THEM5

Summary

THEM5 (thioesterase superfamily member 5, HGNC:26755) is a protein-coding gene on chromosome 1q21.3, encoding Acyl-coenzyme A thioesterase THEM5 (Q8N1Q8). Has acyl-CoA thioesterase activity towards long-chain (C16 and C18) fatty acyl-CoA substrates, with a preference for linoleoyl-CoA and other unsaturated long-chain fatty acid-CoA esters.

Enables long-chain fatty acyl-CoA hydrolase activity. Involved in long-chain fatty-acyl-CoA metabolic process. Located in mitochondrial matrix.

Source: NCBI Gene 284486 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 17 total
• MANE Select transcript: NM_182578

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26755
Approved symbol	THEM5
Name	thioesterase superfamily member 5
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ37964
Ensembl gene	ENSG00000196407
Ensembl biotype	protein_coding
OMIM	615653
Entrez	284486

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000368817, ENST00000453881

RefSeq mRNA: 1 — MANE Select: NM_182578 NM_182578

CCDS: CCDS1005

Canonical transcript exons

ENST00000368817 — 6 exons

Exon	Start	End
ENSE00001072373	151848182	151848292
ENSE00001072388	151847738	151847862
ENSE00001072397	151852258	151852459
ENSE00001072416	151851053	151851191
ENSE00001448019	151853443	151853712
ENSE00001657045	151847101	151847414

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 96.42.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4038 / max 162.1047, expressed in 40 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14471	0.3531	36
14469	0.0360	10
14470	0.0147	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	96.42	gold quality
zone of skin	UBERON:0000014	96.36	gold quality
skin of abdomen	UBERON:0001416	96.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.14	gold quality
lower esophagus mucosa	UBERON:0035834	76.16	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	75.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.89	gold quality
prefrontal cortex	UBERON:0000451	74.84	gold quality
pituitary gland	UBERON:0000007	74.52	gold quality
frontal cortex	UBERON:0001870	74.36	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.89	gold quality
right frontal lobe	UBERON:0002810	73.76	gold quality
esophagus mucosa	UBERON:0002469	73.53	gold quality
right lobe of liver	UBERON:0001114	73.46	gold quality
lymph node	UBERON:0000029	73.30	gold quality
leukocyte	CL:0000738	73.22	gold quality
cerebral cortex	UBERON:0000956	73.22	gold quality
monocyte	CL:0000576	73.10	gold quality
superior frontal gyrus	UBERON:0002661	73.10	gold quality
primary visual cortex	UBERON:0002436	72.41	gold quality
adenohypophysis	UBERON:0002196	72.06	gold quality
anterior cingulate cortex	UBERON:0009835	71.97	gold quality
granulocyte	CL:0000094	71.95	gold quality
minor salivary gland	UBERON:0001830	71.10	gold quality
Ammon’s horn	UBERON:0001954	71.06	gold quality
amygdala	UBERON:0001876	71.00	gold quality
temporal lobe	UBERON:0001871	70.97	gold quality
blood	UBERON:0000178	70.80	gold quality
gall bladder	UBERON:0002110	70.72	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting THEM5, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-3672	94.46	65.67	646

Literature-anchored findings (GeneRIF, showing 1)

• In vitro, Them5 shows strong thioesterase activity with long-chain acyl-CoAs. Loss of Them5 specifically alters the remodeling process of the mitochondrial phospholipid cardiolipin. (PMID:22586271)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Them5	ENSMUSG00000028148
rattus_norvegicus	Them5	ENSRNOG00000043445

Paralogs (1): THEM4 (ENSG00000159445)

Protein

Protein identifiers

Acyl-coenzyme A thioesterase THEM5 — Q8N1Q8 (reviewed: Q8N1Q8)

Alternative names: Acyl-coenzyme A thioesterase 15, Thioesterase superfamily member 5

All UniProt accessions (2): Q8N1Q8, H0Y6P4

UniProt curated annotations — full annotation on UniProt →

Function. Has acyl-CoA thioesterase activity towards long-chain (C16 and C18) fatty acyl-CoA substrates, with a preference for linoleoyl-CoA and other unsaturated long-chain fatty acid-CoA esters. Plays an important role in mitochondrial fatty acid metabolism, and in remodeling of the mitochondrial lipid cardiolipin. Required for normal mitochondrial function.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Similarity. Belongs to the THEM4/THEM5 thioesterase family.

RefSeq proteins (1): NP_872384* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006683	Thioestr_dom	Domain
IPR029069	HotDog_dom_sf	Homologous_superfamily

Pfam: PF03061

Catalyzed reactions (Rhea), 7 shown:

• hexadecanoyl-CoA + H2O = hexadecanoate + CoA + H(+) (RHEA:16645)
• octadecanoyl-CoA + H2O = octadecanoate + CoA + H(+) (RHEA:30139)
• tetradecanoyl-CoA + H2O = tetradecanoate + CoA + H(+) (RHEA:40119)
• (9Z)-hexadecenoyl-CoA + H2O = (9Z)-hexadecenoate + CoA + H(+) (RHEA:40131)
• (9Z)-octadecenoyl-CoA + H2O = (9Z)-octadecenoate + CoA + H(+) (RHEA:40139)
• (9Z,12Z)-octadecadienoyl-CoA + H2O = (9Z,12Z)-octadecadienoate + CoA + H(+) (RHEA:40143)
• (5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA + H2O = (5Z,8Z,11Z,14Z)-eicosatetraenoate + CoA + H(+) (RHEA:40151)

UniProt features (22 total): strand 8, helix 4, sequence variant 3, mutagenesis site 3, turn 2, chain 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4AE7	X-RAY DIFFRACTION	1.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N1Q8-F1	83.90	0.65

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): 167 (proton donor/acceptor)

Mutagenesis-validated functional residues (3):

Position	Phenotype
160	strongly reduces enzyme activity. abolishes enzyme activity; when associated with a-183.
167	abolishes enzyme activity.
183	reduces enzyme activity. abolishes enzyme activity; when associated with a-160.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-77289	Mitochondrial Fatty Acid Beta-Oxidation
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8978868	Fatty acid metabolism

MSigDB gene sets: 64 (showing top): GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, DARWICHE_PAPILLOMA_PROGRESSION_RISK, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_FATTY_ACYL_COA_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, REACTOME_MITOCHONDRIAL_FATTY_ACID_BETA_OXIDATION, GOBP_PURINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_FATTY_ACID_DERIVATIVE_METABOLIC_PROCESS, chr1q21, GOCC_MITOCHONDRIAL_MATRIX, GOBP_FATTY_ACID_METABOLIC_PROCESS, GOMF_ACYL_COA_HYDROLASE_ACTIVITY

GO Biological Process (4): fatty acid metabolic process (GO:0006631), long-chain fatty-acyl-CoA metabolic process (GO:0035336), lipid metabolic process (GO:0006629), small molecule metabolic process (GO:0044281)

GO Molecular Function (3): long-chain fatty acyl-CoA hydrolase activity (GO:0052816), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Fatty acid metabolism	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	1
monocarboxylic acid metabolic process	1
fatty-acyl-CoA metabolic process	1
primary metabolic process	1
metabolic process	1
fatty acyl-CoA hydrolase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

478 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THEM5	ACOT13	Q9NPJ3	512
THEM5	ACOT11	Q8WXI4	496
THEM5	LINGO4	Q6UY18	495
THEM5	ZNF805	Q5CZA5	461
THEM5	PNPLA1	Q8N8W4	453
THEM5	C2CD4D	B7Z1M9	396
THEM5	SMPD3	Q9NY59	389
THEM5	PARK7	Q99497	387
THEM5	ACOT6	Q3I5F7	386
THEM5	TAF1	P21675	383
THEM5	ACOT12	Q8WYK0	377
THEM5	FUS	P35637	360
THEM5	CRCT1	Q9UGL9	335
THEM5	ACSM4	P0C7M7	335
THEM5	TDRKH	Q9Y2W6	329

IntAct

12 interactions, top by confidence:

A	B	Type	Score
MAGEA11	THEM5	psi-mi:“MI:0915”(physical association)	0.560
THEM5	MAGEA11	psi-mi:“MI:0915”(physical association)	0.560
SYNJ2BP	THEM5	psi-mi:“MI:0915”(physical association)	0.560
THEM5	CARHSP1	psi-mi:“MI:0915”(physical association)	0.400
THEM5	PRORP	psi-mi:“MI:0914”(association)	0.350
THEM5	HARS2	psi-mi:“MI:0914”(association)	0.350
THEM5	GTPBP10	psi-mi:“MI:0914”(association)	0.350
THEM5	OAT	psi-mi:“MI:0914”(association)	0.350
SYNJ2BP	THEM5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): THEM5 (Two-hybrid), SYNJ2BP (Two-hybrid), THEM4 (Affinity Capture-MS), GPT2 (Affinity Capture-MS), HARS2 (Affinity Capture-MS), NBR1 (Affinity Capture-MS), KLHL15 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), NDUFA6 (Affinity Capture-MS), COQ9 (Affinity Capture-MS), MRPS36 (Affinity Capture-MS), CYP24A1 (Affinity Capture-MS), ISCU (Affinity Capture-MS), MGME1 (Affinity Capture-MS), GTPBP10 (Affinity Capture-MS)

ESM2 similar proteins: A1A4L1, A4QP75, B0S6U7, E1BPN0, E7FCP8, O00142, O55171, P0C1Q3, P19686, P19687, P33402, P49753, P57075, Q02108, Q08CH3, Q1L5Z9, Q1LWG4, Q3B8B2, Q3SZV6, Q3UUI3, Q4V8A1, Q4ZHS0, Q502J0, Q566R0, Q58CX2, Q5IRJ6, Q5R4H0, Q5R8E4, Q5SY16, Q5ZIU8, Q60963, Q63159, Q66GI4, Q6GLK2, Q6PML9, Q6TEC1, Q810S1, Q8BMS4, Q8BWM0, Q8N159

Diamond homologs: A1A4L1, Q3UUI3, Q566R0, Q5T1C6, Q6GLK2, Q8N1Q8, Q9CQJ0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

849 predictions. Top by Δscore:

Variant	Effect	Δscore
1:151847832:CAT:C	acceptor_gain	1.0000
1:151847834:T:TC	acceptor_gain	1.0000
1:151847841:C:CT	acceptor_gain	1.0000
1:151847858:TCAAG:T	acceptor_gain	1.0000
1:151847859:CAAG:C	acceptor_gain	1.0000
1:151847859:CAAGC:C	acceptor_gain	1.0000
1:151847860:A:T	acceptor_gain	1.0000
1:151847863:C:CC	acceptor_gain	1.0000
1:151848178:TTA:T	donor_loss	1.0000
1:151848179:TAC:T	donor_loss	1.0000
1:151848180:A:AC	donor_gain	1.0000
1:151848181:C:CA	donor_gain	1.0000
1:151848181:CT:C	donor_gain	1.0000
1:151848181:CTT:C	donor_gain	1.0000
1:151848181:CTTT:C	donor_gain	1.0000
1:151847412:CAC:C	acceptor_gain	0.9900
1:151847413:ACC:A	acceptor_loss	0.9900
1:151847415:C:CC	acceptor_gain	0.9900
1:151847732:CTTTA:C	donor_loss	0.9900
1:151847733:TTTAC:T	donor_loss	0.9900
1:151847734:TTAC:T	donor_loss	0.9900
1:151847735:TAC:T	donor_loss	0.9900
1:151847736:A:AG	donor_loss	0.9900
1:151847737:C:CG	donor_loss	0.9900
1:151847860:AAG:A	acceptor_gain	0.9900
1:151847860:AAGCT:A	acceptor_loss	0.9900
1:151847861:AG:A	acceptor_gain	0.9900
1:151847861:AGCTG:A	acceptor_loss	0.9900
1:151847862:GCTGG:G	acceptor_loss	0.9900
1:151847863:CTG:C	acceptor_loss	0.9900

AlphaMissense

1618 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:151851121:A:C	F132L	0.969
1:151851121:A:T	F132L	0.969
1:151851123:A:G	F132L	0.969
1:151847407:G:C	F236L	0.966
1:151847407:G:T	F236L	0.966
1:151847409:A:G	F236L	0.966
1:151848187:G:C	F190L	0.965
1:151848187:G:T	F190L	0.965
1:151848189:A:G	F190L	0.965
1:151851136:A:C	F127L	0.954
1:151851136:A:T	F127L	0.954
1:151851138:A:G	F127L	0.954
1:151852399:A:G	W62R	0.951
1:151852399:A:T	W62R	0.951
1:151852339:A:G	W82R	0.949
1:151852339:A:T	W82R	0.949
1:151851122:A:G	F132S	0.943
1:151852397:C:A	W62C	0.941
1:151852397:C:G	W62C	0.941
1:151848236:G:T	A174D	0.939
1:151847779:G:T	A220D	0.936
1:151848241:T:A	K172N	0.933
1:151848241:T:G	K172N	0.933
1:151848188:A:G	F190S	0.930
1:151851164:C:A	R118M	0.930
1:151851093:A:G	C142R	0.929
1:151851099:A:G	S140P	0.926
1:151848258:C:G	D167H	0.923
1:151851091:A:C	C142W	0.922
1:151847749:G:T	A230D	0.920

dbSNP variants (sampled 300 via entrez): RS1000610431 (1:151850936 A>C), RS1000851200 (1:151848483 C>T), RS1000964832 (1:151855077 C>T), RS1001637374 (1:151852516 G>A,T), RS1001851328 (1:151847086 G>A), RS1001925007 (1:151846835 A>G,T), RS1002042962 (1:151853484 G>C), RS1002707358 (1:151850693 A>T), RS1002750594 (1:151851898 G>T), RS1002866751 (1:151846675 C>G,T), RS1003341678 (1:151853331 C>T), RS1003870340 (1:151853016 G>A), RS1004166173 (1:151853857 TG>T), RS1004467802 (1:151855162 A>C,G), RS1004523145 (1:151853730 G>A,C)

Disease associations

OMIM: gene MIM:615653 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004751_22	Serum uric acid levels in response to allopurinol in gout	2.000000e-06
GCST008362_140	Birth weight	4.000000e-08
GCST008916_82	Asthma	5.000000e-27
GCST008916_88	Asthma	1.000000e-25
GCST012020_557	Serum metabolite levels	2.000000e-16
GCST012021_30	Serum metabolite levels	2.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement
EFO:0004344	birth weight

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Estradiol	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Plant Extracts	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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