HTD2

Summary

HTD2 (hydroxyacyl-thioester dehydratase type 2, HGNC:53111) is a protein-coding gene on chromosome 3p14.3, encoding Hydroxyacyl-thioester dehydratase type 2, mitochondrial (P86397). Mitochondrial 3-hydroxyacyl-thioester dehydratase, which may be involved in fatty acid biosynthesis.

This gene encodes a protein that localizes to the mitochondria and can function as a 3-hydroxyacyl thioester dehydratase. This gene is located just downstream of the gene for ribonuclease P/MRP subunit p14 (RPP14) in a genomic context that is conserved among animals. The upstream RPP14 gene is thought to be co-transcribed with this gene, and bicistronic transcripts may include open reading frames for both proteins.

Source: NCBI Gene 109703458 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 29 total
• MANE Select transcript: NM_001348712

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:53111
Approved symbol	HTD2
Name	hydroxyacyl-thioester dehydratase type 2
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000255154
Ensembl biotype	protein_coding
OMIM	620769
Entrez	109703458

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000461393, ENST00000474660, ENST00000475412, ENST00000476007, ENST00000477305, ENST00000481972, ENST00000498618

RefSeq mRNA: 4 — MANE Select: NM_001348712 NM_001348712, NM_001348713, NM_001348714, NM_001348715

CCDS: CCDS87096

Canonical transcript exons

ENST00000461393 — 5 exons

Exon	Start	End
ENSE00001849775	58317440	58320193
ENSE00001897116	58306520	58306651
ENSE00003724072	58316515	58316591
ENSE00003741711	58316915	58316993
ENSE00003746656	58310507	58310591

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 90.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.0521 / max 110.7990, expressed in 1774 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37039	8.0521	1774
37040	6.9940	1740

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.50	gold quality
muscle of leg	UBERON:0001383	84.85	gold quality
gastrocnemius	UBERON:0001388	84.43	gold quality
skeletal muscle tissue	UBERON:0001134	83.98	gold quality
muscle tissue	UBERON:0002385	82.70	gold quality
duodenum	UBERON:0002114	81.44	gold quality
islet of Langerhans	UBERON:0000006	80.96	gold quality
heart left ventricle	UBERON:0002084	80.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	80.60	gold quality
rectum	UBERON:0001052	80.16	gold quality
smooth muscle tissue	UBERON:0001135	80.01	gold quality
heart	UBERON:0000948	79.47	gold quality
apex of heart	UBERON:0002098	78.84	gold quality
right atrium auricular region	UBERON:0006631	78.63	gold quality
stromal cell of endometrium	CL:0002255	78.41	gold quality
prefrontal cortex	UBERON:0000451	78.02	gold quality
adrenal tissue	UBERON:0018303	77.93	gold quality
placenta	UBERON:0001987	77.72	gold quality
mucosa of transverse colon	UBERON:0004991	77.57	gold quality
ventricular zone	UBERON:0003053	77.56	gold quality
gall bladder	UBERON:0002110	77.27	gold quality
leukocyte	CL:0000738	77.13	gold quality
monocyte	CL:0000576	76.90	gold quality
vermiform appendix	UBERON:0001154	76.54	gold quality
granulocyte	CL:0000094	76.53	gold quality
lymph node	UBERON:0000029	76.47	gold quality
endometrium	UBERON:0001295	76.37	gold quality
adult mammalian kidney	UBERON:0000082	76.22	gold quality
adrenal gland	UBERON:0002369	76.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.12

Regulation

Is transcription factor: no

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Htd2	ENSMUSG00000144287
rattus_norvegicus	Rpp14	ENSRNOG00000063660

Protein

Protein identifiers

Hydroxyacyl-thioester dehydratase type 2, mitochondrial — P86397 (reviewed: P86397)

Alternative names: 3-hydroxyacyl-[acyl-carrier-protein] dehydratase

All UniProt accessions (5): A0A087WTC8, A0A087WUW1, A0A087WYB6, P86397, L0R6P0

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial 3-hydroxyacyl-thioester dehydratase, which may be involved in fatty acid biosynthesis.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in heart and liver. Expressed at lower levels in skeletal muscle, spleen, kidney and placenta.

Miscellaneous. This protein is produced by a bicistronic gene which also produces the RPP14 protein from an overlapping reading frame.

Similarity. Belongs to the HTD2 family.

RefSeq proteins (4): NP_001335641, NP_001335642, NP_001335643, NP_001335644 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002539	MaoC-like_dom	Domain
IPR029069	HotDog_dom_sf	Homologous_superfamily
IPR050965	UPF0336/Enoyl-CoA_hydratase	Family

Pfam: PF01575

Catalyzed reactions (Rhea), 3 shown:

• a (3R)-hydroxyacyl-[ACP] = a (2E)-enoyl-[ACP] + H2O (RHEA:13097)
• (3R)-hydroxyhexanoyl-[ACP] = (2E)-hexenoyl-[ACP] + H2O (RHEA:41828)
• (3R)-hydroxydecanoyl-[ACP] = (2E)-decenoyl-[ACP] + H2O (RHEA:41860)

UniProt features (14 total): strand 5, helix 3, mutagenesis site 2, transit peptide 1, chain 1, turn 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3IR3	X-RAY DIFFRACTION	1.99

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P86397-F1	84.54	0.74

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (2):

Position	Phenotype
62	abolishes ability to complement a htd2-delta mutant yeast.
67	abolishes ability to complement a htd2-delta mutant yeast.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-75105	Fatty acyl-CoA biosynthesis

MSigDB gene sets: 67 (showing top): GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACYL_COA_METABOLIC_PROCESS, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACID_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (4): fatty acid biosynthetic process (GO:0006633), fatty-acyl-CoA biosynthetic process (GO:0046949), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (4): 3-hydroxyacyl-CoA dehydratase activity (GO:0018812), (3R)-hydroxyacyl-[acyl-carrier-protein] dehydratase activity (GO:0019171), lyase activity (GO:0016829), hydro-lyase activity (GO:0016836)

GO Cellular Component (3): nucleolus (GO:0005730), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Fatty acid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
fatty-acyl-CoA metabolic process	1
acyl-CoA biosynthetic process	1
fatty acid derivative biosynthetic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
enoyl-CoA hydratase activity	1
hydro-lyase activity	1
catalytic activity	1
carbon-oxygen lyase activity	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTD2	OXSM	Q9NWU1	458
HTD2	MCAT	Q8IVS2	456
HTD2	CHCHD1	Q96BP2	446
HTD2	RPP38	P78345	443
HTD2	SLC35A4	Q96G79	433
HTD2	DMAC2	Q9NW81	426
HTD2	POP1	Q99575	419
HTD2	MRPL42	Q9Y6G3	410
HTD2	UQCC3	Q6UW78	403
HTD2	ACAA1	P09110	394
HTD2	DEFA4	P12838	380
HTD2	LIPT2	A6NK58	367
HTD2	MECR	Q9BV79	364
HTD2	ZNF708	P17019	359
HTD2	SLC35F6	Q8N357	353
HTD2	SCP2	P22307	353

IntAct

2 interactions, top by confidence:

A	B	Type	Score
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A1D6NER6, A0A3Q7HWE4, A4GNA8, B7TWW5, F4HU51, F4JTE7, F4JYE9, F4JZC2, M4IS90, O48651, O65090, O81000, O82497, O82796, P34419, P51660, P55228, P55232, P86397, P87304, P97852, Q07G10, Q0WW55, Q338C0, Q5FYU1, Q6DRD9, Q6GLK2, Q6JQN1, Q6NMK6, Q8BH55, Q8H151, Q8H4D4, Q8K370, Q8LEA0, Q8VYI3, Q8VZ10, Q8W471, Q93WU4, Q93Z01, Q944R7

Diamond homologs: A0A3Q7HWE4, C5AZ74, O32472, P49251, P86397, P9WNP2, P9WNP3, Q2RQ36, Q7U2S5, Q9FJI2, Q9VXJ0, P51659, P51660, P97852, Q01373, Q8VYI3, P22414, Q02207, P77455

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

854 predictions. Top by Δscore:

Variant	Effect	Δscore
3:58310496:A:AG	acceptor_gain	1.0000
3:58310497:C:G	acceptor_gain	1.0000
3:58310502:TTTA:T	acceptor_loss	1.0000
3:58310505:A:AG	acceptor_gain	1.0000
3:58310505:A:T	acceptor_loss	1.0000
3:58310506:G:GA	acceptor_gain	1.0000
3:58310506:GA:G	acceptor_gain	1.0000
3:58310506:GAGA:G	acceptor_gain	1.0000
3:58310506:GAGAA:G	acceptor_gain	1.0000
3:58310589:G:GT	donor_gain	1.0000
3:58310589:G:T	donor_gain	1.0000
3:58310589:GAGG:G	donor_loss	1.0000
3:58310591:GGTA:G	donor_loss	1.0000
3:58316587:AGCAG:A	donor_loss	1.0000
3:58316589:CAGGT:C	donor_loss	1.0000
3:58316590:AGG:A	donor_loss	1.0000
3:58316591:GGTA:G	donor_loss	1.0000
3:58316592:GTATG:G	donor_loss	1.0000
3:58316593:T:A	donor_loss	1.0000
3:58316913:A:AG	acceptor_gain	1.0000
3:58316913:AGT:A	acceptor_gain	1.0000
3:58316914:G:GA	acceptor_gain	1.0000
3:58316914:GT:G	acceptor_gain	1.0000
3:58316914:GTG:G	acceptor_gain	1.0000
3:58310577:G:GT	donor_gain	0.9900
3:58310587:GGGAG:G	donor_gain	0.9900
3:58310588:GGAG:G	donor_gain	0.9900
3:58310588:GGAGG:G	donor_gain	0.9900
3:58310589:GAG:G	donor_gain	0.9900
3:58316510:TGCA:T	acceptor_loss	0.9900

AlphaMissense

1092 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:58317953:T:C	F114L	0.996
3:58317955:T:A	F114L	0.996
3:58317955:T:G	F114L	0.996
3:58317779:T:C	F56L	0.994
3:58317781:C:A	F56L	0.994
3:58317781:C:G	F56L	0.994
3:58317756:T:C	F48S	0.989
3:58318071:T:A	V153D	0.987
3:58317799:T:A	D62E	0.986
3:58317799:T:G	D62E	0.986
3:58317861:T:A	V83E	0.986
3:58317990:C:A	A126D	0.986
3:58317995:G:C	A128P	0.986
3:58317755:T:C	F48L	0.985
3:58317757:C:A	F48L	0.985
3:58317757:C:G	F48L	0.985
3:58317797:G:C	D62H	0.985
3:58317798:A:T	D62V	0.985
3:58317954:T:C	F114S	0.985
3:58317984:T:A	V124D	0.985
3:58318043:T:C	C144R	0.984
3:58318079:G:C	G156R	0.984
3:58317845:T:C	F78L	0.983
3:58317847:T:A	F78L	0.983
3:58317847:T:G	F78L	0.983
3:58317805:T:A	N64K	0.982
3:58317805:T:G	N64K	0.982
3:58317812:C:G	H67D	0.982
3:58317954:T:G	F114C	0.982
3:58318045:T:G	C144W	0.982

dbSNP variants (sampled 300 via entrez): RS1000274592 (3:58308684 T>G), RS1000635913 (3:58312825 G>T), RS1000643635 (3:58316767 G>A,C), RS1000969611 (3:58317989 G>A,C,T), RS1000990659 (3:58318553 T>C,G), RS1001110062 (3:58311456 A>G), RS1001188625 (3:58313747 C>A), RS1001243426 (3:58307506 C>G), RS1001318525 (3:58307920 G>A), RS1001370830 (3:58308290 T>A), RS1001373520 (3:58320654 A>G), RS1001561457 (3:58311287 T>C), RS1001563995 (3:58304480 G>A), RS1001773346 (3:58309157 C>T), RS1001818262 (3:58320375 C>G)

Disease associations

OMIM: gene MIM:620769 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression	1
Okadaic Acid	decreases expression	1
S-Nitrosoglutathione	decreases expression	1

Clinical trials (associated diseases)

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