HADHB

Summary

HADHB (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta, HGNC:4803) is a protein-coding gene on chromosome 2p23.3, encoding Trifunctional enzyme subunit beta, mitochondrial (P55084). Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.

This gene encodes the beta subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 3032 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial trifunctional protein deficiency (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 650 total — 45 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 69
• Druggable target: yes
• MANE Select transcript: NM_000183

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4803
Approved symbol	HADHB
Name	hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	MTPB
Ensembl gene	ENSG00000138029
Ensembl biotype	protein_coding
OMIM	143450
Entrez	3032

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 50 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000317799, ENST00000405867, ENST00000412805, ENST00000425035, ENST00000448743, ENST00000479347, ENST00000494615, ENST00000537713, ENST00000545822, ENST00000859582, ENST00000859583, ENST00000859584, ENST00000859585, ENST00000859586, ENST00000859587, ENST00000859588, ENST00000859589, ENST00000859590, ENST00000859591, ENST00000859592, ENST00000859593, ENST00000859594, ENST00000859595, ENST00000859596, ENST00000859597, ENST00000859598, ENST00000859599, ENST00000859600, ENST00000859601, ENST00000942424, ENST00000942425, ENST00000942426, ENST00000942427, ENST00000942428, ENST00000942429, ENST00000942430, ENST00000942431, ENST00000942432, ENST00000942433, ENST00000942434, ENST00000942435, ENST00000942436, ENST00000942437, ENST00000942438, ENST00000942439, ENST00000942440, ENST00000942441, ENST00000942442, ENST00000942443, ENST00000942444, ENST00000942445, ENST00000942446

RefSeq mRNA: 3 — MANE Select: NM_000183 NM_000183, NM_001281512, NM_001281513

CCDS: CCDS1722, CCDS62871, CCDS62872

Canonical transcript exons

ENST00000317799 — 16 exons

Exon	Start	End
ENSE00001168977	26244939	26244990
ENSE00001555892	26289918	26290465
ENSE00003480534	26283004	26283051
ENSE00003537001	26273651	26273750
ENSE00003558911	26263380	26263479
ENSE00003572626	26279994	26280115
ENSE00003575019	26254247	26254318
ENSE00003598693	26254430	26254474
ENSE00003615909	26279135	26279315
ENSE00003632564	26282845	26282924
ENSE00003635033	26277073	26277160
ENSE00003660287	26278614	26278801
ENSE00003663737	26284117	26284204
ENSE00003670320	26285407	26285571
ENSE00003675621	26284883	26284957
ENSE00003791341	26269953	26269997

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 95.9708 / max 837.1866, expressed in 1826 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19256	92.4540	1826
19257	3.1797	960
19255	0.3371	128

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.73	gold quality
left ventricle myocardium	UBERON:0006566	99.70	gold quality
deltoid	UBERON:0001476	99.62	gold quality
myocardium	UBERON:0002349	99.57	gold quality
tibialis anterior	UBERON:0001385	99.51	gold quality
jejunal mucosa	UBERON:0000399	99.48	gold quality
cardiac ventricle	UBERON:0002082	99.48	gold quality
gastrocnemius	UBERON:0001388	99.47	gold quality
heart left ventricle	UBERON:0002084	99.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.42	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.40	gold quality
quadriceps femoris	UBERON:0001377	99.39	gold quality
triceps brachii	UBERON:0001509	99.39	gold quality
diaphragm	UBERON:0001103	99.37	gold quality
vastus lateralis	UBERON:0001379	99.37	gold quality
biceps brachii	UBERON:0001507	99.37	gold quality
apex of heart	UBERON:0002098	99.36	gold quality
skeletal muscle tissue	UBERON:0001134	99.34	gold quality
cardiac atrium	UBERON:0002081	99.30	gold quality
right atrium auricular region	UBERON:0006631	99.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.28	gold quality
muscle organ	UBERON:0001630	99.26	gold quality
muscle of leg	UBERON:0001383	99.22	gold quality
muscle tissue	UBERON:0002385	99.19	gold quality
adrenal tissue	UBERON:0018303	99.16	gold quality
jejunum	UBERON:0002115	99.13	gold quality
right adrenal gland cortex	UBERON:0035827	99.13	gold quality
duodenum	UBERON:0002114	99.12	gold quality
heart	UBERON:0000948	99.11	gold quality
right adrenal gland	UBERON:0001233	99.10	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-124858	no	681.60
E-MTAB-7606	no	655.24
E-MTAB-6058	no	395.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

62 targeting HADHB, 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-3924	100.00	72.09	2394
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-587	99.64	70.86	2611

Literature-anchored findings (GeneRIF, showing 19)

• HADHB trifunctional enzyme, human renin, and poly(C)-binding protein are novel renin mRNA-binding proteins that target a cis-element in the 3’-UTR of renin mRNA and regulate renin production (PMID:12933794)
• Both alpha- and beta-subunit mutations result in TFP complex instability, demonstrating that the mechanism of disease is the same in alpha- or beta-mutation-derived disease and explaining the biochemical and clinical similarities. (PMID:14630990)
• The common disease causing mutation of G1528C in MTP gene in caucasian in probably not a common mutation in Chinese Han people in Beijing. (PMID:17199921)
• The present findings showed that all missense mutations in HADHB were disease-causing. (PMID:19699128)
• Recombinant mitochondrial trifunctional protein displayed 2-enoyl-CoA hydratase, l-3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase activities. (PMID:20825197)
• Results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects. (PMID:21549624)
• mutational analysis of the HADHB gene, which encodes long-chain 3-ketoacyl-CoA thiolase, identified compound heterozygous mutations of c.520C>T (p.R141C) and c.1331G>A (p.R411K) in a case of mitochondrial trifunctional protein deficiency (PMID:22000755)
• HADHB is a functional molecular target of estrogen receptor alpha in the mitochondria, and the interaction may play an important role in the estrogen-mediated lipid metabolism in animals and humans. (PMID:22375075)
• The results demonstrated that ERbeta was indeed associated and colocalized with HADHB within mitochondria. (PMID:23000159)
• Heterozygous mutation in HADHB gene cause early-onset axonal axonal Charcot-Marie-tooth disease. (PMID:24314034)
• Mutations in HADHB, which encodes the beta-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy. (PMID:24664533)
• nonstructural protein 5 (NS5) interacted with hydroxyacyl-CoA dehydrogenase alpha and beta subunits, two components of the mitochondrial trifunctional protein (MTP) involved in LCFA beta-oxidation (PMID:25816318)
• Exposure to bezafibrate (400 muM for 48 h) increased the abundance of HADHA and HADHB mRNAs. (PMID:26109258)
• Results find that hypermethylation of HADHB gene was persistently correlated with downregulation of its transcription in colorectal cancer (CRC). Tumor functional analysis indicated that HADHB reduced CRC migration and invasiveness. (PMID:29507648)
• Gene analysis identified two compound heterozygous mutations (c.184A>G/c.340A>G and c.488G>A/c.1175C>T, respectively) in the HADHB gene (PMID:29956646)
• The current study broadens the genetic spectrum of HADHB and highlights the importance of screening fatty acid oxidation deficiency-related gene mutations among patients with intermittent rhabdomyolysis, as in the patient reported here, although extremely rare. (PMID:31521624)
• Targeting viperin to the mitochondrion inhibits the thiolase activity of the trifunctional enzyme complex. (PMID:31980458)
• MTP deficiency caused by HADHB mutations: Pathophysiology and clinical manifestations. (PMID:33744096)
• HADHB, a fatty acid beta-oxidation enzyme, is a potential prognostic predictor in malignant lymphoma. (PMID:34531036)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hadhb	ENSDARG00000102055
mus_musculus	Hadhb	ENSMUSG00000059447
rattus_norvegicus	Hadhb	ENSRNOG00000010800
drosophila_melanogaster	Mtpbeta	FBGN0025352
caenorhabditis_elegans		WBGENE00015125

Paralogs (4): ACAA1 (ENSG00000060971), ACAT1 (ENSG00000075239), ACAT2 (ENSG00000120437), ACAA2 (ENSG00000167315)

Protein

Protein identifiers

Trifunctional enzyme subunit beta, mitochondrial — P55084 (reviewed: P55084)

Alternative names: TP-beta

All UniProt accessions (6): P55084, B5MD38, C9JE81, C9JEY0, C9K0M0, F5GZQ3

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway. The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA. Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids. Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the trifunctional enzyme subunit beta/HADHB described here bears the 3-ketoacyl-CoA thiolase activity.

Subunit / interactions. Heterotetramer of 2 alpha/HADHA and 2 beta/HADHB subunits; forms the mitochondrial trifunctional enzyme. Also purified as higher order heterooligomers including a 4 alpha/HADHA and 4 beta/HADHB heterooligomer which physiological significance remains unclear. The mitochondrial trifunctional enzyme interacts with MTLN. Interacts with RSAD2/viperin.

Subcellular location. Mitochondrion. Mitochondrion inner membrane. Mitochondrion outer membrane. Endoplasmic reticulum.

Disease relevance. Mitochondrial trifunctional protein deficiency 2 (MTPD2) [MIM:620300] An autosomal recessive metabolic disorder of long-chain fatty acid oxidation, biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. The disease phenotype ranges from a fatal form characterized by early-onset cardiomyopathy, cardiac failure and early death to less severe, late-onset forms with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy as key features. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Lipid metabolism; fatty acid beta-oxidation.

Similarity. Belongs to the thiolase-like superfamily. Thiolase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P55084-1	1	yes
P55084-2	2

RefSeq proteins (3): NP_000174, NP_001268441, NP_001268442 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002155	Thiolase	Family
IPR016039	Thiolase-like	Homologous_superfamily
IPR020610	Thiolase_AS	Active_site
IPR020613	Thiolase_CS	Conserved_site
IPR020615	Thiolase_acyl_enz_int_AS	Active_site
IPR020616	Thiolase_N	Domain
IPR020617	Thiolase_C	Domain

Pfam: PF00108, PF02803

Catalyzed reactions (Rhea), 7 shown:

• tetradecanoyl-CoA + acetyl-CoA = 3-oxohexadecanoyl-CoA + CoA (RHEA:18161)
• an acyl-CoA + acetyl-CoA = a 3-oxoacyl-CoA + CoA (RHEA:21564)
• octanoyl-CoA + acetyl-CoA = 3-oxodecanoyl-CoA + CoA (RHEA:31087)
• dodecanoyl-CoA + acetyl-CoA = 3-oxotetradecanoyl-CoA + CoA (RHEA:31091)
• butanoyl-CoA + acetyl-CoA = 3-oxohexanoyl-CoA + CoA (RHEA:31111)
• decanoyl-CoA + acetyl-CoA = 3-oxododecanoyl-CoA + CoA (RHEA:31183)
• hexanoyl-CoA + acetyl-CoA = 3-oxooctanoyl-CoA + CoA (RHEA:31203)

UniProt features (40 total): sequence variant 18, modified residue 14, active site 2, transit peptide 1, chain 1, intramembrane region 1, splice variant 1, sequence conflict 1, site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6DV2	X-RAY DIFFRACTION	3.6
5ZQZ	ELECTRON MICROSCOPY	4.2
5ZRV	ELECTRON MICROSCOPY	7.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55084-F1	90.89	0.83

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): 138 (acyl-thioester intermediate); 458 (proton donor/acceptor); 428 (increases nucleophilicity of active site cys)

Post-translational modifications (14): 190, 272, 291, 293, 293, 298, 332, 332, 348, 361, 72, 72, 188, 188

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1482798	Acyl chain remodeling of CL
R-HSA-77285	Beta oxidation of myristoyl-CoA to lauroyl-CoA
R-HSA-77288	mitochondrial fatty acid beta-oxidation of unsaturated fatty acids
R-HSA-77305	Beta oxidation of palmitoyl-CoA to myristoyl-CoA
R-HSA-77310	Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA
R-HSA-77346	Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA
R-HSA-77348	Beta oxidation of octanoyl-CoA to hexanoyl-CoA
R-HSA-77350	Beta oxidation of hexanoyl-CoA to butanoyl-CoA

MSigDB gene sets: 415 (showing top): GOBP_LIPID_MODIFICATION, MODULE_93, GOBP_FATTY_ACID_CATABOLIC_PROCESS, MORF_MBD4, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, MORF_HDAC1, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MORF_HDAC2, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, RODWELL_AGING_KIDNEY_NO_BLOOD_DN

GO Biological Process (5): fatty acid beta-oxidation (GO:0006635), gene expression (GO:0010467), cellular response to lipopolysaccharide (GO:0071222), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (12): RNA binding (GO:0003723), (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity (GO:0003857), acetyl-CoA C-acetyltransferase activity (GO:0003985), acetyl-CoA C-acyltransferase activity (GO:0003988), enoyl-CoA hydratase activity (GO:0004300), protein-containing complex binding (GO:0044877), acetyl-CoA C-myristoyltransferase activity (GO:0050633), lncRNA binding (GO:0106222), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747)

GO Cellular Component (10): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial envelope (GO:0005740), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), endoplasmic reticulum (GO:0005783), mitochondrial fatty acid beta-oxidation multienzyme complex (GO:0016507), mitochondrial nucleoid (GO:0042645), sperm principal piece (GO:0097228), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
mitochondrial fatty acid beta-oxidation of saturated fatty acids	6
Glycerophospholipid biosynthesis	1
Mitochondrial Fatty Acid Beta-Oxidation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
mitochondrion	3
binding	2
cytoplasm	2
intracellular membrane-bounded organelle	2
mitochondrial membrane	2
mitochondrial matrix	2
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
macromolecule biosynthetic process	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
nucleic acid binding	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
acetyl-CoA C-acyltransferase activity	1
C-acetyltransferase activity	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
hydro-lyase activity	1
myristoyltransferase activity	1
RNA binding	1
catalytic activity	1
transferase activity	1
acyltransferase activity	1
nuclear lumen	1
organelle envelope	1
organelle outer membrane	1
organelle inner membrane	1
endomembrane system	1
fatty acid beta-oxidation multienzyme complex	1
mitochondrial protein-containing complex	1
nucleoid	1
intracellular membraneless organelle	1
sperm flagellum	1

Protein interactions and networks

STRING

3198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HADHB	HADHA	P40939	999
HADHB	ECHS1	P30084	981
HADHB	EHHADH	Q08426	971
HADHB	HADH	Q16836	953
HADHB	ACOX1	Q15067	936
HADHB	ACADL	P28330	903
HADHB	HSD17B4	P51659	862
HADHB	ACOX3	O15254	837
HADHB	TBXA2R	P21731	797
HADHB	CROT	Q9UKG9	777
HADHB	ACADSB	P45954	768
HADHB	ACADVL	P49748	763
HADHB	ACADS	P16219	756
HADHB	ACADM	P11310	747
HADHB	HMGCS2	P54868	722

IntAct

276 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
HADHA	HADHB	psi-mi:“MI:0407”(direct interaction)	0.870
HADHB	HADHA	psi-mi:“MI:0407”(direct interaction)	0.870
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
RELL2	OXSR1	psi-mi:“MI:0914”(association)	0.830
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
PKMYT1	CCNB2	psi-mi:“MI:0914”(association)	0.730
CDH1	CTNND1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GABARAPL2	IPO5	psi-mi:“MI:0914”(association)	0.690
LRRC46	TFPT	psi-mi:“MI:0914”(association)	0.640
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
GABARAPL1	IPO5	psi-mi:“MI:0914”(association)	0.590
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
	HADHA	psi-mi:“MI:0915”(physical association)	0.540
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
HADHB	POTEI	psi-mi:“MI:0914”(association)	0.530
PRKCZ	IPO5	psi-mi:“MI:0914”(association)	0.530
PDPK1	AGRN	psi-mi:“MI:0914”(association)	0.530
MINK1	CNOT1	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CDH8	ARVCF	psi-mi:“MI:0914”(association)	0.530

BioGRID (573): HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), HADHB (Affinity Capture-MS), ATP1A1 (Co-fractionation), ATP1B1 (Co-fractionation), DDOST (Co-fractionation), HADHB (Co-fractionation)

ESM2 similar proteins: A0A384E138, A0A384E143, A0B8Z1, A4FWW6, A4WJ12, A4YH99, A5UNI8, A6LU96, A6UPL1, A6VGF1, A9AAA1, B2TM49, B2V2T4, B6YXH7, C5A401, C6A2L5, O26883, O46629, O58410, P07600, P14638, P34255, P40830, P40869, P51086, P55084, Q0W7K1, Q12UR3, Q2NHU7, Q39VG1, Q46F10, Q4J933, Q58941, Q5JFL6, Q5R1W7, Q5WGS1, Q60587, Q6L233, Q6LXY3, Q87MM2

Diamond homologs: A0KK76, A0KV75, A1ADI9, A1JK23, A1RI91, A1S7L7, A3D685, A3QFP4, A4SMT9, A4TM83, A4WCW7, A4Y898, A5F2P1, A6TC20, A6WQ26, A7FGK0, A7MH80, A7ZPF9, A8A2L1, A8ADP1, A8FTR6, A8GH87, A8H5T2, A9KTW7, A9MJ36, A9N452, A9R7W9, B0TL22, B1IXA4, B1JGG1, B1KKT1, B1LME8, B1X9L5, B2K8J6, B2TWV5, B2VJ10, B4RTU9, B4SZR1, B4TCA9, B4TQC3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HADHB	“form complex”	“Trifunctional enzyme”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 236 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.

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	8	12.7×	2e-04
autophagosome maturation	6	10.5×	5e-03
autophagosome assembly	7	7.8×	6e-03
protein autophosphorylation	10	7.2×	7e-04
protein phosphorylation	14	4.7×	7e-04
positive regulation of ERK1 and ERK2 cascade	11	4.7×	5e-03
cell migration	13	4.0×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	46
Uncertain significance	164
Likely benign	287
Benign	36

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066626	NC_000002.11:g.(?26507731)(26508459_?)del	Pathogenic
1075534	NM_000183.3(HADHB):c.97C>T (p.Arg33Ter)	Pathogenic
1360920	NM_000183.3(HADHB):c.989del (p.Gly330fs)	Pathogenic
1400432	NC_000002.11:g.(?26492801)(26496638_?)del	Pathogenic
1410430	NM_000183.3(HADHB):c.646G>T (p.Glu216Ter)	Pathogenic
14844	NM_000183.3(HADHB):c.788A>G (p.Asp263Gly)	Pathogenic
14847	NM_000183.3(HADHB):c.1331G>A (p.Arg444Lys)	Pathogenic
14848	NM_000183.3(HADHB):c.776_777insT (p.Leu260fs)	Pathogenic
14849	NM_000183.3(HADHB):c.1364T>G (p.Val455Gly)	Pathogenic
1695419	NM_000183.3(HADHB):c.693del (p.Ala232fs)	Pathogenic
1806798	NM_000183.3(HADHB):c.1137del (p.His379fs)	Pathogenic
190379	NM_000183.3(HADHB):c.1175C>T (p.Ala392Val)	Pathogenic
1912480	NM_000183.3(HADHB):c.882dup (p.Ala295fs)	Pathogenic
1961325	NM_000183.3(HADHB):c.590_591delinsAA (p.Ser197Ter)	Pathogenic
203752	NM_000183.3(HADHB):c.1059del (p.Gly354fs)	Pathogenic
2135077	NM_000183.3(HADHB):c.417del (p.Ser140fs)	Pathogenic
2193793	NM_000183.3(HADHB):c.50G>A (p.Trp17Ter)	Pathogenic
253049	NM_000183.3(HADHB):c.357dup (p.Ala120fs)	Pathogenic
2627356	NC_000002.11:g.(26477343_26486247)_(26486348_26492820)del	Pathogenic
2635256	NM_000183.3(HADHB):c.739C>T (p.Arg247Cys)	Pathogenic
2675985	NM_000183.3(HADHB):c.209C>G (p.Ser70Ter)	Pathogenic
2675990	NM_000183.3(HADHB):c.630+2_630+6del	Pathogenic
2675999	NM_000183.3(HADHB):c.209+1G>C	Pathogenic
2676002	NM_000183.3(HADHB):c.442+663A>G	Pathogenic
2724901	NM_000183.3(HADHB):c.747_748del (p.His249fs)	Pathogenic
2756202	NM_000183.3(HADHB):c.615_616insCTCTAAT (p.Phe206delinsLeuTer)	Pathogenic
2761657	NM_000183.3(HADHB):c.410dup (p.Cys138fs)	Pathogenic
2784408	NM_000183.3(HADHB):c.568A>T (p.Lys190Ter)	Pathogenic
2829027	NM_000183.3(HADHB):c.1279G>T (p.Gly427Ter)	Pathogenic
2835352	NM_000183.3(HADHB):c.637_638delinsTA (p.Ala213Ter)	Pathogenic

SpliceAI

2640 predictions. Top by Δscore:

Variant	Effect	Δscore
2:26244989:AG:A	donor_loss	1.0000
2:26244990:GGTGA:G	donor_loss	1.0000
2:26244991:GT:G	donor_loss	1.0000
2:26244992:T:G	donor_loss	1.0000
2:26263475:ACTTC:A	donor_gain	1.0000
2:26263476:CTTC:C	donor_gain	1.0000
2:26263477:TTC:T	donor_gain	1.0000
2:26263478:TC:T	donor_gain	1.0000
2:26263478:TCGT:T	donor_loss	1.0000
2:26263479:CG:C	donor_loss	1.0000
2:26263480:G:GG	donor_gain	1.0000
2:26263480:GT:G	donor_loss	1.0000
2:26263481:T:A	donor_loss	1.0000
2:26263482:AAGT:A	donor_loss	1.0000
2:26263483:AG:A	donor_loss	1.0000
2:26263484:G:C	donor_loss	1.0000
2:26263484:G:GG	donor_gain	1.0000
2:26269998:G:GG	donor_gain	1.0000
2:26273643:A:AG	acceptor_gain	1.0000
2:26273644:C:G	acceptor_gain	1.0000
2:26273647:CCA:C	acceptor_loss	1.0000
2:26273648:CA:C	acceptor_loss	1.0000
2:26273649:A:AG	acceptor_gain	1.0000
2:26273649:AG:A	acceptor_gain	1.0000
2:26273649:AGG:A	acceptor_gain	1.0000
2:26273650:G:GA	acceptor_loss	1.0000
2:26273650:G:GG	acceptor_gain	1.0000
2:26273650:GG:G	acceptor_gain	1.0000
2:26273650:GGG:G	acceptor_gain	1.0000
2:26273746:GAGAG:G	donor_gain	1.0000

AlphaMissense

3079 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:26277132:T:G	C138W	1.000
2:26284199:T:C	F382L	1.000
2:26284201:C:A	F382L	1.000
2:26284201:C:G	F382L	1.000
2:26273738:T:A	N114K	0.999
2:26273738:T:G	N114K	0.999
2:26277130:T:C	C138R	0.999
2:26277131:G:A	C138Y	0.999
2:26277137:C:T	S140F	0.999
2:26278677:C:T	S169F	0.999
2:26279190:G:C	R229P	0.999
2:26279226:A:C	Q241P	0.999
2:26280068:T:C	F296L	0.999
2:26280070:C:A	F296L	0.999
2:26280070:C:G	F296L	0.999
2:26280096:C:A	A305D	0.999
2:26280103:T:A	N307K	0.999
2:26280103:T:G	N307K	0.999
2:26280104:T:C	S308P	0.999
2:26282848:G:C	D313H	0.999
2:26282848:G:T	D313Y	0.999
2:26282849:A:T	D313V	0.999
2:26284190:C:G	H379D	0.999
2:26284200:T:C	F382S	0.999
2:26285462:G:A	G427E	0.999
2:26285464:C:G	H428D	0.999
2:26285465:A:G	H428R	0.999
2:26285466:C:A	H428Q	0.999
2:26285466:C:G	H428Q	0.999
2:26285470:T:C	F430L	0.999

dbSNP variants (sampled 300 via entrez): RS1000085580 (2:26257260 A>G), RS1000126643 (2:26244821 G>A), RS1000127079 (2:26290350 G>A), RS1000152403 (2:26257624 T>C), RS1000165142 (2:26246013 G>C), RS1000167727 (2:26281780 A>C,G), RS1000272824 (2:26257706 C>T), RS1000275876 (2:26250350 C>G), RS1000349583 (2:26264118 A>C,G), RS1000441713 (2:26245261 GGGGT>G,GGGGTGGGT), RS1000485142 (2:26257380 A>G), RS1000499105 (2:26290035 T>C,G), RS1000534426 (2:26261515 C>T), RS1000638295 (2:26268733 C>A), RS1000679620 (2:26274635 T>C)

Disease associations

OMIM: gene MIM:143450 | disease phenotypes: MIM:609015, MIM:620300, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial trifunctional protein deficiency	Definitive	Autosomal recessive
mitochondrial trifunctional protein deficiency 1	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial trifunctional protein deficiency	Definitive	AR

Mondo (7): mitochondrial trifunctional protein deficiency (MONDO:0012172), mitochondrial trifunctional protein deficiency 2 (MONDO:0958185), mitochondrial trifunctional protein deficiency 1 (MONDO:0958181), Charcot-Marie-Tooth disease (MONDO:0015626), metabolic acidosis (MONDO:0000440), renal tubular acidosis (MONDO:0001909), rickets (MONDO:0005520)

Orphanet (2): Mitochondrial trifunctional protein deficiency (Orphanet:746), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000580	Pigmentary retinopathy
HP:0000829	Hypoparathyroidism
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001324	Muscle weakness
HP:0001342	Cerebral hemorrhage
HP:0001396	Cholestasis
HP:0001522	Death in infancy
HP:0001531	Failure to thrive in infancy
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001653	Mitral regurgitation
HP:0001712	Left ventricular hypertrophy
HP:0001761	Pes cavus
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001985	Hypoketotic hypoglycemia
HP:0001987	Hyperammonemia
HP:0002033	Poor suck
HP:0002069	Bilateral tonic-clonic seizure
HP:0002093	Respiratory insufficiency
HP:0002151	Increased circulating lactate concentration
HP:0002359	Frequent falls

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000141	Acidosis, Renal Tubular	C12.050.351.968.419.815.093; C12.200.777.419.815.093; C12.950.419.815.093; C16.320.831.093; C18.452.076.176.210
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D012279	Rickets	C05.116.198.816; C18.452.104.816; C18.452.174.845; C18.654.521.500.133.770.734
C566945	Trifunctional Protein Deficiency With Myopathy And Neuropathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523245 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.03	Kd	9.346	nM	CHEMBL5653589
8.03	ED50	9.346	nM	CHEMBL5653589
6.18	Kd	655.4	nM	CHEMBL3752910
6.18	ED50	655.4	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 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	2148483: Binding affinity to human HADHB incubated for 45 mins by Kinobead based pull down assay	kd	0.0093	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148483: Binding affinity to human HADHB incubated for 45 mins by Kinobead based pull down assay	kd	0.6554	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Fenofibrate	increases expression	2
Valproic Acid	decreases methylation, increases expression	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
fenofibric acid	affects binding, increases expression	1
nobiletin	decreases reaction, decreases expression	1
sodium arsenate	decreases expression, decreases reaction	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression, affects localization, decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	decreases expression, increases abundance	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	decreases expression	1
GW 7647	affects cotreatment, increases expression, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Rosiglitazone	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, decreases expression	1
Benztropine	increases expression	1
Clozapine	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4341438	Binding	Binding affinity to HADHB in human A549 cells lysates grown on SILAC media at 10 uM incubated for 1 hr by LC-MS/MS analysis relative to untreated control	Profiling withanolide A for therapeutic targets in neurodegenerative diseases. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_CV44	GM17482	Finite cell line	Female
CVCL_CV47	GM20265	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03035812	PHASE4	COMPLETED	Alkalinization by Urologists & Nephrologists
NCT03846258	PHASE4	WITHDRAWN	High Versus Low Bicarbonate Bath in Critically-ill Patients Receiving Continuous Renal Replacement Therapy
NCT05005793	PHASE4	RECRUITING	Effect of Alkali Therapy on Vascular and Graft Function in Kidney Transplant Recipients
NCT07424625	PHASE4	NOT_YET_RECRUITING	A Study of Tris-Hydroxymethyl Aminomethane (THAM) Versus Sodium Bicarbonate in Cardiac Surgical Patients
NCT07464431	PHASE4	NOT_YET_RECRUITING	Sodium Bicarbonate for Critically Ill Patients With Metabolic Acidosis and Acute Kidney Injury
NCT00949832	PHASE4	COMPLETED	Vitamin D and Genetics in Nutritional Rickets
NCT01067898	PHASE4	COMPLETED	A Study on Oral Vitamin D Megadoses
NCT01578434	PHASE4	COMPLETED	Role of Calcium And Vitamin D In Nutritional Rickets And It’s Management
NCT03403933	PHASE4	COMPLETED	Vitamin D Supplementation on in Major Orthopedic Surgery
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT01640119	PHASE3	UNKNOWN	Correction of Metabolic Acidosis in End Stage Renal Disease (ESRD)
NCT02476253	PHASE3	COMPLETED	Sodium Bicarbonate to Treat Severe Acidosis in the Critically Ill
NCT03317444	PHASE3	COMPLETED	Evaluation of TRC101 in Subjects With Metabolic Acidosis Associated With Chronic Kidney Disease
NCT03390842	PHASE3	COMPLETED	Long-term Safety Extension to Study TRCA-301
NCT03710291	PHASE3	TERMINATED	Evaluation of Effect of TRC101 on Progression of Chronic Kidney Disease in Subjects With Metabolic Acidosis
NCT04727528	PHASE3	TERMINATED	Study of the Effect of SZC on Serum Potassium and Serum Bicarbonate in Patients With Hyperkalemia and Metabolic Acidosis Associated With Chronic Kidney Disease
NCT05697770	PHASE3	ACTIVE_NOT_RECRUITING	SODium BICarbonate for Metabolic Acidosis in the ICU
NCT06545565	PHASE3	RECRUITING	Prevention of Metabolic Acidosis in Preterm Neonates by Replacing Sodium Chloride With Sodium Acetate in Parenteral Nutrition
NCT07355062	PHASE3	RECRUITING	A Study to Evaluate the Efficacy and Safety of Veverimer for the Treatment of Metabolic Acidosis
NCT00960232	PHASE3	COMPLETED	Vitamin D, Blood Pressure, Lipids, Infection and Depression
NCT01012414	PHASE3	TERMINATED	Effect of Vitamin D Supplement on Inflammation Markers in High-Risk Cardiovascular Patients With Chronic Kidney Disease
NCT01315366	PHASE3	COMPLETED	Hypovitaminosis D : A Link Between Bone/Mineral and Fat/Fuel Metabolism
NCT01689779	PHASE3	COMPLETED	High Dose Preoperative Cholecalciferol Supplementation and Perioperative Vitamin D Status
NCT01896544	PHASE3	COMPLETED	Cholecalciferol Supplementation for Sepsis in the ICU
NCT02328404	PHASE3	COMPLETED	The Effect of Vitamin D Supplementation Among Overweight Jordanian Women With Polycystic Ovary Syndrome (PCOS)
NCT02434380	PHASE3	COMPLETED	Effect of Vitamin D Replacement on Maternal and Neonatal Outcomes
NCT03272126	PHASE3	COMPLETED	Importance of Dosing Regimen for the Effect of Vitamin D Supplementation
NCT05306704	PHASE3	COMPLETED	High-Dose Vitamin D3 Supplementation in the Treatment of Human Immune Deficiency Virus Patients Trial
NCT05425914	PHASE3	COMPLETED	Impact of Vitamin D3 Supplementation in Non-Sjogren Dry Eye Patients With Low Serum Vitamin D Level
NCT01379625	PHASE2	COMPLETED	Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorder
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00913796	PHASE2	COMPLETED	Metabolic Acidosis in Renal Transplant Patients