AASDH

Summary

AASDH (aminoadipate-semialdehyde dehydrogenase, HGNC:23993) is a protein-coding gene on chromosome 4q12, encoding Beta-alanine-activating enzyme (Q4L235). Covalently binds beta-alanine in an ATP-dependent manner to form a thioester bond with its phosphopantetheine group and transfers it to an, as yet, unknown acceptor.

This gene encodes a member of the non-ribosome peptide syntesase (NRPS) enzyme family. The encoded protein contains an AMP-binding domain, PP-binding (phosphopantetheine, or pantetheine 4’phosphate-binding) domain and the Pyrrolo-quinoline quinon (PQQ) binding domain. The protein is expressed in several adult tissues.

Source: NCBI Gene 132949 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 176 total — 8 pathogenic
• MANE Select transcript: NM_181806

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23993
Approved symbol	AASDH
Name	aminoadipate-semialdehyde dehydrogenase
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	NRPS998, LYS2, ACSF4
Ensembl gene	ENSG00000157426
Ensembl biotype	protein_coding
OMIM	614365
Entrez	132949

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000205214, ENST00000451613, ENST00000502617, ENST00000503808, ENST00000510012, ENST00000510762, ENST00000513376, ENST00000514745, ENST00000514796, ENST00000602986, ENST00000861600, ENST00000861601, ENST00000911523, ENST00000911524, ENST00000911525, ENST00000947331, ENST00000947332, ENST00000947333, ENST00000947334, ENST00000947335

RefSeq mRNA: 10 — MANE Select: NM_181806 NM_001286668, NM_001286669, NM_001286670, NM_001286671, NM_001286672, NM_001323890, NM_001323892, NM_001323893, NM_001323899, NM_181806

CCDS: CCDS3504, CCDS68705, CCDS68706, CCDS75126, CCDS75127

Canonical transcript exons

ENST00000205214 — 15 exons

Exon	Start	End
ENSE00001672937	56338290	56338791
ENSE00003462884	56349263	56350058
ENSE00003468337	56355182	56355423
ENSE00003489502	56378148	56378464
ENSE00003492494	56371451	56371643
ENSE00003500457	56384070	56384341
ENSE00003500991	56354705	56354811
ENSE00003502460	56382477	56382597
ENSE00003529935	56353404	56353596
ENSE00003573585	56345127	56345290
ENSE00003573971	56351342	56351457
ENSE00003673538	56354039	56354211
ENSE00003719365	56343562	56343684
ENSE00003726064	56342835	56342966
ENSE00003846880	56387362	56387491

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 93.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9940 / max 276.5256, expressed in 1766 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52190	11.8933	1765
52189	0.1007	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	93.57	gold quality
pancreatic ductal cell	CL:0002079	90.38	gold quality
nipple	UBERON:0002030	89.37	gold quality
corpus epididymis	UBERON:0004359	88.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.01	gold quality
caput epididymis	UBERON:0004358	86.57	gold quality
renal medulla	UBERON:0000362	86.47	gold quality
oocyte	CL:0000023	86.31	gold quality
cauda epididymis	UBERON:0004360	86.28	gold quality
ileal mucosa	UBERON:0000331	85.56	gold quality
tibialis anterior	UBERON:0001385	85.31	gold quality
sperm	CL:0000019	83.87	gold quality
pylorus	UBERON:0001166	83.28	gold quality
deltoid	UBERON:0001476	83.19	silver quality
corpus callosum	UBERON:0002336	82.91	gold quality
cardia of stomach	UBERON:0001162	82.87	gold quality
inferior vagus X ganglion	UBERON:0005363	82.23	gold quality
adrenal tissue	UBERON:0018303	82.15	gold quality
pons	UBERON:0000988	82.10	gold quality
calcaneal tendon	UBERON:0003701	82.06	gold quality
ventricular zone	UBERON:0003053	82.00	gold quality
oviduct epithelium	UBERON:0004804	81.93	gold quality
pigmented layer of retina	UBERON:0001782	81.29	gold quality
endometrium	UBERON:0001295	81.22	gold quality
ventral tegmental area	UBERON:0002691	81.13	gold quality
tendon	UBERON:0000043	81.03	gold quality
islet of Langerhans	UBERON:0000006	80.97	gold quality
cortical plate	UBERON:0005343	80.64	gold quality
upper leg skin	UBERON:0004262	80.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting AASDH, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4662A-5P	98.48	67.18	1007
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-1468-5P	94.18	69.04	176

Literature-anchored findings (GeneRIF, showing 2)

• Human 2-aminoadipic 6-semialdehyde dehydrogenase gene was cloned; its mRNA is ubiquitously expressed in adult tissues and is highly expressed in colon adenocarcinoma (CX-1) and colon adenocarcinoma (GI-112) cell lines. (PMID:15865210)
• ACSF4 (U26) is a beta-alanine activating enzyme homologous to bacterial nonribosomal peptide synthetase. Experiments using the mouse protein suggest this enzyme may be involved in a rare intracellular reaction, possibly an infrequent post-translational or post-transcriptional modification. (PMID:24467666)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aasdh	ENSDARG00000022730
mus_musculus	Aasdh	ENSMUSG00000055923
rattus_norvegicus	Aasdh	ENSRNOG00000002137
drosophila_melanogaster	Aasdh	FBGN0027780
caenorhabditis_elegans		WBGENE00012356

Paralogs (13): ACSM3 (ENSG00000005187), ACSM2B (ENSG00000066813), AACS (ENSG00000081760), ACSS3 (ENSG00000111058), ACSS2 (ENSG00000131069), ACSS1 (ENSG00000154930), ACSM1 (ENSG00000166743), ACSF2 (ENSG00000167107), ACSM6 (ENSG00000173124), ACSF3 (ENSG00000176715), ACSM5 (ENSG00000183549), ACSM2A (ENSG00000183747), ACSM4 (ENSG00000215009)

Protein

Protein identifiers

Beta-alanine-activating enzyme — Q4L235 (reviewed: Q4L235)

Alternative names: Acyl-CoA synthetase family member 4, Protein NRPS998

All UniProt accessions (4): Q4L235, D6RJA2, E9PH98, R4GNB1

UniProt curated annotations — full annotation on UniProt →

Function. Covalently binds beta-alanine in an ATP-dependent manner to form a thioester bond with its phosphopantetheine group and transfers it to an, as yet, unknown acceptor. May be required for a post-translational protein modification or for post-transcriptional modification of an RNA.

Tissue specificity. Ubiquitously expressed in adult tissues.

Similarity. Belongs to the ATP-dependent AMP-binding enzyme family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q4L235-1	1	yes
Q4L235-2	2
Q4L235-3	3
Q4L235-4	4

RefSeq proteins (10): NP_001273597, NP_001273598, NP_001273599, NP_001273600, NP_001273601, NP_001310819, NP_001310821, NP_001310822, NP_001310828, NP_861522* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000873	AMP-dep_synth/lig_dom	Domain
IPR002372	PQQ_rpt_dom	Domain
IPR009081	PP-bd_ACP	Domain
IPR011047	Quinoprotein_ADH-like_sf	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR018391	PQQ_b-propeller_rpt	Repeat
IPR020845	AMP-binding_CS	Conserved_site
IPR036736	ACP-like_sf	Homologous_superfamily
IPR042099	ANL_N_sf	Homologous_superfamily
IPR045851	AMP-b_sf	Homologous_superfamily
IPR048005	AASDH_AMP	Domain
IPR052091	Beta-ala_Activ/Resist	Family

Pfam: PF00501, PF00550, PF13570

Enzyme classification (BRENDA):

• EC 1.2.1.31 — L-aminoadipate-semialdehyde dehydrogenase (BRENDA: 17 organisms, 29 substrates, 35 inhibitors, 21 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADPH	0.1–0.62	4
ALPHA-AMINOADIPATE	0.2–0.78	3
ATP	0.5–1.3	3
MGCL2	0.77–3.8	2
NAD+	0.2–0.454	2
NALPHA-BENZYLOXYCARBONYL-L-AMINOADIPATE-DELTA-SE	0.888–1.34	2
2-AMINOADIPIC SEMIALDEHYDE	0.02	1
DELTA1-PIPERIDINE 6-CARBOXYLATE	0.002	1
L-2-AMINOADIPATE	1.4	1
L-2-AMINOADIPATE 6-SEMIALDEHYDE	0.181	1
NADH	0.38	1
ALPHA-AMINOADIPATE SEMIALDEHYDE	—	0

UniProt features (27 total): sequence variant 7, sequence conflict 6, splice variant 5, binding site 4, modified residue 3, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4L235-F1	81.50	0.54

Functional residue map

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

Ligand- & substrate-binding residues (4): 198–206; 428; 442; 527

Post-translational modifications (3): 589, 649, 724

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 91 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_PEPTIDE_METABOLIC_PROCESS, GOBP_NONRIBOSOMAL_PEPTIDE_BIOSYNTHETIC_PROCESS, KEGG_LYSINE_DEGRADATION, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, BENPORATH_NOS_TARGETS, CDPCR3HD_01, BENPORATH_OCT4_TARGETS, GOBP_FATTY_ACID_METABOLIC_PROCESS, GOMF_ADENYL_NUCLEOTIDE_BINDING, chr4q12, GOBP_PEPTIDE_BIOSYNTHETIC_PROCESS

GO Biological Process (4): fatty acid metabolic process (GO:0006631), obsolete beta-alanine metabolic process (GO:0019482), amino acid activation for nonribosomal peptide biosynthetic process (GO:0043041), lipid metabolic process (GO:0006629)

GO Molecular Function (4): ATP binding (GO:0005524), ligase activity (GO:0016874), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	1
monocarboxylic acid metabolic process	1
nonribosomal peptide biosynthetic process	1
amino acid activation	1
primary metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1

Protein interactions and networks

STRING

4532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AASDH	ACSL1	P33121	938
AASDH	SLC27A1	Q6PCB7	931
AASDH	CPT2	P23786	921
AASDH	SLC25A20	O43772	914
AASDH	ACSL5	Q9ULC5	906
AASDH	ACSL3	O95573	902
AASDH	CPT1A	P50416	873
AASDH	DGAT2	Q96PD7	869
AASDH	SLC27A4	Q6P1M0	843
AASDH	CPT1C	Q8TCG5	831
AASDH	CPT1B	Q92523	828
AASDH	AASDHPPT	Q9NRN7	827
AASDH	ACSL4	O60488	785
AASDH	ACOX3	O15254	773
AASDH	ACSL6	Q9UKU0	769

IntAct

7 interactions, top by confidence:

A	B	Type	Score
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
RNF113A	CSNK2A2	psi-mi:“MI:0914”(association)	0.530
RPL36	AASDH	psi-mi:“MI:0915”(physical association)	0.400
KRT40	ANKRD36	psi-mi:“MI:0914”(association)	0.350
ZNF174	FAM171A2	psi-mi:“MI:0914”(association)	0.350
GORASP1	RTCA	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), RPL36 (Proximity Label-MS), AASDH (Proximity Label-MS), AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), AASDH (Affinity Capture-MS), AASDH (Proximity Label-MS), AASDH (Proximity Label-MS), AASDH (Proximity Label-MS)

ESM2 similar proteins: A2Y8B9, A7LFZ6, B5X561, C0LT23, F4K1G2, F4K2M8, F4KFT7, O43543, O82387, P84634, Q0DV28, Q10HL3, Q15KI9, Q4L235, Q58CU3, Q5R4D2, Q5RG49, Q5SNL7, Q5VS72, Q5W9E7, Q5Z856, Q682D3, Q69LX2, Q6AXL5, Q6E7H0, Q6P2P2, Q6TAS3, Q6USK2, Q7XD96, Q80WC9, Q84ND9, Q8BZT9, Q8H4D4, Q8L5Z4, Q8L870, Q8LPN3, Q8RWD9, Q8S8F2, Q8W032, Q8W4K1

Diamond homologs: P0DUV4, Q4L235, Q5RG49, Q80WC9, Q9I1H3, E9Q9W4, O05307, O14975, O35488, O42633, O53551, O88561, P38225, P97524, P97849, Q3ZKN0, Q4LDG0, Q4R3Y4, Q5K4L6, Q5RDY4, Q60714, Q6P1M0, Q6PCB7, Q7TWC5, Q8J0E9, Q91VE0, Q9ES38, Q9Y2P4, Q9Y2P5, O54154, Q9VLL0, A0A0H2ZF83, B0CN26, O06417, O07899, P10378, P38135, P39002, P40871, P47912

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	0
Uncertain significance	129
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1340288	GRCh37/hg19 4q12-31.21(chr4:52866944-143582507)x3	Pathogenic
1340920	GRCh37/hg19 4q11-12(chr4:52685685-58104722)x1	Pathogenic
2685108	GRCh37/hg19 4q11-13.1(chr4:52685685-61903883)x1	Pathogenic
58028	GRCh38/hg38 4q12-13.2(chr4:51831622-66991489)x3	Pathogenic
58029	GRCh38/hg38 4q12-22.3(chr4:51831622-97505618)x3	Pathogenic
58030	GRCh38/hg38 4q12-13.1(chr4:51899860-59984479)x3	Pathogenic
59423	GRCh38/hg38 4q12-13.1(chr4:52639018-59984479)x1	Pathogenic
59424	GRCh38/hg38 4q12-13.1(chr4:54198601-62270115)x1	Pathogenic

SpliceAI

2965 predictions. Top by Δscore:

Variant	Effect	Δscore
4:56343560:A:AC	donor_gain	1.0000
4:56343561:C:CC	donor_gain	1.0000
4:56345178:T:TA	donor_gain	1.0000
4:56353397:A:AC	donor_gain	1.0000
4:56353398:C:CC	donor_gain	1.0000
4:56353400:TTA:T	donor_loss	1.0000
4:56353401:TAC:T	donor_loss	1.0000
4:56353593:CAAC:C	acceptor_gain	1.0000
4:56353596:CCTA:C	acceptor_loss	1.0000
4:56353597:C:CC	acceptor_gain	1.0000
4:56354238:A:C	acceptor_gain	1.0000
4:56354713:A:AC	donor_gain	1.0000
4:56354714:C:CC	donor_gain	1.0000
4:56354715:TTGGC:T	donor_gain	1.0000
4:56354716:TGGCC:T	donor_gain	1.0000
4:56354724:G:GA	donor_gain	1.0000
4:56354728:T:TA	donor_gain	1.0000
4:56355180:A:AC	donor_gain	1.0000
4:56355181:C:CC	donor_gain	1.0000
4:56387360:A:AC	donor_gain	1.0000
4:56387361:C:CC	donor_gain	1.0000
4:56387361:CTTAG:C	donor_gain	1.0000
4:56387365:G:C	donor_gain	1.0000
4:56338790:ACCTA:A	acceptor_loss	0.9900
4:56338791:CCTAT:C	acceptor_loss	0.9900
4:56343685:C:CC	acceptor_gain	0.9900
4:56345125:A:AC	donor_gain	0.9900
4:56345126:C:CC	donor_gain	0.9900
4:56350059:C:CC	acceptor_gain	0.9900
4:56351464:A:C	acceptor_gain	0.9900

AlphaMissense

7175 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:56371586:G:C	F242L	0.997
4:56371586:G:T	F242L	0.997
4:56371588:A:G	F242L	0.997
4:56351347:A:G	W563R	0.994
4:56351347:A:T	W563R	0.994
4:56354076:C:G	R449P	0.994
4:56355231:A:G	W352R	0.994
4:56355231:A:T	W352R	0.994
4:56355232:A:C	S351R	0.994
4:56355232:A:T	S351R	0.994
4:56355234:T:G	S351R	0.994
4:56345205:G:C	S858R	0.993
4:56345205:G:T	S858R	0.993
4:56345207:T:G	S858R	0.993
4:56378193:A:T	V208D	0.992
4:56349476:A:G	W759R	0.991
4:56349476:A:T	W759R	0.991
4:56371584:T:C	D243G	0.991
4:56371584:T:A	D243V	0.990
4:56354140:C:G	D428H	0.989
4:56384244:G:T	A19D	0.989
4:56342919:G:C	F941L	0.988
4:56342919:G:T	F941L	0.988
4:56342921:A:G	F941L	0.988
4:56349335:A:G	W806R	0.988
4:56349335:A:T	W806R	0.988
4:56349395:A:C	Y786D	0.988
4:56354077:G:T	R449S	0.988
4:56355251:C:A	G345V	0.988
4:56338495:G:C	F1068L	0.987

dbSNP variants (sampled 300 via entrez): RS1000073960 (4:56342354 C>G,T), RS1000226496 (4:56362028 A>G), RS1000259093 (4:56361786 C>A,T), RS1000321453 (4:56348393 T>A), RS10003484 (4:56341840 G>A,T), RS1000366100 (4:56361484 G>A), RS1000383557 (4:56341037 A>C), RS1000426622 (4:56342659 G>A), RS1000536837 (4:56349583 T>C), RS1000608260 (4:56347968 T>C), RS1000687842 (4:56375159 A>G), RS1000711761 (4:56342615 T>C), RS1000742815 (4:56343052 G>C), RS1000772715 (4:56388440 A>C,G), RS1000813746 (4:56366559 G>C)

Disease associations

OMIM: gene MIM:614365 | 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

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, affects expression, increases abundance, decreases expression	3
Ozone	increases abundance, affects cotreatment, affects expression	3
methacrylaldehyde	increases abundance, affects cotreatment, affects expression	2
Acrolein	affects cotreatment, affects expression, increases abundance	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Gallic Acid	increases expression	1
Quercetin	increases phosphorylation	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1
Volatile Organic Compounds	affects cotreatment, affects expression	1

Clinical trials (associated diseases)

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