HSD17B10

Summary

HSD17B10 (hydroxysteroid 17-beta dehydrogenase 10, HGNC:4800) is a protein-coding gene on chromosome Xp11.22, encoding 3-hydroxyacyl-CoA dehydrogenase type-2 (Q99714). Mitochondrial dehydrogenase involved in pathways of fatty acid, branched-chain amino acid and steroid metabolism. It is a selective cancer dependency (DepMap: 46.0% of cell lines).

This gene encodes 3-hydroxyacyl-CoA dehydrogenase type II, a member of the short-chain dehydrogenase/reductase superfamily. The gene product is a mitochondrial protein that catalyzes the oxidation of a wide variety of fatty acids and steroids, and is a subunit of mitochondrial ribonuclease P, which is involved in tRNA maturation. The protein has been implicated in the development of Alzheimer disease, and mutations in the gene are the cause of 17beta-hydroxysteroid dehydrogenase type 10 (HSD10) deficiency. Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined.

Source: NCBI Gene 3028 — RefSeq curated summary.

At a glance

• Gene–disease (curated): HSD10 mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 224 total — 9 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes — 249 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 46.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004493

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4800
Approved symbol	HSD17B10
Name	hydroxysteroid 17-beta dehydrogenase 10
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Aliases	ERAB, MHBD, 17b-HSD10, ABAD, SDR5C1, MRPP2, CAMR
Ensembl gene	ENSG00000072506
Ensembl biotype	protein_coding
OMIM	300256
Entrez	3028

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000168216, ENST00000375298, ENST00000375304, ENST00000477706, ENST00000495986, ENST00000682365, ENST00000684251, ENST00000684503, ENST00000684692, ENST00000868389, ENST00000868390, ENST00000927395, ENST00000948116

RefSeq mRNA: 2 — MANE Select: NM_004493 NM_001037811, NM_004493

CCDS: CCDS14354, CCDS35300

Canonical transcript exons

ENST00000168216 — 6 exons

Exon	Start	End
ENSE00000671346	53431798	53431906
ENSE00001038851	53434319	53434370
ENSE00003520919	53432247	53432411
ENSE00003560479	53431988	53432116
ENSE00003616165	53433722	53433886
ENSE00003896917	53431261	53431594

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 98.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.1384 / max 200.6655, expressed in 1822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199348	39.7269	1821
199347	2.4278	1335
199349	0.9838	663

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.38	gold quality
liver	UBERON:0002107	97.82	gold quality
right adrenal gland	UBERON:0001233	97.61	gold quality
right adrenal gland cortex	UBERON:0035827	97.59	gold quality
left adrenal gland	UBERON:0001234	97.47	gold quality
left adrenal gland cortex	UBERON:0035825	97.40	gold quality
apex of heart	UBERON:0002098	97.23	gold quality
adult mammalian kidney	UBERON:0000082	97.17	gold quality
esophagus mucosa	UBERON:0002469	97.00	gold quality
right atrium auricular region	UBERON:0006631	96.85	gold quality
heart left ventricle	UBERON:0002084	96.80	gold quality
mucosa of transverse colon	UBERON:0004991	96.76	gold quality
adrenal gland	UBERON:0002369	96.70	gold quality
esophagus	UBERON:0001043	96.69	gold quality
lower esophagus mucosa	UBERON:0035834	96.64	gold quality
heart	UBERON:0000948	96.56	gold quality
skin of leg	UBERON:0001511	96.56	gold quality
mucosa of stomach	UBERON:0001199	96.47	gold quality
left coronary artery	UBERON:0001626	96.43	gold quality
adenohypophysis	UBERON:0002196	96.41	gold quality
popliteal artery	UBERON:0002250	96.41	gold quality
tibial artery	UBERON:0007610	96.41	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.39	gold quality
lower esophagus	UBERON:0013473	96.38	gold quality
islet of Langerhans	UBERON:0000006	96.37	gold quality
zone of skin	UBERON:0000014	96.37	gold quality
aorta	UBERON:0000947	96.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.27	gold quality
thoracic aorta	UBERON:0001515	96.22	gold quality
ascending aorta	UBERON:0001496	96.21	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	25.89
E-MTAB-7052	no	180.85
E-GEOD-125970	no	3.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB

miRNA regulators (miRDB)

12 targeting HSD17B10, 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-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-7113-5P	97.88	67.33	1735

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 46.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• tissue distribution, subcellular localization, and metabolic functions (PMID:11559359)
• Sequence analysis of the HADH2 gene from patients with MHBD deficiency revealed the presence of two missense mutations (R130C and L122V)which almost completely abolish enzyme activity (PMID:12696021)
• Comparison of substrate specificity of human and Drosophila melanogaster type 10 17b-hydroxysteroid dehydrogenases (PMID:12917011)
• Abeta interacts with ABAD in the mitochondria of Alzheimer’s disease patients and transgenic mice; data suggest that the ABAD-Abeta interaction may be a therapeutic target in Alzheimer’s disease (PMID:15087549)
• Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. (PMID:15087549)
• crystal structure of ABAD/HSD10 complexed with NAD(+) and an inhibitory small molecule (PMID:15342248)
• findings link amyloid-beta peptide (Abeta) binding alcohol dehydrogenase (ABAD)-induced oxidant stress to critical aspects of Alzheimer’s disease (AD)-associated cellular dysfunction, suggesting a pivotal role for this enzyme in the pathogenesis of AD (PMID:15665036)
• Brain astrocytes contain a moderate level of 17beta-HSD10, which is elevated in activated astrocytes of brains with Alzheimer type pathology, including sporadic Alzheimer’s disease (AD) and Down syndrome with AD. (PMID:15804423)
• Reduced expression of the HADH2 protein causes MRXS10, a phenotype different from that caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, which is a neurodegenerative disorder caused by missense mutations in this multifunctional protein. (PMID:17236142)
• These results propose an additional role of ABAD in neural cell death in AD. (PMID:17707551)
• Data suggest that thioredoxin could not only assist ABAD-inhibiting peptide expression, but rebalance the disturbed “redox equilibrium” caused by intracellular amyloid beta in PC12 cells. (PMID:17917077)
• Increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of X-Linked Mental Retardation. (PMID:18252223)
• In Alzheimer disease and schizophrenia, significant shifts to left/right asymmetry were found and the changes were associated with more marked increases in mRNA/enzyme expression in the left hemisphere (PMID:18765932)
• These findings suggest that the ERalpha estrogen receptor might be involved in regulating intracellular estrogen levels by modulating 17beta-HSD10 activity. (PMID:19422801)
• Up-rulation of HSD17B10 expression is associated with poor response to chemotherapy in conventional osteosarcomas. (PMID:19449377)
• Amyloid-beta-peptide binding to mitochondrial Abeta-binding alcohol dehydrogenase (ABAD) enzyme triggers a series of events leading to mitochondrial dysfunction characteristic of Alzheimer’s disease. (PMID:19601895)
• results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17beta) dehydrogenase 10 deficiency. (PMID:19706438)
• The data indicated pronounced increases in the 17beta-hydroxysteroid dehydrogenase type 10 levels, specifically to 179% in multiple sclerosis and to 573% in Alzheimer disease when compared to the age-matched controls. (PMID:19756307)
• This finding indicates that the symptoms in patients with mutations in the HSD17B10 gene are unrelated to accumulation of toxic metabolites in the isoleucine pathway and, rather, related to defects in general mitochondrial function. (PMID:20077426)
• HSD17B10 is regulated by several isoforms of C/EBP-beta in HepG2 cells. (PMID:20638476)
• These results suggest that the HSD17B10 gene does not escape X-inactivation as has been reported previously. (PMID:20664630)
• behavioral stress causes protein up-regulation in the brain of a mouse model of Alzheimer disease (PMID:21382475)
• analysis of clinical consequences of mutations in the HSD17B10 gene (PMID:22127393)
• The role of ABAD in amyloid beta toxicity, was investigated. (PMID:22174920)
• A 5-methylcytosine is present in both active and inactive X chromosomes at + 2259 nucleotide from the initiation ATG of the HSD17B10 gene, explaining the prevalence of the p.R130C mutation among HSD10 deficiency patients. (PMID:23266819)
• Inhibition of mitochondrial RNase P by beta-amyloid is an unspecific effect and is not mediated by beta-amyloid interaction with SDR5C1. (PMID:23755257)
• Two major HSD17B10 transcription start sites were identified by primer extension at -37 and -6 as well as a minor start site at -12 nucleotides from the initiation codon ATG. (PMID:23834306)
• Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases than in non-malignant and/or malignant prostate tissue (PMID:24244276)
• loss of HSD10 causes impaired mitochondrial precursor transcript processing which may explain mitochondrial dysfunction observed in HSD10 disease (PMID:24549042)
• Defects in this gene are a cause of 17beta-hydroxysteroid dehydrogenase type 10 (HSD10) deficiency. The encoded protein does not exhibit generalized alcohol dehydrogenase activity as was previously thought. (PMID:25007702)
• upon exposure to E2, ERalpha rapidly localizes to mitochondria, in which it interacts with HSD17B10 to modulate the expression of mitochondrial RNA transcripts. (PMID:25375021)
• The authors demonstrate elevated amounts of unprocessed pre-tRNAs and mRNA transcripts encoding mitochondrial subunits indicating deficient RNase P activity in HSD10 disease. (PMID:25575635)
• Our findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction. (PMID:25879199)
• The study showed that pathogenic mutations impair SDR5C1-dependent dehydrogenation, tRNA processing and methylation. (PMID:25925575)
• Three HSD10 variants associated with neurodegenerative disorders are inactive with cardiolipin (PMID:26338420)
• Data suggest that HSD10 plays a role in alterations of energy metabolism by regulating mtDNA content in colorectal carcinomas. (PMID:26884257)
• The S-nitrosation of a cysteine residue distal to the 3-hydroxyacyl-CoA dehydrogenase type 2 (HADH2) active site impaired catalytic activity. (PMID:27291402)
• A computational study and enzyme inhibition assay with full length human 17-beta-HSD10 identifies risperidone as enzyme inhibitor and possible antineoplastic agent. (PMID:28188816)
• Authors report two patients with novel missense mutations in the HSD17B10 gene (c.34G>C and c.526G>A), resulting in the p.V12L and p.V176M substitutions. Val12 and Val176 are highly conserved residues located at different regions of the MRPP2 structure. (PMID:28888424)
• in addition to being an essential component of the RNase P reaction, MRPP1/2 serves as a processing platform for several down-stream tRNA maturation steps in human mitochondria. (PMID:29040705)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hsd17b10	ENSDARG00000017781
mus_musculus	Hsd17b10	ENSMUSG00000025260
rattus_norvegicus	Hsd17b10	ENSRNOG00000003049
drosophila_melanogaster	scu	FBGN0021765
caenorhabditis_elegans		WBGENE00000181

Paralogs (25): HSD17B6 (ENSG00000025423), RDH11 (ENSG00000072042), DHRS9 (ENSG00000073737), HSD17B2 (ENSG00000086696), HSD17B14 (ENSG00000087076), DHRS12 (ENSG00000102796), HSDL1 (ENSG00000103160), HSD17B1 (ENSG00000108786), RDH10 (ENSG00000121039), HSD17B3 (ENSG00000130948), HSD17B7 (ENSG00000132196), HSD17B4 (ENSG00000133835), RDH5 (ENSG00000135437), RDH16 (ENSG00000139547), RDH12 (ENSG00000139988), HSD17B12 (ENSG00000149084), BDH1 (ENSG00000161267), DHRS3 (ENSG00000162496), SDR9C7 (ENSG00000170426), HSD17B13 (ENSG00000170509), SDR16C5 (ENSG00000170786), HSD11B2 (ENSG00000176387), WWOX (ENSG00000186153), HSD17B11 (ENSG00000198189), HSD17B8 (ENSG00000204228)

Protein

Protein identifiers

3-hydroxyacyl-CoA dehydrogenase type-2 — Q99714 (reviewed: Q99714)

Alternative names: 17-beta-estradiol 17-dehydrogenase, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase, 3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+)), 3-hydroxy-2-methylbutyryl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase type II, 3alpha(or 20beta)-hydroxysteroid dehydrogenase, 7-alpha-hydroxysteroid dehydrogenase, Endoplasmic reticulum-associated amyloid beta-peptide-binding protein, Mitochondrial ribonuclease P protein 2, Short chain dehydrogenase/reductase family 5C member 1, Short-chain type dehydrogenase/reductase XH98G2, Type II HADH

All UniProt accessions (4): Q99714, A0A0S2Z410, A0A804HHW5, Q5H928

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial dehydrogenase involved in pathways of fatty acid, branched-chain amino acid and steroid metabolism. Acts as (S)-3-hydroxyacyl-CoA dehydrogenase in mitochondrial fatty acid beta-oxidation, a major degradation pathway of fatty acids. Catalyzes the third step in the beta-oxidation cycle, namely the reversible conversion of (S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA. Preferentially accepts straight medium- and short-chain acyl-CoA substrates with highest efficiency for (3S)-hydroxybutanoyl-CoA. Acts as 3-hydroxy-2-methylbutyryl-CoA dehydrogenase in branched-chain amino acid catabolic pathway. Catalyzes the oxidation of 3-hydroxy-2-methylbutanoyl-CoA into 2-methyl-3-oxobutanoyl-CoA, a step in isoleucine degradation pathway. Has hydroxysteroid dehydrogenase activity toward steroid hormones and bile acids. Catalyzes the oxidation of 3alpha-, 17beta-, 20beta- and 21-hydroxysteroids and 7alpha- and 7beta-hydroxy bile acids. Oxidizes allopregnanolone/brexanolone at the 3alpha-hydroxyl group, which is known to be critical for the activation of gamma-aminobutyric acid receptors (GABAARs) chloride channel. Has phospholipase C-like activity toward cardiolipin and its oxidized species. Likely oxidizes the 2’-hydroxyl in the head group of cardiolipin to form a ketone intermediate that undergoes nucleophilic attack by water and fragments into diacylglycerol, dihydroxyacetone and orthophosphate. Has higher affinity for cardiolipin with oxidized fatty acids and may degrade these species during the oxidative stress response to protect cells from apoptosis. By interacting with intracellular amyloid-beta, it may contribute to the neuronal dysfunction associated with Alzheimer disease (AD). Essential for structural and functional integrity of mitochondria. In addition to mitochondrial dehydrogenase activity, moonlights as a component of mitochondrial ribonuclease P, a complex that cleaves tRNA molecules in their 5’-ends. Together with TRMT10C/MRPP1, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity. The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; HSD17B10/MRPP2 acting as a non-catalytic subunit. The MRPP1-MRPP2 subcomplex also acts as a tRNA maturation platform: following 5’-end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-MRPP2 subcomplex enhances the efficiency of 3’-processing catalyzed by ELAC2, retains the tRNA product after ELAC2 processing and presents the nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1 enzyme. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.

Subunit / interactions. Homotetramer. Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3. Interacts with TRMT10C/MRPP1; forming the MRPP1-MRPP2 subcomplex of the mitochondrial ribonuclease P complex.

Subcellular location. Mitochondrion. Mitochondrion matrix. Mitochondrion nucleoid.

Tissue specificity. Ubiquitously expressed in normal tissues but is overexpressed in neurons affected in AD.

Disease relevance. HSD10 mitochondrial disease (HSD10MD) [MIM:300438] An X-linked multisystemic disorder with highly variable severity. Age at onset ranges from the neonatal period to early childhood. Features include progressive neurodegeneration, psychomotor retardation, loss of mental and motor skills, seizures, cardiomyopathy, and visual and hearing impairment. Some patients manifest lactic acidosis and metabolic acidosis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The phospholipase C-like activity toward cardiolipin is inhibited by amyloid-beta peptide.

Pathway. Amino-acid degradation; L-isoleucine degradation. Lipid metabolism; fatty acid beta-oxidation. Steroid metabolism. Lipid metabolism; bile acid biosynthesis.

Similarity. Belongs to the short-chain dehydrogenases/reductases (SDR) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99714-1	1	yes
Q99714-2	2

RefSeq proteins (2): NP_001032900, NP_004484* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002347	SDR_fam	Family
IPR020904	Sc_DH/Rdtase_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00106

Enzyme classification (BRENDA):

• EC 1.1.1.135 — GDP-6-deoxy-D-talose 4-dehydrogenase (BRENDA: 4 organisms, 2 substrates, 0 inhibitors, 0 Km, 0 kcat entries)
• EC 1.1.1.178 — 3-hydroxy-2-methylbutyryl-CoA dehydrogenase (BRENDA: 5 organisms, 9 substrates, 1 inhibitors, 2 Km, 0 kcat entries)
• EC 1.1.1.35 — 3-hydroxyacyl-CoA dehydrogenase (BRENDA: 24 organisms, 99 substrates, 16 inhibitors, 84 Km, 49 kcat entries)
• EC 1.1.1.62 — 17beta-estradiol 17-dehydrogenase (BRENDA: 20 organisms, 283 substrates, 790 inhibitors, 95 Km, 44 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ACETOACETYL-COA	0.003–0.263	22
ESTRADIOL-17BETA	0.0008–0.025	14
ESTRONE	—	10
NAD+	0.0001–29.5	9
NADH	0.0009–50	9
NADP+	0.0001–9	9
(S)-3-HYDROXYBUTYRYL-COA	0.0001–43.5	7
17BETA-ESTRADIOL	0.0006–0.082	7
NADPH	0.0003–0.16	7
ESTRADIOL	0.0036–0.118	6
(R)-3-HYDROXYACYL-COA	0.0505–0.1157	4
ACETOACETYL-PANTETHEINE	0.08–1.19	4
TESTOSTERONE	0.0071–0.263	4
3-ACETOACETYL-COA	0.0096–65.6	3
DEHYDROEPIANDROSTERONE	0.0172–0.0598	3

Catalyzed reactions (Rhea), 12 shown:

• (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA + NAD(+) = 2-methyl-3-oxobutanoyl-CoA + NADH + H(+) (RHEA:13281)
• testosterone + NAD(+) = androst-4-ene-3,17-dione + NADH + H(+) (RHEA:14929)
• cholate + NAD(+) = 3alpha,12alpha-dihydroxy-7-oxo-5beta-cholanate + NADH + H(+) (RHEA:19409)
• a (3S)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH + H(+) (RHEA:22432)
• 17beta-estradiol + NAD(+) = estrone + NADH + H(+) (RHEA:24612)
• (3S)-3-hydroxybutanoyl-CoA + NAD(+) = acetoacetyl-CoA + NADH + H(+) (RHEA:30799)
• (3S)-hydroxyhexadecanoyl-CoA + NAD(+) = 3-oxohexadecanoyl-CoA + NADH + H(+) (RHEA:31159)
• (3S)-hydroxyoctanoyl-CoA + NAD(+) = 3-oxooctanoyl-CoA + NADH + H(+) (RHEA:31195)
• 3alpha-hydroxy-5alpha-pregnan-20-one + NAD(+) = 5alpha-pregnane-3,20-dione + NADH + H(+) (RHEA:41980)
• 17beta-hydroxy-5alpha-androstan-3-one + NAD(+) = 5alpha-androstan-3,17-dione + NADH + H(+) (RHEA:41992)
• 5alpha-androstane-3alpha,17beta-diol + NAD(+) = 17beta-hydroxy-5alpha-androstan-3-one + NADH + H(+) (RHEA:42004)
• 5alpha-pregnan-20beta-ol-3-one + NAD(+) = 5alpha-pregnane-3,20-dione + NADH + H(+) (RHEA:42008)

UniProt features (61 total): sequence variant 12, helix 12, binding site 11, strand 10, modified residue 8, mutagenesis site 2, turn 2, initiator methionine 1, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
2O23	X-RAY DIFFRACTION	1.2
9GCH	ELECTRON MICROSCOPY	1.9
1U7T	X-RAY DIFFRACTION	2
1SO8	X-RAY DIFFRACTION	2.3
8CBK	ELECTRON MICROSCOPY	2.76
9EY0	ELECTRON MICROSCOPY	2.78
8CBL	ELECTRON MICROSCOPY	2.79
9EY1	ELECTRON MICROSCOPY	2.9
8RR1	ELECTRON MICROSCOPY	2.93
9EY2	ELECTRON MICROSCOPY	2.96
7ONU	ELECTRON MICROSCOPY	3
8CBM	ELECTRON MICROSCOPY	3.14
8CBO	ELECTRON MICROSCOPY	3.2
8RR4	ELECTRON MICROSCOPY	3.2
8RR3	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99714-F1	96.95	0.96

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 (1): 168 (proton acceptor)

Ligand- & substrate-binding residues (11): 168; 172; 201; 203; 20; 22; 41; 64; 65; 91; 155

Post-translational modifications (8): 2, 53, 53, 69, 99, 105, 212, 212

Mutagenesis-validated functional residues (2):

Position	Phenotype
20	decreased dehydrogenase activity. does not affect mitochondrial trna 5’-end processing. does not affect trna methylation
172	abolishes dehydrogenase activity. does not affect mitochondrial trna 5’-end processing. does not affect trna methylation

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6785470	tRNA processing in the mitochondrion
R-HSA-6787450	tRNA modification in the mitochondrion
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-8868766	rRNA processing in the mitochondrion
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 362 (showing top): GOBP_LIPID_MODIFICATION, MODULE_93, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_TRNA_METABOLIC_PROCESS, GOBP_C21_STEROID_HORMONE_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, KYNG_DNA_DAMAGE_DN, MODULE_16, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_RNA_METHYLATION, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION

GO Biological Process (16): L-isoleucine catabolic process (GO:0006550), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid beta-oxidation (GO:0006635), bile acid biosynthetic process (GO:0006699), mitochondrion organization (GO:0007005), C21-steroid hormone metabolic process (GO:0008207), androgen metabolic process (GO:0008209), estrogen metabolic process (GO:0008210), protein homotetramerization (GO:0051289), brexanolone metabolic process (GO:0062173), mitochondrial tRNA methylation (GO:0070901), mitochondrial tRNA 5’-end processing (GO:0097745), mitochondrial tRNA 3’-end processing (GO:1990180), tRNA processing (GO:0008033), steroid metabolic process (GO:0008202)

GO Molecular Function (16): tRNA binding (GO:0000049), RNA binding (GO:0003723), (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity (GO:0003857), estradiol 17-beta-dehydrogenase [NAD(P)+] activity (GO:0004303), cholate 7-alpha-dehydrogenase (NAD+) activity (GO:0008709), 17-beta-hydroxysteroid dehydrogenase (NAD+) activity (GO:0044594), 3-hydroxy-2-methylbutyryl-CoA dehydrogenase activity (GO:0047015), testosterone dehydrogenase (NAD+) activity (GO:0047035), androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity (GO:0047044), chenodeoxycholate 7-alpha-dehydrogenase (NAD+) activity (GO:0106281), isoursodeoxycholate 7-beta-dehydrogenase (NAD+) activity (GO:0106282), ursodeoxycholate 7-beta-dehydrogenase (NAD+) activity (GO:0106283), cardiolipin dehydrogenase (NAD+) activity (GO:0160241), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), obsolete testosterone dehydrogenase [NAD(P)+] activity (GO:0030283)

GO Cellular Component (7): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), plasma membrane (GO:0005886), mitochondrial ribonuclease P complex (GO:0030678), mitochondrial nucleoid (GO:0042645), tRNA methyltransferase complex (GO:0043527)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
tRNA processing	2
Metabolism of amino acids and derivatives	1
rRNA processing	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
steroid dehydrogenase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	7
mitochondrion	5
steroid metabolic process	4
hormone metabolic process	3
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	3
lipid metabolic process	2
mitochondrial tRNA processing	2
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
primary metabolic process	1
monocarboxylic acid metabolic process	1
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
bile acid metabolic process	1
monocarboxylic acid biosynthetic process	1
organelle organization	1
protein homooligomerization	1
protein tetramerization	1
ketone metabolic process	1
tRNA methylation	1
mitochondrial tRNA modification	1
mitochondrial RNA 5’-end processing	1
tRNA 5’-end processing	1
mitochondrial RNA 3’-end processing	1
tRNA 3’-end processing	1
RNA processing	1
tRNA metabolic process	1
RNA binding	1
nucleic acid binding	1
17-beta-hydroxysteroid dehydrogenase (NAD+) activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
membrane	1

Protein interactions and networks

STRING

2156 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSD17B10	TRMT10C	Q7L0Y3	996
HSD17B10	PRORP	O15091	994
HSD17B10	FSIP1	Q8NA03	982
HSD17B10	HUWE1	Q7Z6Z7	964
HSD17B10	DHRS11	Q6UWP2	884
HSD17B10	HADH	Q16836	841
HSD17B10	APP	P05067	699
HSD17B10	ELAC2	Q9BQ52	610
HSD17B10	HSD17B1	P14061	608
HSD17B10	TRMT10B	Q6PF06	596
HSD17B10	TRMT10A	Q8TBZ6	596
HSD17B10	ECHS1	P30084	582
HSD17B10	HSD17B4	P51659	552
HSD17B10	HSD17B6	O14756	531
HSD17B10	ESR1	P03372	526

IntAct

157 interactions, top by confidence:

A	B	Type	Score
HSD17B10	TRMT10C	psi-mi:“MI:0407”(direct interaction)	0.880
HSD17B10	TRMT10C	psi-mi:“MI:0915”(physical association)	0.880
APP	HSD17B10	psi-mi:“MI:0915”(physical association)	0.750
HSD17B10	APP	psi-mi:“MI:0915”(physical association)	0.750
HSD17B10	PRORP	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSD17B10		psi-mi:“MI:0915”(physical association)	0.670
HSD17B10		psi-mi:“MI:0213”(methylation reaction)	0.670
HSD17B10		psi-mi:“MI:0902”(rna cleavage)	0.670
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
	TRMT10C	psi-mi:“MI:0915”(physical association)	0.540
DLD	PDHB	psi-mi:“MI:0914”(association)	0.530
HSD17B10	SSB	psi-mi:“MI:0914”(association)	0.530

BioGRID (648): HSD17B10 (Affinity Capture-MS), HSD17B10 (Affinity Capture-MS), HSD17B10 (Affinity Capture-MS), HSD17B10 (Affinity Capture-MS), IGHG2 (Affinity Capture-MS), IGHG1 (Affinity Capture-MS), ACAA2 (Co-fractionation), ACTR3 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B15 (Co-fractionation), ALDOA (Co-fractionation), ALDOC (Co-fractionation), ARFGAP2 (Co-fractionation), ARFGAP3 (Co-fractionation), ARHGDIA (Co-fractionation)

ESM2 similar proteins: A0A067FT93, A0A0B4FP77, A0A0B4GT47, A0A0B4GU97, A0A0B4HVU2, A0A165U5V5, A0A1V0QSC6, A0A2H3D8Y2, A0A384JQF5, A0A3G9HAL8, A0A3Q8GL18, A0A3Q8GLE8, A0A3Q8GYY4, A0A411PQN6, A0A5B8YU81, A0A8F5SIS3, A0A8F5XX49, A3F5F0, A3LZU7, B0ZT44, E9EHG1, E9ET40, F1SWA0, F4J300, F9XMW6, G4N1P8, H9BFQ0, H9BFQ1, K4N0V2, L7I518, O08756, O80713, O80714, O93868, P0DXH3, P66775, P66776, P99120, P9WES5, Q14RS1

Diamond homologs: A0A023I4C8, A0A067FT93, A0A084R1K1, A0A097ZPC9, A0A0U5GHD4, A0A165U5V5, A0A1U8QGV2, A0A1U8QWA2, A0A2I1C3T5, A0A2U8U2K8, A0A3Q8GYY4, A0A455R5K2, A0A8F5SIS3, A3F5F0, B6H061, B6H065, B8H1Z0, F4J2Z7, F4J300, G4N1P8, H9BFQ0, H9BFQ1, I6Y778, I6YCF0, K4N0V2, L7I518, O02691, O08756, O31680, O70351, O80713, O80714, P0A2D1, P0A2D2, P0CG22, P0CU75, P0DXH3, P15428, P16542, P16544

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKN	“down-regulates quantity by destabilization”	HSD17B10	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 156 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SHC-mediated cascade:FGFR1	5	22.2×	2e-04
FRS-mediated FGFR1 signaling	5	20.4×	2e-04
FCERI mediated MAPK activation	6	18.5×	1e-04
DAP12 signaling	5	16.4×	4e-04
FLT3 Signaling	5	15.4×	4e-04
Signaling by FGFR1 in disease	5	13.1×	7e-04
NCAM signaling for neurite out-growth	5	12.1×	1e-03
SARS-CoV-1 Infection	6	7.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	6	16.4×	7e-04
autophagosome maturation	5	13.4×	8e-03
Ras protein signal transduction	6	9.4×	8e-03
mRNA processing	9	5.4×	8e-03
DNA damage response	11	4.5×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	9
Uncertain significance	68
Likely benign	95
Benign	5

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
11442	NM_004493.3(HSD17B10):c.388C>T (p.Arg130Cys)	Pathogenic
11444	NM_004493.3(HSD17B10):c.740A>G (p.Asn247Ser)	Pathogenic
11445	NM_004493.3(HSD17B10):c.574C>A (p.Arg192=)	Pathogenic
144033	NM_004493.3(HSD17B10):c.257A>G (p.Asp86Gly)	Pathogenic
145974	GRCh38/hg38 Xp21.1-q28(chrX:37076284-156016920)x1	Pathogenic
1703582	Single allele	Pathogenic
2684984	GRCh37/hg19 Xp11.22(chrX:53372729-53797237)x3	Pathogenic
3780972	NM_004493.3(HSD17B10):c.551G>A (p.Arg184Gln)	Pathogenic
4724828	NM_004493.3(HSD17B10):c.334del (p.Glu112fs)	Pathogenic
1028768	NM_004493.3(HSD17B10):c.85C>G (p.Arg29Gly)	Likely pathogenic
1802990	NM_004493.3(HSD17B10):c.628C>G (p.Pro210Ala)	Likely pathogenic
2502293	NM_004493.3(HSD17B10):c.706C>T (p.Leu236Phe)	Likely pathogenic
254239	NM_004493.3(HSD17B10):c.592C>A (p.Pro198Thr)	Likely pathogenic
2636224	NM_004493.3(HSD17B10):c.380A>G (p.Asn127Ser)	Likely pathogenic
3339520	NM_004493.3(HSD17B10):c.59C>T (p.Ser20Leu)	Likely pathogenic
813313	NM_004493.3(HSD17B10):c.517G>C (p.Gly173Arg)	Likely pathogenic
973446	NM_004493.3(HSD17B10):c.753C>G (p.Ile251Met)	Likely pathogenic
996911	NM_004493.3(HSD17B10):c.164G>A (p.Gly55Glu)	Likely pathogenic

SpliceAI

854 predictions. Top by Δscore:

Variant	Effect	Δscore
X:53431972:ACC:A	donor_gain	1.0000
X:53431973:CCC:C	donor_gain	1.0000
X:53431983:CACA:C	donor_loss	1.0000
X:53432009:A:AC	donor_gain	1.0000
X:53432010:C:CC	donor_gain	1.0000
X:53432043:C:A	donor_gain	1.0000
X:53432112:TTCAC:T	acceptor_gain	1.0000
X:53432113:TCAC:T	acceptor_gain	1.0000
X:53432114:CAC:C	acceptor_gain	1.0000
X:53432114:CACC:C	acceptor_gain	1.0000
X:53432115:AC:A	acceptor_gain	1.0000
X:53432116:CC:C	acceptor_gain	1.0000
X:53432117:C:CC	acceptor_gain	1.0000
X:53432118:T:A	acceptor_loss	1.0000
X:53432234:T:TA	donor_gain	1.0000
X:53432245:A:AC	donor_gain	1.0000
X:53432246:C:CA	donor_gain	1.0000
X:53432246:CA:C	donor_gain	1.0000
X:53432246:CAT:C	donor_gain	1.0000
X:53432269:T:TA	donor_gain	1.0000
X:53432409:CACCT:C	acceptor_loss	1.0000
X:53432410:ACC:A	acceptor_loss	1.0000
X:53432412:C:CC	acceptor_gain	1.0000
X:53432412:C:CG	acceptor_loss	1.0000
X:53432415:C:CT	acceptor_gain	1.0000
X:53432416:A:T	acceptor_gain	1.0000
X:53433720:A:AC	donor_gain	1.0000
X:53433721:C:CC	donor_gain	1.0000
X:53433721:CGT:C	donor_gain	1.0000
X:53432119:G:GC	acceptor_gain	0.9900

AlphaMissense

1668 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:53432009:A:C	S155R	0.997
X:53432009:A:T	S155R	0.997
X:53432011:T:G	S155R	0.997
X:53432331:A:C	C91W	0.992
X:53431881:G:A	S171F	0.991
X:53432334:G:C	N90K	0.991
X:53432334:G:T	N90K	0.991
X:53431881:G:T	S171Y	0.990
X:53432010:C:A	S155I	0.990
X:53431842:C:G	R184P	0.988
X:53431891:A:G	Y168H	0.987
X:53432014:C:G	A154P	0.987
X:53431877:C:A	K172N	0.986
X:53431877:C:G	K172N	0.986
X:53431884:G:T	A170D	0.986
X:53433870:A:T	I15K	0.984
X:53431845:G:T	A183D	0.983
X:53432018:G:C	N152K	0.983
X:53432018:G:T	N152K	0.983
X:53432111:A:C	N121K	0.983
X:53432111:A:T	N121K	0.983
X:53431806:A:T	I196N	0.982
X:53431836:A:G	L186P	0.982
X:53432010:C:T	S155N	0.982
X:53432338:A:T	V89D	0.982
X:53431427:C:A	G255W	0.981
X:53431449:A:C	N247K	0.981
X:53431449:A:T	N247K	0.981
X:53432085:C:G	R130P	0.981
X:53431803:G:T	A197D	0.980

dbSNP variants (sampled 300 via entrez): RS1002401694 (X:53431199 G>A,T), RS1003074276 (X:53436284 T>C), RS1003193515 (X:53434433 A>G), RS1007318996 (X:53433038 C>T), RS1009827132 (X:53432186 G>C), RS1010778997 (X:53434460 A>C,G,T), RS1010814064 (X:53434744 G>A), RS1013687010 (X:53431060 A>G), RS1015902236 (X:53433055 G>A), RS1016059280 (X:53433505 A>T), RS1018396609 (X:53435637 C>T), RS1025664760 (X:53435757 C>T), RS1029514059 (X:53434863 A>G), RS1033582959 (X:53434121 T>C), RS1035924732 (X:53436363 C>T)

Disease associations

OMIM: gene MIM:300256 | disease phenotypes: MIM:300220, MIM:300438, MIM:309530, MIM:300590

GenCC curated gene-disease

Disease	Classification	Inheritance
HSD10 mitochondrial disease	Definitive	X-linked
HSD10 disease, infantile type	Supportive	X-linked
HSD10 disease, neonatal type	Supportive	X-linked
syndromic X-linked intellectual disability type 10	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
HSD10 mitochondrial disease	Definitive	XL

Mondo (7): HSD10 mitochondrial disease (MONDO:0010327), intellectual disability, X-linked 1 (MONDO:0010656), Turner syndrome (MONDO:0019499), Cornelia de Lange syndrome 2 (MONDO:0010370), HSD10 disease, infantile type (MONDO:0018322), HSD10 disease, neonatal type (MONDO:0018323), (MONDO:0010272)

Orphanet (6): HSD10 disease (Orphanet:391417), HSD10 disease, atypical type (Orphanet:85295), X-linked non-syndromic intellectual disability (Orphanet:777), Turner syndrome (Orphanet:881), Cornelia de Lange syndrome (Orphanet:199), Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome (Orphanet:397933)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000546	Retinal degeneration
HP:0000572	Visual loss
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000711	Restlessness
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000749	Paroxysmal bursts of laughter
HP:0000750	Delayed speech and language development
HP:0000961	Cyanosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0001266	Choreoathetosis
HP:0001285	Spastic tetraparesis
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001392	Abnormality of the liver
HP:0001423	X-linked dominant inheritance

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004904_11	Body mass index	3.000000e-08
GCST008103_88	Bipolar disorder	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D014424	Turner Syndrome	C12.050.351.875.253.309.872; C12.050.351.875.253.795.750; C12.200.706.316.309.872; C12.200.706.316.795.750; C12.800.316.309.872; C12.800.316.795.750; C14.240.400.980; C14.280.400.980; C16.131.240.400.970; C16.131.260.830.835.750; C16.131.939.316.309.872; C16.131.939.316.795.750; C16.320.180.830.835.750; C19.391.119.309.872; C19.391.119.795.750
C567906	Mental Retardation, X-Linked 1 (supp.)
C564489	Mental Retardation, X-Linked 78 (supp.)
C564560	Mental Retardation, X-Linked, Syndromic 10 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4159 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

249 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 493,234 (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
CHEMBL1009	LEVODOPA	4	103,854
CHEMBL101	PHENYLBUTAZONE	4	59,455
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL1018	DIENESTROL	4	5,607
CHEMBL1042	CHOLECALCIFEROL	4	64,162
CHEMBL1072	BUMETANIDE	4	22,087
CHEMBL1082607	SALMETEROL XINAFOATE	4	15,201
CHEMBL1109	SULFAPHENAZOLE	4	4,065
CHEMBL1116	RALOXIFENE HYDROCHLORIDE	4	28,574
CHEMBL1123	DICYCLOMINE	4	8,691
CHEMBL11359	CISPLATIN	4
CHEMBL117785	TETRABENAZINE	4	9,645
CHEMBL1190	DECAMETHONIUM	4	1,139
CHEMBL1200323	LABETALOL HYDROCHLORIDE	4	2,621
CHEMBL1200406	DIMENHYDRINATE	4	26,424
CHEMBL1200467	HYDROXYZINE PAMOATE	4	7,357
CHEMBL1200468	MALATHION	4	36,800
CHEMBL1200471	PYRITHIONE ZINC	4	24,834
CHEMBL1200522	AVOBENZONE	4	34,067
CHEMBL1200530	CEFOXITIN SODIUM	4
CHEMBL1200585	OXYMETHOLONE	4
CHEMBL1200618	FEXOFENADINE HYDROCHLORIDE	4
CHEMBL1200621	GEMIFLOXACIN MESYLATE	4
CHEMBL1200758	AMPICILLIN SODIUM	4
CHEMBL1200761	CHLOROTRIANISENE	4
CHEMBL1200798	TRAZODONE HYDROCHLORIDE	4
CHEMBL1200970	ETHOPROPAZINE HYDROCHLORIDE	4
CHEMBL1201022	PHENAZOPYRIDINE HYDROCHLORIDE	4
CHEMBL1201038	ACRISORCIN	4

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

Binding affinities (BindingDB)

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

Ligand	Measure	Value	Patent
methyl 5-[(R)-diethoxyphosphoryl-[(6-methoxy-1,3-benzothiazol-2-yl)amino]methyl]-2-hydroxybenzoate	KD	256 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
2-[(R)-dimethoxyphosphoryl-[(6-methoxy-1,3-benzothiazol-2-yl)amino]methyl]phenol	KD	264 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
N-[(R)-dimethoxyphosphoryl-(4-fluorophenyl)methyl]-6-methoxy-1,3-benzothiazol-2-amine	KD	264 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
4-[(R)-dimethoxyphosphoryl-[(6-methoxy-1,3-benzothiazol-2-yl)amino]methyl]phenol	KD	291 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
N-[(R)-dimethoxyphosphoryl(1H-pyrrol-2-yl)methyl]-6-methoxy-1,3-benzothiazol-2-amine	KD	380 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
methyl 5-[(R)-dimethoxyphosphoryl-[(6-methoxy-1,3-benzothiazol-2-yl)amino]methyl]-2-hydroxybenzoate	KD	496 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
methyl 5-[(R)-dimethoxyphosphoryl-[(5-fluoro-1,3-benzothiazol-2-yl)amino]methyl]-2-hydroxybenzoate	KD	954 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
N-[(R)-dimethoxyphosphoryl(thiophen-2-yl)methyl]-6-methoxy-1,3-benzothiazol-2-amine	KI	34000 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease
methyl 5-[(R)-diethoxyphosphoryl-[(5-methoxy-1,3-benzothiazol-2-yl)amino]methyl]-2-hydroxybenzoate	KI	44900 nM	US-9346839: Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer’s disease

ChEMBL bioactivities

4020 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.89	Potency	1.3	nM	ESTRONE
8.70	Potency	2	nM	CHEMBL1334965
8.40	Potency	4	nM	GABAZINE
8.40	Potency	4	nM	CHEMBL1484751
8.30	Potency	5	nM	CHEMBL1591294
8.30	Potency	5	nM	DIZOCILPINE
8.20	Potency	6.3	nM	CHEMBL1415499
8.20	Potency	6.3	nM	CHEMBL1340479
8.20	Potency	6.3	nM	CHEMBL1527946
8.20	Potency	6.3	nM	CHEMBL1377070
8.20	Potency	6.3	nM	CHEMBL1342226
8.20	Potency	6.3	nM	CHEMBL1466656
8.20	Potency	6.3	nM	CHEMBL1531663
8.20	Potency	6.3	nM	TRIMETHOPRIM
8.00	Potency	10	nM	CHEMBL1517382
8.00	Potency	10	nM	CHEMBL1518120
8.00	Potency	10	nM	CHEMBL1389951
7.90	Potency	12.6	nM	LEVISOPRENALINE
7.90	Potency	12.6	nM	CHEMBL1498297
7.90	Potency	12.6	nM	CHEMBL1505677
7.80	Potency	15.8	nM	CHEMBL1397044
7.80	Potency	15.8	nM	CHEMBL1375429
7.70	Potency	20	nM	APOMORPHINE
7.70	Potency	20	nM	CHEMBL1606283
7.70	Potency	20	nM	CHEMBL1559351
7.60	Potency	25.1	nM	CHEMBL1328320
7.60	Potency	25.1	nM	CHEMBL1407145
7.60	Potency	25.1	nM	CHEMBL1415504
7.60	Potency	25.1	nM	E927A
7.60	Potency	25.1	nM	LEVISOPRENALINE
7.60	Potency	25.1	nM	CHEMBL1604374
7.60	Potency	25.1	nM	CHEMBL1364723
7.60	Potency	25.1	nM	CHEMBL1417308
7.60	Potency	25.1	nM	CHEMBL1315100
7.60	Potency	25.1	nM	CHEMBL1303974
7.50	Potency	31.6	nM	CHEMBL277127
7.50	Potency	31.6	nM	CHEMBL1331252
7.50	Potency	31.6	nM	CHEMBL1359152
7.50	Potency	31.6	nM	CHEMBL1470485
7.50	Potency	31.6	nM	CHEMBL1525273
7.50	Potency	31.6	nM	CHEMBL1521483
7.50	Potency	31.6	nM	CHEMBL1542929
7.50	Potency	31.6	nM	CHEMBL1352687
7.50	Potency	31.6	nM	CHEMBL1459530
7.50	Potency	31.6	nM	CHEMBL1534369
7.50	Potency	31.6	nM	CHEMBL1455912
7.50	Potency	31.6	nM	CLORGILINE
7.50	Potency	31.6	nM	CHEMBL1317244
7.50	Potency	31.6	nM	CHEMBL1422370
7.50	Potency	31.6	nM	CHEMBL1574297

PubChem BioAssay actives

39 with measured affinity, of 194 total; 24 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148542: Binding affinity to human HSD17B10 incubated for 45 mins by Kinobead based pull down assay	kd	0.0508	uM
1-(3-chloro-4-hydroxyphenyl)-3-[6-(2H-tetrazol-5-yl)-1,3-benzothiazol-2-yl]urea	2038651: Inhibition of recombinant 17beta-HSD10 (unknown origin) using ALLOP as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	0.0950	uM
2-[(3-chloro-4-hydroxyphenyl)carbamoylamino]-1,3-benzothiazole-6-carboxylic acid	2133564: Inhibition of recombinant 17beta-HSD10 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as residual activity using acetoacetyl-CoA as substrate by SAAC method	ki	0.2300	uM
N-[2-[(3-chloro-4-hydroxyphenyl)carbamoylamino]-1,3-benzothiazol-6-yl]acetamide	2133564: Inhibition of recombinant 17beta-HSD10 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as residual activity using acetoacetyl-CoA as substrate by SAAC method	ki	0.2500	uM
2-[[4-hydroxy-3-(trifluoromethyl)phenyl]carbamoylamino]-1,3-benzothiazole-6-carboxylic acid	2038651: Inhibition of recombinant 17beta-HSD10 (unknown origin) using ALLOP as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	0.2500	uM
1-[6-(carbamoylamino)-1,3-benzothiazol-2-yl]-3-(3-chloro-4-hydroxyphenyl)urea	2038652: Mixed type inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	0.2700	uM
1-(3-chloro-4-hydroxyphenyl)-3-[6-(methanesulfonamido)-1,3-benzothiazol-2-yl]urea	2038651: Inhibition of recombinant 17beta-HSD10 (unknown origin) using ALLOP as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	0.2900	uM
1-[4-hydroxy-3-(trifluoromethyl)phenyl]-3-(6-methoxy-1,3-benzothiazol-2-yl)urea	2133564: Inhibition of recombinant 17beta-HSD10 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as residual activity using acetoacetyl-CoA as substrate by SAAC method	ki	0.4400	uM
2-[(3-chloro-4-hydroxyphenyl)carbamoylamino]-1,3-benzothiazole-6-carboxamide	2133564: Inhibition of recombinant 17beta-HSD10 (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as residual activity using acetoacetyl-CoA as substrate by SAAC method	ki	0.6500	uM
1-(3-chloro-4-hydroxyphenyl)-3-(6-sulfamoyl-1,3-benzothiazol-2-yl)urea	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	0.7800	uM
1-(3-chloro-4-hydroxyphenyl)-3-(6-methylsulfonyl-1,3-benzothiazol-2-yl)urea	2133557: Inhibition of human recombinant 17beta-HSD10 expressed in bacterial expression system assessed as decrease in NADH using acetoacetyl-CoA as substrate	ic50	0.9000	uM
N-[2-[2-(3-chloro-4-hydroxyphenyl)ethylamino]-1,3-benzothiazol-6-yl]acetamide	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	0.9300	uM
2-[2-(3-chloro-4-hydroxyphenyl)ethylamino]-1,3-benzothiazole-6-carboxylic acid	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	1.0100	uM
1-(3-chloro-4-hydroxyphenyl)-3-(6-hydroxy-1,3-benzothiazol-2-yl)urea	2133557: Inhibition of human recombinant 17beta-HSD10 expressed in bacterial expression system assessed as decrease in NADH using acetoacetyl-CoA as substrate	ic50	1.2000	uM
1-(3-bromo-4-hydroxyphenyl)-3-(6-methoxy-1,3-benzothiazol-2-yl)urea	2133557: Inhibition of human recombinant 17beta-HSD10 expressed in bacterial expression system assessed as decrease in NADH using acetoacetyl-CoA as substrate	ic50	1.3000	uM
2-[(3-chloro-4-hydroxybenzoyl)amino]-1,3-benzothiazole-6-carboxylic acid	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	1.3400	uM
N-[2-[acetyl-[2-(3-chloro-4-hydroxyphenyl)ethyl]amino]-1,3-benzothiazol-6-yl]acetamide	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	1.3800	uM
1-(3-chloro-4-hydroxyphenyl)-3-(6-ethoxy-1,3-benzothiazol-2-yl)urea	2133557: Inhibition of human recombinant 17beta-HSD10 expressed in bacterial expression system assessed as decrease in NADH using acetoacetyl-CoA as substrate	ic50	1.6000	uM
1-(6-amino-1,3-benzothiazol-2-yl)-3-(3-chloro-4-hydroxyphenyl)urea	2133557: Inhibition of human recombinant 17beta-HSD10 expressed in bacterial expression system assessed as decrease in NADH using acetoacetyl-CoA as substrate	ic50	1.6000	uM
N-[2-[[4-hydroxy-3-(trifluoromethyl)phenyl]methylamino]-1,3-benzothiazol-6-yl]acetamide	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	1.6900	uM
2-[(3-chloro-4-hydroxyphenyl)carbamoylamino]-1,3-benzothiazole-5-carboxylic acid	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	1.9800	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178586: Inhibition of HSD17B10 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	2.0800	uM
N-[2-[(3-chloro-4-hydroxyphenyl)methylamino]-1,3-benzothiazol-6-yl]acetamide	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	2.3800	uM
2-[(3-chloro-4-hydroxyphenyl)methylamino]-1,3-benzothiazole-6-carboxylic acid	2038650: Inhibition of recombinant 17beta-HSD10 (unknown origin) using E2 as substrate and NAD+ as cofactor preincubated for 5 mins followed by substrate addition and measured after 20 mins by fluorometric assay	ic50	6.5600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	5
sodium arsenite	decreases expression, increases abundance, increases expression	4
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Arsenic	increases methylation, increases abundance, increases expression	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment	1
cholest-5-en-3 beta,7 alpha-diol	affects binding, affects cotreatment	1
diethyl maleate	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	increases expression	1
20-hydroxycholesterol	affects binding, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
tanespimycin	decreases expression, affects cotreatment	1
K 7174	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide	decreases expression	1
STA 9090	decreases expression	1
dibutyldi(4-chlorobenzohydroxamato)tin(IV)	decreases expression	1
bisphenol S	increases expression	1
VER 155008	affects cotreatment, decreases expression	1
LDN 193189	increases expression, affects cotreatment	1
bisphenol AF	increases expression	1

ChEMBL screening assays

41 unique, capped per target: 39 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613910	Functional	PUBCHEM_BIOASSAY: qHTS Assay for Inhibitors of HSD17B4, hydroxysteroid (17-beta) dehydrogenase 4. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL3826271	Binding	Inhibition of recombinant ABAD (unknown origin) assessed as remaining activity at 25 uM using acetoacetyl-CoA as substrate in presence of NADH by spectrophotometry	Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1N7	Abcam K-562 HSD17B10 KO	Cancer cell line	Female
CVCL_D2JS	Abcam Raji HSD17B10 KO	Cancer cell line	Male
CVCL_UQ73	Abcam Jurkat HSD17B10 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00134745	PHASE4	COMPLETED	Defining the Optimal Hormonal Replacement Therapy in Turner Syndrome
NCT00256126	PHASE4	COMPLETED	Predictive Markers in Growth Hormone Deficiency (GHD) and Turner Syndrome (TS) Children Treated With SAIZEN®
NCT00266656	PHASE4	COMPLETED	Long-Term Growth and Skeletal Effects of Early Growth Hormone Treatment in Turner Syndrome
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01245374	PHASE4	COMPLETED	Norditropin NordiFlex® Device Compared to the Device Previously Used by Patients or Parents
NCT01419249	PHASE4	COMPLETED	First Year Growth Response Associated Genetic Markers Validation Phase IV Open-label Study in Growth Hormone Deficient and Turner Syndrome Pre-pubertal Children: the PREDICT Pharmacogenetics Validation Study
NCT01518062	PHASE4	COMPLETED	Safety of Somatropin and Induction of Puberty With 17-beta-oestradiol in Girls With Turner Syndrome
NCT01734486	PHASE4	COMPLETED	Growth Response in Girls With Turner Syndrome
NCT03015909	PHASE4	COMPLETED	Evaluation of the Ease of Use, Preference, and Safety of EutropinPen Inj.
NCT06544473	PHASE4	RECRUITING	Determining Dose Equivalence Between Oral and Transdermal Estrogen Treatment in Women With Turner Syndrome
NCT06570460	PHASE4	RECRUITING	Long Term Effects of Oral Versus Transdermal Estrogen Replacement Therapy in Turner Syndrome
NCT06834594	PHASE4	RECRUITING	Bleeding Patterns in Sequential and Continuous Progesterone Supplementation in Adolescents With Turner Syndrome
NCT00029159	PHASE3	COMPLETED	The Effect of Androgen and Growth Hormone on Height and Learning in Girls With Turner Syndrome
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00191113	PHASE3	COMPLETED	Somatropin Treatment to Final Height in Turner Syndrome
NCT00234533	PHASE3	COMPLETED	Study to Define Optimal IGF-1 Monitoring in Children Treated With NutropinAq
NCT00406926	PHASE3	COMPLETED	The Effect of Growth Hormone in Very Young Girls With Turner Syndrome
NCT01518036	PHASE3	COMPLETED	Use of Somatropin in Turner Syndrome
NCT01563926	PHASE3	COMPLETED	Evaluating Acceptance of New Liquid Somatropin Formulation in Children With Growth Hormone Deficiency
NCT01710696	PHASE3	COMPLETED	Induction of Puberty With 17-beta Estradiol in Girls With Turner Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT07221851	PHASE3	RECRUITING	Trial Investigating the Efficacy and Safety of Weekly Lonapegsomatropin Compared to Daily Somatropin in Children and Adolescents With Short Stature or Growth Failure Due to Growth Hormone Sufficient Disorders
NCT07614152	PHASE3	NOT_YET_RECRUITING	The Efficacy and Safety of Inpegsomatropin Injection in Children With Turner Syndrome(TS) and Short Stature
NCT00001221	PHASE2	COMPLETED	Effect of Biosynthetic Growth Hormone and/or Ethinyl Estradiol on Adult Height in Patients With Turner Syndrome
NCT00001253	PHASE2	COMPLETED	The Effects of Estrogen on Cognition in Girls With Turner Syndrome
NCT03189160	PHASE2	UNKNOWN	A Study of PEG-somatropin Injection to Treat Children of Turner Syndrome
NCT05690386	PHASE2	ACTIVE_NOT_RECRUITING	A Trial to Investigate Different Doses of Lonapegsomatropin Compared to Somatropin in Individuals With Turner Syndrome
NCT05838885	PHASE2	COMPLETED	A Trial of YPEG-rhGH in Children With Short Stature
NCT05849389	PHASE2	RECRUITING	Vosoritide for Short Stature in Turner Syndrome
NCT07041814	PHASE2	NOT_YET_RECRUITING	A Study Comparing Different Treatment Approaches for the Initiation of Puberty in Girls With Turner Syndrome Using a TRIFECTA-DARED Approach for Rare Diseases
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
NCT00097526	Not specified	COMPLETED	Bone Mineral Density (BMD) in Adolescents With Growth Hormone Deficiency (GHD)
NCT00097552	Not specified	COMPLETED	A Study to Evaluate Subjects With Turner Syndrome Treated With Growth Hormone
NCT00121875	Not specified	TERMINATED	Study to Identify Markers of Insulin Resistance During Growth Hormone Treatment for Short Stature
NCT00419107	Not specified	TERMINATED	Beta Cell Function in Women With Turner Syndrome
NCT00420654	Not specified	COMPLETED	Growth Hormone Treatment of Women With Turner Syndrome
NCT00443144	Not specified	COMPLETED	D3-GHR Polymorphism and Turner Syndrome
NCT00471731	Not specified	COMPLETED	Dry Eye in Women With Turner Syndrome and Women With Premature Ovarian Failure
NCT00624949	Not specified	UNKNOWN	Aortic Dimensions in Turner Syndrome
NCT00625001	Not specified	UNKNOWN	Long Term Follow-up of Bone Mineral Density in Hormone Treated Turner Syndrome