995
20:2403404:C:G	H333D	0.995
20:2403419:A:C	S338R	0.995
20:2403421:C:A	S338R	0.995

dbSNP variants (sampled 300 via entrez): RS1000013452 (20:2402826 C>T), RS1000110358 (20:2397037 G>A), RS1000410213 (20:2402609 A>C), RS1000413656 (20:2380074 A>G), RS1000416488 (20:2408890 A>G), RS1000420600 (20:2408623 C>T), RS1000518740 (20:2407121 T>A,G), RS1000571602 (20:2413981 A>G), RS1000626939 (20:2413657 T>C), RS1000644190 (20:2415653 G>A,C), RS1000665677 (20:2399959 T>C), RS1000768382 (20:2395005 A>G), RS1000861348 (20:2385356 TGGGGAGGGGGGA>T,TGGGGA), RS1000974723 (20:2391112 T>C), RS1000995929 (20:2431326 T>C)

Disease associations

OMIM: gene MIM:613900 | disease phenotypes: MIM:613908, MIM:168600, MIM:601626

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 35	Strong	Autosomal dominant

Mondo (6): spinocerebellar ataxia type 35 (MONDO:0013485), Parkinson disease (MONDO:0005180), parkinsonian disorder (MONDO:0021095), vascular parkinsonism (MONDO:0956980), acute myeloid leukemia (MONDO:0018874), polyneuropathy (MONDO:0001824)

Orphanet (3): Spinocerebellar ataxia type 35 (Orphanet:276193), Acute myeloid leukemia (Orphanet:519), NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000467	Neck muscle weakness
HP:0000473	Torticollis
HP:0000514	Slow saccadic eye movements
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000641	Dysmetric saccades
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002080	Intention tremor
HP:0002311	Incoordination
HP:0002342	Moderate intellectual disability
HP:0002505	Loss of ambulation
HP:0003487	Babinski sign
HP:0003596	Middle age onset
HP:0003677	Slowly progressive
HP:0007024	Pseudobulbar paralysis
HP:0009830	Peripheral neuropathy
HP:0010831	Impaired proprioception

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001915_42	Alzheimer’s disease (cognitive decline)	3.000000e-08
GCST006619_2	Tuberculosis	2.000000e-11
GCST009313_5	Prepulse inhibition of the startle response	3.000000e-06
GCST009391_213	Metabolite levels	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007969	cognitive inhibition measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
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
D011115	Polyneuropathies	C10.668.829.800

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2079852 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

4 measured of 6 human assays (6 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]prop-2-enamide (3e)	IC50	125 nM
[2-[[2-[4-(1-Adamantylmethoxycarbonyl)piperazin-1-yl]-2-oxo-ethyl]amino]-2-oxoethyl]-dimethyl-sulfonium bromide (1f)	IC50	775 nM
[2-[[2-[4-(Adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]amino]-2-oxo-ethyl]-dimethyl-sulfonium bromide (1e)	IC50	889 nM
1-Adamantylmethyl 4-[2-(prop-2-enoylamino)acetyl]piperazine-1-carboxylate (3f)	IC50	1620 nM

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.77	IC50	17	nM	CHEMBL5803781
6.08	IC50	840	nM	CHEMBL2086528
5.05	IC50	8900	nM	CHEMBL2152090

PubChem BioAssay actives

4 with measured affinity, of 24 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
N-[4-[4-(adamantane-1-carbonyl)piperazin-1-yl]sulfonylphenyl]prop-2-enamide	683893: Inhibition of human recombinant TG6 by fluorescent transamidation assay	ic50	0.8400	uM
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxoethyl]prop-2-enamide	1801716: TG Activity Assays from Article 10.1016/j.chembiol.2015.08.013: “Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.”	ic50	2.0000	uM
N-[2-[4-[5-(dimethylamino)naphthalen-1-yl]sulfonylpiperazin-1-yl]-2-oxoethyl]prop-2-enamide	1801716: TG Activity Assays from Article 10.1016/j.chembiol.2015.08.013: “Development of Potent and Selective Tissue Transglutaminase Inhibitors: Their Effect on TG2 Function and Application in Pathological Conditions.”	ic50	5.0000	uM
benzyl N-[4-[4-(prop-2-enoylamino)piperidin-1-yl]sulfonylphenyl]carbamate	692648: Inhibition of human TGM6	ic50	8.9000	uM

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol S	decreases methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2091166	Binding	Inhibition of human recombinant TG6 by fluorescent transamidation assay	Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington’s disease. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
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
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
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
NCT00646204	PHASE4	COMPLETED	Namenda (Memantine) for Non-motor Symptoms in Parkinson’s Disease