CPA3

Summary

CPA3 (carboxypeptidase A3, HGNC:2298) is a protein-coding gene on chromosome 3q24, encoding Mast cell carboxypeptidase A (P15088).

This gene encodes a member of the carboxypeptidase A family of zinc metalloproteases. The encoded preproprotein is proteolytically processed to generate a mature protease that is released by mast cells and may be involved in the degradation of endogenous proteins and the inactivation of venom-associated peptides. Expression of this gene may be elevated in human asthma patients.

Source: NCBI Gene 1359 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 73 total
• Druggable target: yes
• MANE Select transcript: NM_001870

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2298
Approved symbol	CPA3
Name	carboxypeptidase A3
Location	3q24
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163751
Ensembl biotype	protein_coding
OMIM	114851
Entrez	1359

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000296046, ENST00000477926, ENST00000899613, ENST00000899614

RefSeq mRNA: 1 — MANE Select: NM_001870 NM_001870

CCDS: CCDS3138

Canonical transcript exons

ENST00000296046 — 11 exons

Exon	Start	End
ENSE00001077928	148865296	148865375
ENSE00001077930	148879788	148879889
ENSE00001077933	148896520	148897203
ENSE00001077934	148865473	148865548
ENSE00001077935	148881522	148881632
ENSE00001077937	148878441	148878543
ENSE00001077938	148878647	148878748
ENSE00001077939	148868915	148869039
ENSE00003462871	148882505	148882595
ENSE00003508507	148883613	148883815
ENSE00003620074	148886093	148886177

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 98.28.

FANTOM5 (CAGE): breadth broad, TPM avg 36.0093 / max 16107.7684, expressed in 238 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39105	35.2751	162
39106	0.4360	33
39113	0.1914	77
39107	0.0534	14
39115	0.0298	11
39114	0.0235	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	98.28	gold quality
skin of hip	UBERON:0001554	97.38	gold quality
upper leg skin	UBERON:0004262	94.48	gold quality
rectum	UBERON:0001052	92.50	gold quality
visceral pleura	UBERON:0002401	91.99	gold quality
right lung	UBERON:0002167	91.97	gold quality
ileal mucosa	UBERON:0000331	90.87	gold quality
upper lobe of left lung	UBERON:0008952	89.99	gold quality
upper lobe of lung	UBERON:0008948	89.70	gold quality
right coronary artery	UBERON:0001625	89.56	gold quality
lower lobe of lung	UBERON:0008949	89.41	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.16	gold quality
mucosa of stomach	UBERON:0001199	89.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.54	gold quality
colonic epithelium	UBERON:0000397	88.48	gold quality
lung	UBERON:0002048	88.08	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.86	gold quality
trabecular bone tissue	UBERON:0002483	86.79	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.78	gold quality
lower esophagus	UBERON:0013473	86.73	gold quality
pleura	UBERON:0000977	86.42	gold quality
urinary bladder	UBERON:0001255	86.20	gold quality
fundus of stomach	UBERON:0001160	85.93	gold quality
vermiform appendix	UBERON:0001154	85.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.65	gold quality
body of stomach	UBERON:0001161	85.51	gold quality
skin of leg	UBERON:0001511	84.97	gold quality
mucosa of transverse colon	UBERON:0004991	84.49	gold quality
cauda epididymis	UBERON:0004360	84.33	gold quality
zone of skin	UBERON:0000014	84.29	gold quality

Single-cell (SCXA)

Detected in 40 experiment(s), a significant marker in 38.

Experiment	Marker?	Max mean expression
E-GEOD-130148	yes	11832.54
E-HCAD-15	yes	6812.69
E-MTAB-10042	yes	5543.05
E-MTAB-6653	yes	5441.14
E-MTAB-6505	yes	3832.80
E-GEOD-139324	yes	3823.22
E-GEOD-130473	yes	3713.29
E-MTAB-8410	yes	3677.75
E-MTAB-6308	yes	3628.09
E-CURD-122	yes	3418.08
E-CURD-114	yes	2940.03
E-CURD-88	yes	2545.03
E-HCAD-36	yes	2515.10
E-HCAD-31	yes	2458.02
E-CURD-79	yes	2387.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1, GATA2

miRNA regulators (miRDB)

41 targeting CPA3, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4422	99.72	72.07	2908
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-3934-5P	99.67	64.04	846
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-4738-3P	98.98	67.98	1846

Literature-anchored findings (GeneRIF, showing 6)

• The cDNA encoding human colon mast cell carboxypeptidase can be successfully cloned and expressed in E. coli and P. pastoris. (PMID:14760754)
• Role in regulating innate immunity responses and regulating secretory granule homeostasis (PMID:19643669)
• Urine CPA3 was increased in patients with chronic prostatitis/chronic pelvic pain syndrome compared to controls. (PMID:24726923)
• Carboxypeptidase A3 was differentially expressed between Fibromyalgia patients and healthy controls. (PMID:27157394)
• Decreased serum level of carboxypeptidase is a hallmark of more advanced coronary artery disease. (PMID:29512095)
• Severe COVID-19 is marked by dysregulated serum levels of carboxypeptidase A3 and serotonin. (PMID:34057753)

Cross-species orthologs

23 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cpa3	ENSMUSG00000001865
rattus_norvegicus	Cpa3	ENSRNOG00000011181
drosophila_melanogaster	CG3097	FBGN0029804
drosophila_melanogaster	CG3108	FBGN0029807
drosophila_melanogaster	CG18585	FBGN0031929
drosophila_melanogaster	CG7025	FBGN0031930
drosophila_melanogaster	CG4017	FBGN0032143
drosophila_melanogaster	CG17633	FBGN0032144
drosophila_melanogaster	CG2915	FBGN0033241
drosophila_melanogaster	CG12374	FBGN0033774
drosophila_melanogaster	CG14820	FBGN0035718
drosophila_melanogaster	CG8563	FBGN0035777
drosophila_melanogaster	CG8562	FBGN0035779
drosophila_melanogaster	CG18417	FBGN0035780
drosophila_melanogaster	CG8560	FBGN0035781
drosophila_melanogaster	CG8539	FBGN0035791
drosophila_melanogaster	CG4408	FBGN0039073
drosophila_melanogaster	CG32379	FBGN0052379
drosophila_melanogaster	CG42264	FBGN0259149
caenorhabditis_elegans		WBGENE00004747
caenorhabditis_elegans	T06A4.1	WBGENE00020281
caenorhabditis_elegans	Y47G6A.19	WBGENE00021645
caenorhabditis_elegans		WBGENE00021984

Paralogs (8): CPB2 (ENSG00000080618), CPA1 (ENSG00000091704), CPA4 (ENSG00000128510), CPO (ENSG00000144410), CPB1 (ENSG00000153002), CPA2 (ENSG00000158516), CPA5 (ENSG00000158525), CPA6 (ENSG00000165078)

Protein

Protein identifiers

Mast cell carboxypeptidase A — P15088 (reviewed: P15088)

Alternative names: Carboxypeptidase A3

All UniProt accessions (1): P15088

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cytoplasmic vesicle. Secretory vesicle.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M14 family.

RefSeq proteins (1): NP_001861* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000834	Peptidase_M14	Domain
IPR003146	M14A_act_pep	Domain
IPR034253	CPB_M14_CPD	Domain
IPR036990	M14A-like_propep	Homologous_superfamily
IPR057247	CARBOXYPEPT_ZN_2	Binding_site

Pfam: PF00246, PF02244

Enzyme classification (BRENDA):

• EC 3.4.17.1 — carboxypeptidase A (BRENDA: 32 organisms, 224 substrates, 281 inhibitors, 110 Km, 101 kcat entries)

Substrate kinetics (BRENDA)

64 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HIPPURYL-L-PHENYLALANINE	0.075–1.5	11
HIPPURYL-L-PHE	0.33–60	8
CARBOBENZOXY-GLY-L-PHE	0.21–16.1	5
BENZOYL-GLY-L-PHE	0.23–10	3
HIPPURYL-L-PHENYLLACTATE	0.062–0.11	3
N-[3-(2-FURYL)ACRYLOYL]-PHE-PHE	27–340	3
O-(TRANS-P-CHLOROCINNAMOYL)-L-BETA-PHENYLLACTATE	0.49–120	3
ANGIOTENSIN I	0.227–0.78	2
CARBOBENZOXY-GLY-L-LEU	0.16–33	2
HIPPURYL-DL-BETA-PHENYLLACTATE	780–1300	2
N-(3-[2-FURYL]ACRYLOYL)-PHE-PHE	0.024–0.034	2
N-CARBOBENZOXY-GLY-GLY-L-LEU	0.74–6.53	2
N-CARBOBENZOXY-GLY-GLY-L-PHE	0.0346–0.314	2
N-CARBOBENZOXY-GLY-L-PHE	0.0449–0.985	2
N-CARBOBENZOXY-GLY-L-TYR	0.143–0.145	2

UniProt features (16 total): sequence conflict 4, binding site 3, sequence variant 2, disulfide bond 2, signal peptide 1, propeptide 1, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15088-F1	94.77	0.92

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): 378 (proton donor/acceptor)

Ligand- & substrate-binding residues (3): 176; 179; 304

Disulfide bonds (2): 173–186, 245–268

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 191 (showing top): MODULE_172, chr3q24, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, LI_PROSTATE_CANCER_EPIGENETIC, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_PROTEIN_MATURATION, MARTINEZ_RB1_TARGETS_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3

GO Biological Process (3): angiotensin maturation (GO:0002003), proteolysis (GO:0006508), regulation of angiotensin levels in blood (GO:0002002)

GO Molecular Function (7): metallocarboxypeptidase activity (GO:0004181), zinc ion binding (GO:0008270), carboxypeptidase activity (GO:0004180), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), transport vesicle (GO:0030133), secretory granule (GO:0030141), extracellular matrix (GO:0031012), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide hormone metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	2
regulation of angiotensin levels in blood	1
peptide hormone processing	1
protein metabolic process	1
regulation of systemic arterial blood pressure by circulatory renin-angiotensin	1
regulation of hormone levels	1
carboxypeptidase activity	1
metalloexopeptidase activity	1
transition metal ion binding	1
exopeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1
cytoplasmic vesicle	1
secretory vesicle	1
external encapsulating structure	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

1244 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPA3	NDST2	P52849	897
CPA3	CMA1	P23946	865
CPA3	FCER1A	P12319	782
CPA3	TPSAB1	P15157	734
CPA3	SRGN	P10124	718
CPA3	MS4A2	Q01362	711
CPA3	CTSG	P08311	707
CPA3	A0A087X1U0	A0A087X1U0	638
CPA3	MS4A1	P08984	629
CPA3	GATA2	P23769	610
CPA3	NDST1	P52848	566
CPA3	MRGPRX2	Q96LB1	500
CPA3	PCDH15	Q96QU1	497
CPA3	TPSG1	Q9NRR2	491
CPA3	HDC	P19113	487

IntAct

3 interactions, top by confidence:

A	B	Type	Score
H1-10	CPA3	psi-mi:“MI:0915”(physical association)	0.400
CPA3	DMTN	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3): H1FX (Proximity Label-MS), DMTN (Affinity Capture-MS), CPA3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4F020, A6XGK3, B6V865, B8JLQ9, B8XGR3, C5FH26, C5FVN6, D4AS12, D4B5N0, D4D675, D4DL57, O02350, O17754, O97397, P00730, P00731, P00732, P09954, P09955, P15085, P15086, P15088, P15089, P16406, P19222, P19223, P21961, P37892, P38836, P42787, P48052, P54969, P55261, Q0II73, Q29NC4, Q2KIG3, Q2KJ83, Q3T905, Q4R7R2, Q504N0

Diamond homologs: A1CSU3, A1DGH9, A2QZA2, A6RCF5, A6XGK3, A7EUC0, B0XRS8, B6H233, B6Q972, B6V865, B8JLQ9, B8M2K0, B8NBP9, B8XGR3, C0NM08, C0SAI5, C1GDH9, C1HE31, C4JEE1, C5FH26, C5FPR9, C5FVN6, C5G6U8, C5JZS0, C5PHW9, C6H4F1, D4AKU7, D4AS12, D4B5N0, D4D675, D4DIW7, D4DL57, E4UPZ6, E5A0U8, E9DD69, O74818, P00730, P04069, P09954, P15085

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2778 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:148882577:T:C	F254L	0.985
3:148882579:T:A	F254L	0.985
3:148882579:T:G	F254L	0.985
3:148879853:G:C	W180C	0.983
3:148879853:G:T	W180C	0.983
3:148896612:T:C	F387L	0.982
3:148896614:T:A	F387L	0.982
3:148896614:T:G	F387L	0.982
3:148882521:A:T	K235I	0.980
3:148881602:T:A	N219K	0.979
3:148881602:T:G	N219K	0.979
3:148882516:G:C	W233C	0.976
3:148882516:G:T	W233C	0.976
3:148879851:T:A	W180R	0.975
3:148879851:T:C	W180R	0.975
3:148881522:G:C	A193P	0.974
3:148879871:C:G	C186W	0.970
3:148882576:T:A	N253K	0.969
3:148882576:T:G	N253K	0.969
3:148879869:T:C	C186R	0.968
3:148881610:G:A	G222E	0.968
3:148882514:T:A	W233R	0.968
3:148882514:T:C	W233R	0.968
3:148881610:G:T	G222V	0.965
3:148882508:C:A	R231S	0.965
3:148896647:C:G	C398W	0.965
3:148878717:C:T	T148I	0.964
3:148879870:G:A	C186Y	0.963
3:148881606:G:C	D221H	0.963
3:148882527:G:C	R237P	0.962

dbSNP variants (sampled 300 via entrez): RS1000149856 (3:148875927 T>C), RS1000150732 (3:148896859 C>T), RS1000173826 (3:148873367 GCGCACACGCGCACA>G), RS1000201125 (3:148867116 C>T), RS1000204078 (3:148869736 C>A), RS1000230166 (3:148864037 G>C), RS1000500883 (3:148876300 ATATT>A), RS1000502447 (3:148878849 A>G), RS1000804292 (3:148895884 T>C), RS1000856735 (3:148895600 G>T), RS1000983104 (3:148892182 A>C), RS1001286368 (3:148875253 A>G), RS1001435234 (3:148889866 T>A,C), RS1001478592 (3:148865666 G>A), RS1001483539 (3:148882409 A>T)

Disease associations

OMIM: gene MIM:114851 | 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: yes

ChEMBL targets (1): CHEMBL2645 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M14: Carboxypeptidase A

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.11	Ki	7.8	nM	CHEMBL90403
6.35	Ki	450	nM	CHEMBL151284
5.30	Ki	5000	nM	CHEMBL153232

PubChem BioAssay actives

2 with measured affinity, of 7 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
2-benzylbutanedioic acid	48493: The compound was evaluated for the inhibition of Carboxypeptidase A	ki	0.4500	uM
2-benzylpentanedioic acid	48493: The compound was evaluated for the inhibition of Carboxypeptidase A	ki	5.0000	uM

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
1,2-dielaidoylphosphatidylethanolamine	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	increases expression, affects cotreatment	1
Decitabine	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Allergens	increases expression	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	decreases expression	1
Copper	affects cotreatment, increases expression	1
Endosulfan	decreases expression, decreases reaction	1
Latex	decreases expression	1
Selenium	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4413988	Binding	Binding affinity to CPA3 expressing human HeLa cells assessed as compound co-localization with CPA3 at 1 to 5 uM treated for 6 hrs followed by cell wash and measured by DAPI-staining based fluorescence confocal microscopy	Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes. — J Med Chem

Clinical trials (associated diseases)

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