AOAH

Summary

AOAH (acyloxyacyl hydrolase, HGNC:548) is a protein-coding gene on chromosome 7p14.2, encoding Acyloxyacyl hydrolase (P28039). Removes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides.

This locus encodes both the light and heavy subunits of acyloxyacyl hydrolase. The encoded enzyme catalyzes the hydrolysis of acyloxylacyl-linked fatty acyl chains from bacterial lipopolysaccharides, effectively detoxifying these molecules. The encoded protein may play a role in modulating host inflammatory response to gram-negative bacteria. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 313 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 106 total
• MANE Select transcript: NM_001637

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:548
Approved symbol	AOAH
Name	acyloxyacyl hydrolase
Location	7p14.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000136250
Ensembl biotype	protein_coding
OMIM	102593
Entrez	313

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000414637, ENST00000435386, ENST00000480201, ENST00000487014, ENST00000491444, ENST00000495942, ENST00000543742, ENST00000612871, ENST00000614254, ENST00000617267, ENST00000617537, ENST00000621510, ENST00000860663, ENST00000860664, ENST00000941760

RefSeq mRNA: 3 — MANE Select: NM_001637 NM_001177506, NM_001177507, NM_001637

CCDS: CCDS5448, CCDS55102, CCDS75584

Canonical transcript exons

ENST00000617537 — 21 exons

Exon	Start	End
ENSE00000832386	36673943	36674009
ENSE00003582548	36659166	36659265
ENSE00003711963	36512941	36513380
ENSE00003713925	36623190	36623250
ENSE00003714379	36621710	36621780
ENSE00003714535	36618297	36618345
ENSE00003715843	36548612	36548686
ENSE00003716938	36576574	36576656
ENSE00003718119	36632036	36632106
ENSE00003722906	36532147	36532206
ENSE00003732255	36594339	36594430
ENSE00003733539	36530418	36530514
ENSE00003733565	36522039	36522115
ENSE00003734236	36724022	36724494
ENSE00003734343	36637851	36637910
ENSE00003738410	36620781	36620829
ENSE00003740291	36540319	36540491
ENSE00003740620	36549439	36549475
ENSE00003743741	36686699	36686794
ENSE00003746074	36532286	36532344
ENSE00003750146	36616380	36616474

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 99.02.

FANTOM5 (CAGE): breadth broad, TPM avg 19.0806 / max 1070.0289, expressed in 521 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83590	10.1813	462
83591	6.2114	418
83587	0.8514	134
83589	0.5168	198
83585	0.5132	101
83592	0.2853	131
83579	0.2170	29
83588	0.1209	62
83582	0.0875	39
83578	0.0489	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.02	gold quality
monocyte	CL:0000576	98.90	gold quality
leukocyte	CL:0000738	98.60	gold quality
mononuclear cell	CL:0000842	98.59	gold quality
blood	UBERON:0000178	96.31	gold quality
spleen	UBERON:0002106	95.77	gold quality
rectum	UBERON:0001052	91.10	gold quality
pancreatic ductal cell	CL:0002079	90.20	gold quality
vermiform appendix	UBERON:0001154	90.02	gold quality
mucosa of transverse colon	UBERON:0004991	89.92	gold quality
bone marrow cell	CL:0002092	89.86	gold quality
lymph node	UBERON:0000029	88.12	gold quality
right lung	UBERON:0002167	88.00	gold quality
bone marrow	UBERON:0002371	87.74	gold quality
gall bladder	UBERON:0002110	87.42	gold quality
upper lobe of left lung	UBERON:0008952	84.91	gold quality
caecum	UBERON:0001153	83.81	gold quality
trabecular bone tissue	UBERON:0002483	83.15	gold quality
right coronary artery	UBERON:0001625	82.95	gold quality
upper lobe of lung	UBERON:0008948	82.69	gold quality
transverse colon	UBERON:0001157	82.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.52	gold quality
nucleus accumbens	UBERON:0001882	81.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.19	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.07	gold quality
caudate nucleus	UBERON:0001873	80.92	gold quality
right lobe of liver	UBERON:0001114	80.68	gold quality
small intestine	UBERON:0002108	80.47	gold quality
smooth muscle tissue	UBERON:0001135	79.82	gold quality
omental fat pad	UBERON:0010414	79.62	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1715.36
E-CURD-119	yes	1096.81
E-CURD-122	yes	47.73
E-HCAD-35	yes	37.30
E-MTAB-6678	yes	22.58
E-ANND-3	yes	17.60
E-MTAB-8498	yes	10.09
E-MTAB-9067	yes	3.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting AOAH, 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-507	99.97	70.11	1915
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-154-5P	98.92	66.65	733
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-3943	95.87	64.57	523
HSA-MIR-2861	95.24	65.47	1056

Literature-anchored findings (GeneRIF, showing 5)

• Polymorphisms in RYBP and AOAH genes are associated with chronic rhinosinusitis in a Chinese population. (PMID:22723975)
• AOAH rs60023210 variants may be associated with carotid intima-media thickness at bifurcation. (PMID:26319989)
• AOAH - Gene involved in innate immunity that have been associated with Chronic Rhinosinusitis. (PMID:27888910)
• analysis of AOAH function through its crystal structure and complex with lipopolysaccharide (PMID:29343645)
• Acyloxyacyl Hydrolase Protects against Kidney Injury via Inhibition of Tubular CD74-Macrophage Crosstalk. (PMID:38904010)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Aoah	ENSMUSG00000021322
rattus_norvegicus	Aoah	ENSRNOG00000054964

Protein

Protein identifiers

Acyloxyacyl hydrolase — P28039 (reviewed: P28039)

All UniProt accessions (4): A0A087WVT3, C9JJA7, P28039, F8WCP9

UniProt curated annotations — full annotation on UniProt →

Function. Removes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides. By breaking down LPS, terminates the host response to bacterial infection and prevents prolonged and damaging inflammatory responses. In peritoneal macrophages, seems to be important for recovery from a state of immune tolerance following infection by Gram-negative bacteria.

Subunit / interactions. Heterodimer of the large and small subunits; disulfide-linked.

Subcellular location. Secreted. Cytoplasmic vesicle.

Post-translational modifications. Cleaved into a large and a small subunit. The small subunit is N-glycosylated.

Activity regulation. Inhibited by EDTA.

Cofactor. Binds 3 Ca(2+) ions per subunit. The calcium ions probably have a structural role.

Isoforms (2)

UniProt ID	Names	Canonical?
P28039-1	1	yes
P28039-2	2

RefSeq proteins (3): NP_001170977, NP_001170978, NP_001628* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001087	GDSL	Family
IPR008139	SaposinB_dom	Domain
IPR011001	Saposin-like	Homologous_superfamily
IPR036514	SGNH_hydro_sf	Homologous_superfamily
IPR039676	AOAH	Family
IPR048593	AOAH_Saposin_N	Domain

Pfam: PF00657, PF20825

Enzyme classification (BRENDA):

• EC 3.1.1.77 — acyloxyacyl hydrolase (BRENDA: 4 organisms, 23 substrates, 4 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
LIPOPOLYSACCHARIDE	0.0005–0.0017	4
DIACYLPHOSPHATIDYLETHANOLAMINE	0.0004	1
LONG CHAIN LIPOPOLYSACCHARIDE	0.0003	1
MEDIUM CHAIN LIPOPOLYSACCHARIDE	0.0003	1
SHORT CHAIN LIPOPOLYSACCHARIDE	0.0003	1

Catalyzed reactions (Rhea), 1 shown:

• a 3-(acyloxy)acyl derivative of bacterial toxin + H2O = a 3-hydroxyacyl derivative of bacterial toxin + a fatty acid + H(+) (RHEA:12032)

UniProt features (107 total): helix 29, binding site 18, turn 13, strand 13, disulfide bond 8, mutagenesis site 8, glycosylation site 4, sequence variant 3, chain 2, region of interest 2, signal peptide 1, propeptide 1, site 1, splice variant 1, domain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5W7C	X-RAY DIFFRACTION	2.23
5W78	X-RAY DIFFRACTION	2.27

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28039-F1	90.68	0.82

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 (2): 345 (interacts with lipopolysaccharide); 263

Ligand- & substrate-binding residues (18): 186; 188; 188; 190; 205; 205; 207; 208; 210; 213; 223; 227 …

Disulfide bonds (8): 41–114, 44–108, 70–83, 123–453, 160–169, 206–230, 249–329, 376–459

Glycosylation sites (4): 59, 207, 409, 466

Mutagenesis-validated functional residues (8):

Position	Phenotype
61	loss of glycosylation. no effect on enzyme activity or localization to cytoplasmic vesicles.
173	no effect on enzyme activity.
263	loss of enzyme activity.
263	nearly abolishes catalytic activity.
345	no effect on enzyme activity; when associated with e-379.
372	loss of enzyme activity with lipopolysaccharide, due to steric hindrance. no effect on activity with small, synthetic su
379	no effect on enzyme activity; when associated with e-345.
419	loss of enzyme activity with lipopolysaccharide, due to steric hindrance. no effect on activity with small, synthetic su

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 218 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_INFLAMMATORY_RESPONSE, MODULE_45, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, FOSTER_TOLERANT_MACROPHAGE_DN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, BROWN_MYELOID_CELL_DEVELOPMENT_UP, GNF2_CD97

GO Biological Process (5): fatty acid metabolic process (GO:0006631), lipopolysaccharide catabolic process (GO:0009104), negative regulation of inflammatory response (GO:0050728), lipid metabolic process (GO:0006629), lipopolysaccharide metabolic process (GO:0008653)

GO Molecular Function (6): calcium ion binding (GO:0005509), acyloxyacyl hydrolase activity (GO:0050528), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on ester bonds (GO:0016788), metal ion binding (GO:0046872)

GO Cellular Component (2): extracellular region (GO:0005576), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	1
monocarboxylic acid metabolic process	1
lipopolysaccharide metabolic process	1
macromolecule catabolic process	1
lipid catabolic process	1
carbohydrate derivative catabolic process	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
primary metabolic process	1
macromolecule metabolic process	1
liposaccharide metabolic process	1
metal ion binding	1
carboxylic ester hydrolase activity	1
binding	1
catalytic activity	1
hydrolase activity	1
cation binding	1
cellular anatomical structure	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

1234 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AOAH	PSAPL1	Q6NUJ1	463
AOAH	ARHGAP24	Q8N264	458
AOAH	PSAP	P07292	421
AOAH	LY96	Q9Y6Y9	396
AOAH	BRD2	P25440	362
AOAH	BPI	P17213	356
AOAH	SFTPB	P07988	356
AOAH	AZGP1	P25311	332
AOAH	GIMAP8	Q8ND71	332
AOAH	TLR4	O00206	324
AOAH	ALPI	P09923	320
AOAH	ELMO1	Q92556	313
AOAH	LYZL6	O75951	305
AOAH	XYLB	O75191	303
AOAH	TBC1D22A	Q8WUA7	303

IntAct

5 interactions, top by confidence:

A	B	Type	Score
AOAH	DLG2	psi-mi:“MI:0915”(physical association)	0.560
IGHG1	PDPK1	psi-mi:“MI:0914”(association)	0.350
AOAH	DLG2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): DLG2 (Two-hybrid), DLG3 (Two-hybrid)

ESM2 similar proteins: A5PJN2, B1H1F9, B4URD6, B6CVD7, O18823, O43556, O43909, O56140, O70258, P0C152, P28039, P97259, Q01H84, Q08834, Q09328, Q28F39, Q29S03, Q2F4V2, Q4R5B1, Q5HYA8, Q5RAP2, Q6AXF6, Q6DD71, Q6DPZ9, Q6DQ19, Q6DQ21, Q6J8E7, Q6YAT4, Q7SEY9, Q7T3D1, Q7X9I4, Q7YTU4, Q86YB8, Q8BR76, Q8IZ81, Q8NBP0, Q8QPL1, Q8R180, Q8R2E9, Q8R3N6

Diamond homologs: O18823, O35298, P28039

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3776 predictions. Top by Δscore:

Variant	Effect	Δscore
7:36522034:CTTAC:C	donor_loss	1.0000
7:36522036:TACCT:T	donor_loss	1.0000
7:36522037:ACCTC:A	donor_loss	1.0000
7:36522038:CCT:C	donor_gain	1.0000
7:36522113:TGA:T	acceptor_gain	1.0000
7:36522113:TGAC:T	acceptor_loss	1.0000
7:36522116:C:CC	acceptor_gain	1.0000
7:36522116:C:G	acceptor_loss	1.0000
7:36522117:T:C	acceptor_loss	1.0000
7:36530410:CTACT:C	donor_loss	1.0000
7:36530411:TACTT:T	donor_loss	1.0000
7:36530412:ACT:A	donor_loss	1.0000
7:36530413:CTT:C	donor_loss	1.0000
7:36530414:TT:T	donor_loss	1.0000
7:36530415:TACT:T	donor_loss	1.0000
7:36530416:A:AC	donor_gain	1.0000
7:36530416:AC:A	donor_loss	1.0000
7:36530416:ACTTT:A	donor_gain	1.0000
7:36530417:C:A	donor_loss	1.0000
7:36530417:C:CG	donor_gain	1.0000
7:36530417:CT:C	donor_gain	1.0000
7:36530417:CTT:C	donor_gain	1.0000
7:36530417:CTTT:C	donor_gain	1.0000
7:36530417:CTTTC:C	donor_gain	1.0000
7:36530513:CT:C	acceptor_gain	1.0000
7:36530514:TC:T	acceptor_loss	1.0000
7:36530515:C:CC	acceptor_gain	1.0000
7:36530516:T:C	acceptor_loss	1.0000
7:36549435:TTACC:T	donor_loss	1.0000
7:36549436:TAC:T	donor_loss	1.0000

AlphaMissense

3804 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:36621758:C:G	R202P	0.991
7:36576609:C:G	C329S	0.988
7:36576610:A:T	C329S	0.988
7:36621760:C:A	W201C	0.988
7:36621760:C:G	W201C	0.988
7:36540392:G:C	S411R	0.985
7:36540392:G:T	S411R	0.985
7:36540394:T:G	S411R	0.985
7:36618302:C:G	C249S	0.985
7:36618303:A:T	C249S	0.985
7:36620793:A:C	C230W	0.984
7:36659233:C:G	C108S	0.983
7:36659234:A:T	C108S	0.983
7:36659234:A:G	C108R	0.982
7:36540387:A:T	V413D	0.980
7:36616406:A:G	W274R	0.980
7:36616406:A:T	W274R	0.980
7:36620794:C:T	C230Y	0.980
7:36621756:C:A	G203W	0.980
7:36621762:A:G	W201R	0.980
7:36621762:A:T	W201R	0.980
7:36532186:C:A	W462C	0.979
7:36532186:C:G	W462C	0.979
7:36576609:C:T	C329Y	0.979
7:36623199:G:C	S191R	0.979
7:36623199:G:T	S191R	0.979
7:36623201:T:G	S191R	0.979
7:36686792:A:G	C44R	0.979
7:36540417:A:G	L403P	0.978
7:36620794:C:A	C230F	0.977

dbSNP variants (sampled 300 via entrez): RS1000006851 (7:36619449 C>T), RS1000011334 (7:36640194 G>C), RS1000018486 (7:36601755 T>A), RS1000070682 (7:36558972 GCTGCACCCACTGTC>G), RS1000086225 (7:36720006 C>A,T), RS1000090520 (7:36565540 T>G), RS1000105530 (7:36701864 G>A), RS1000108521 (7:36516777 C>A), RS1000115756 (7:36542713 A>T), RS1000126614 (7:36576356 C>T), RS1000140255 (7:36558093 G>GT), RS1000148646 (7:36716938 C>T), RS1000158537 (7:36606434 T>A), RS1000164725 (7:36518314 A>G), RS1000167089 (7:36575887 C>T)

Disease associations

OMIM: gene MIM:102593 | 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
GCST000656_6	HIV-1 viral setpoint	3.000000e-06
GCST001762_196	Obesity-related traits	1.000000e-06
GCST007159_25	Corneal astigmatism	2.000000e-06
GCST007294_70	Body fat distribution (trunk fat ratio)	7.000000e-06
GCST008098_10	Atypical femoral fracture in phosphonate treatment	7.000000e-06
GCST012490_542	Femur bone mineral density x serum urate levels interaction	4.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0004338	body weight
EFO:1002040	Corneal astigmatism
EFO:0004341	body fat distribution
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 3.1.1.- Carboxylic Ester Hydrolases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
JZL195	Inhibition	7.36	pIC50

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	4
sodium arsenite	affects methylation, increases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	increases expression	2
Aflatoxin B1	increases methylation	2
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
aflatoxin B2	increases methylation	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic	affects methylation	1
Diuron	decreases expression	1
Hydralazine	decreases expression, affects cotreatment	1
Methamphetamine	affects response to substance	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	increases expression	1
Antirheumatic Agents	decreases expression	1
Metals, Heavy	affects cotreatment, decreases methylation	1

Clinical trials (associated diseases)

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