CPD

Summary

CPD (carboxypeptidase D, HGNC:2301) is a protein-coding gene on chromosome 17q11.2, encoding Carboxypeptidase D (O75976). Functions in the processing of proteins and peptides in the secretory pathway.

The metallocarboxypeptidase family of enzymes is divided into 2 subfamilies based on sequence similarities. The pancreatic carboxypeptidase-like and the regulatory B-type carboxypeptidase subfamilies. Carboxypeptidase D has been identified as a regulatory B-type carboxypeptidase. CPD is a homolog of duck gp180, a hepatitis B virus-binding protein. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

Source: NCBI Gene 1362 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 175 total
• Regional missense constraint (gnomAD): 1 of 6 regions constrained (≈1% of expected missense variation)
• GTEx eGene: eQTL in 19 tissues, sQTL in 6 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.63 (unconstrained)
• MANE Select transcript: NM_001304
• Notable: 175 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2301
Approved symbol	CPD
Name	carboxypeptidase D
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	GP180
Ensembl gene	ENSG00000108582
Ensembl biotype	protein_coding
OMIM	603102
Entrez	1362

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 5 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000225719

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 3, TSL 3: 1, TSL 5: 4

ENST00000225719, ENST00000543464, ENST00000579502, ENST00000580396, ENST00000581826, ENST00000583275, ENST00000584050, ENST00000584051, ENST00000588977, ENST00000892708, ENST00000961764, ENST00001037094, ENST00001139066

RefSeq mRNA: 2 — MANE Select: NM_001304 NM_001199775, NM_001304

CCDS: CCDS11257, CCDS56025

Canonical transcript exons

ENST00000225719 — 21 exons

Exon	Start	End
ENSE00000708946	30443802	30443971
ENSE00000708954	30449553	30449748
ENSE00000708966	30461180	30461311
ENSE00000708968	30461877	30462062
ENSE00000708970	30462370	30462469
ENSE00001114338	30438975	30439077
ENSE00001114339	30431772	30431881
ENSE00001114341	30420841	30420983
ENSE00001114342	30427391	30427558
ENSE00001114343	30422674	30423023
ENSE00001114344	30384989	30385236
ENSE00001114345	30423506	30423697
ENSE00001114346	30421664	30421833
ENSE00001311861	30378927	30379726
ENSE00003547172	30445691	30446020
ENSE00003604475	30442308	30442450
ENSE00003627501	30455339	30455470
ENSE00003639830	30451711	30451846
ENSE00003670585	30456256	30456351
ENSE00003687512	30456462	30456526
ENSE00004794113	30464588	30469989

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.5411 / max 877.7806, expressed in 1814 samples.

Highest expression (Bgee): parotid gland, islet of Langerhans, bronchial epithelial cell, epithelium of bronchus, bronchus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CPD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 25 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	sqtl	1.1e-15	+0.29	17:30494808:C:A
Cells Cultured fibroblasts	eqtl	4.8e-11	+0.19	17:30533315:T:C
Esophagus Muscularis	eqtl	1.5e-10	+0.15	17:30392225:C:G
Muscle Skeletal	eqtl	1.4e-08	+0.12	17:30527833:C:CCACTACTCTAGAGTGT
Artery Aorta	eqtl	3.7e-06	+0.83	17:30429393:C:T
Testis	sqtl	1.4e-05	-0.41	17:30541711:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.5e-05	+0.14	17:30527833:C:CCACTACTCTAGAGTGT
Cells EBV-transformed lymphocytes	eqtl	4.4e-05	+0.24	17:30486517:T:C
Testis	eqtl	5.8e-05	+0.10	17:30426902:T:C
Brain Caudate basal ganglia	eqtl	1.1e-04	+0.16	17:30537892:T:C
Artery Tibial	eqtl	2.0e-04	+0.12	17:30538951:A:G
Skin Sun Exposed Lower leg	eqtl	2.2e-04	+0.10	17:30533315:T:C
Brain Nucleus accumbens basal ganglia	eqtl	3.4e-04	+0.18	17:30480432:A:G
Whole Blood	eqtl	7.5e-04	+0.16	17:30355233:T:A
Esophagus Gastroesophageal Junction	eqtl	2.3e-03	+0.12	17:30370661:A:T
Esophagus Mucosa	eqtl	2.7e-03	-0.12	17:30485102:G:A
Pituitary	eqtl	2.9e-03	-1.02	17:29435275:A:G
Adipose Subcutaneous	sqtl	7.1e-03	+0.30	17:30527833:C:CCACTACTCTAGAGTGT
Adrenal Gland	eqtl	1.6e-02	-0.14	17:30355435:T:A
Colon Transverse	sqtl	2.9e-02	-0.93	17:29691521:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
160132	37.5216	1814
208120	0.0196	5

Top tissues by expression

showing 100 of 301 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	98.54	gold quality
islet of Langerhans	UBERON:0000006	96.51	gold quality
bronchial epithelial cell	CL:0002328	96.38	gold quality
epithelium of bronchus	UBERON:0002031	95.82	gold quality
bronchus	UBERON:0002185	95.79	gold quality
nasal cavity epithelium	UBERON:0005384	95.53	gold quality
calcaneal tendon	UBERON:0003701	95.17	gold quality
pancreatic ductal cell	CL:0002079	95.14	gold quality
nasal cavity mucosa	UBERON:0001826	94.97	gold quality
sperm	CL:0000019	94.81	gold quality
epithelial cell of pancreas	CL:0000083	94.63	gold quality
colonic epithelium	UBERON:0000397	94.03	gold quality
gall bladder	UBERON:0002110	94.01	gold quality
male germ cell	CL:0000015	93.61	gold quality
stromal cell of endometrium	CL:0002255	93.50	gold quality
palpebral conjunctiva	UBERON:0001812	93.43	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.30	gold quality
trachea	UBERON:0003126	93.24	gold quality
jejunal mucosa	UBERON:0000399	93.15	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.69	gold quality
pylorus	UBERON:0001166	92.35	gold quality
blood	UBERON:0000178	92.34	gold quality
endothelial cell	CL:0000115	92.19	gold quality
corpus epididymis	UBERON:0004359	92.15	gold quality
choroid plexus epithelium	UBERON:0003911	91.96	gold quality
periodontal ligament	UBERON:0008266	91.95	gold quality
cartilage tissue	UBERON:0002418	91.94	gold quality
corpus callosum	UBERON:0002336	91.85	gold quality
right testis	UBERON:0004534	91.75	gold quality
left testis	UBERON:0004533	91.67	gold quality
eye	UBERON:0000970	91.37	gold quality
placenta	UBERON:0001987	91.19	gold quality
saliva-secreting gland	UBERON:0001044	91.17	gold quality
duodenum	UBERON:0002114	91.14	gold quality
metanephric glomerulus	UBERON:0004736	91.04	gold quality
testis	UBERON:0000473	90.89	gold quality
renal glomerulus	UBERON:0000074	90.84	gold quality
pericardium	UBERON:0002407	90.82	gold quality
monocyte	CL:0000576	90.56	gold quality
mononuclear cell	CL:0000842	90.41	gold quality
smooth muscle tissue	UBERON:0001135	90.41	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.34	gold quality
leukocyte	CL:0000738	90.29	gold quality
colonic mucosa	UBERON:0000317	90.26	gold quality
skin of hip	UBERON:0001554	89.99	gold quality
tendon	UBERON:0000043	89.95	gold quality
minor salivary gland	UBERON:0001830	89.85	gold quality
secondary oocyte	CL:0000655	89.82	gold quality
visceral pleura	UBERON:0002401	89.79	gold quality
type B pancreatic cell	CL:0000169	89.75	gold quality
caput epididymis	UBERON:0004358	89.70	gold quality
adrenal tissue	UBERON:0018303	89.27	gold quality
endometrium	UBERON:0001295	88.96	gold quality
mouth mucosa	UBERON:0003729	88.94	gold quality
medial globus pallidus	UBERON:0002477	88.84	gold quality
epithelium of nasopharynx	UBERON:0001951	88.76	gold quality
nasopharynx	UBERON:0001728	88.74	gold quality
bone marrow	UBERON:0002371	88.70	gold quality
upper leg skin	UBERON:0004262	88.60	gold quality
urethra	UBERON:0000057	88.57	gold quality
rectum	UBERON:0001052	88.42	gold quality
pleura	UBERON:0000977	88.17	gold quality
ileal mucosa	UBERON:0000331	88.16	gold quality
lower lobe of lung	UBERON:0008949	88.14	gold quality
pancreas	UBERON:0001264	88.13	gold quality
bone marrow cell	CL:0002092	88.04	gold quality
kidney epithelium	UBERON:0004819	87.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.85	gold quality
epithelium of mammary gland	UBERON:0003244	87.75	gold quality
mammary duct	UBERON:0001765	87.62	gold quality
lung	UBERON:0002048	87.62	gold quality
oral cavity	UBERON:0000167	87.51	gold quality
cardia of stomach	UBERON:0001162	87.51	gold quality
metanephros	UBERON:0000081	87.49	gold quality
nephron tubule	UBERON:0001231	87.33	gold quality
thoracic mammary gland	UBERON:0005200	87.18	gold quality
mammary gland	UBERON:0001911	87.06	gold quality
spinal cord	UBERON:0002240	86.96	gold quality
tonsil	UBERON:0002372	86.91	gold quality
liver	UBERON:0002107	86.87	gold quality
parietal pleura	UBERON:0002400	86.77	gold quality
gingiva	UBERON:0001828	86.62	gold quality
globus pallidus	UBERON:0001875	86.61	gold quality
cortex of kidney	UBERON:0001225	86.38	gold quality
connective tissue	UBERON:0002384	86.37	gold quality
adipose tissue	UBERON:0001013	86.29	gold quality
upper lobe of lung	UBERON:0008948	86.25	gold quality
kidney	UBERON:0002113	86.18	gold quality
jejunum	UBERON:0002115	86.17	gold quality
decidua	UBERON:0002450	86.11	gold quality
upper lobe of left lung	UBERON:0008952	85.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.89	gold quality
right lung	UBERON:0002167	85.83	gold quality
tibia	UBERON:0000979	85.76	gold quality
fallopian tube	UBERON:0003889	85.72	gold quality
cauda epididymis	UBERON:0004360	85.71	gold quality
stomach	UBERON:0000945	85.68	gold quality
vermiform appendix	UBERON:0001154	85.41	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.35	gold quality
heart right ventricle	UBERON:0002080	85.20	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.24
E-MTAB-6142	no	169.45

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 159 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pancreas	tissue	213.3	high
Corpus callosum	tissue	175.0
Choroid plexus	tissue	162.3
Spinal cord	tissue	143.7
Medulla oblongata	tissue	120.4
Skeletal muscle	tissue	101.9	medium
Midbrain	tissue	100.5
Substantia nigra	tissue	87.7
Thalamus	tissue	83.4
Putamen	tissue	83.2
Superior colliculi	tissue	76.2
Ventral forebrain	tissue	74.1
Pons	tissue	73.4
Hippocampal formation	tissue	71.6
Salivary gland	tissue	67.1	medium
Periaqueductal gray	tissue	66.3
Septum	tissue	58.8
Prostate	tissue	54.2	high
Cerebral cortex	tissue	54.2	medium
Somatosensory cortex	tissue	54.2
Thyroid gland	tissue	53.7	not detected
Hypothalamus	tissue	53.3
Tongue	tissue	52.3
Basal ganglia	tissue	51.5	medium
Occipital cortex	tissue	51.5
Motor cortex	tissue	50.2
Retrosplenial cortex	tissue	47.7
Retrosplenial and cingulate cortex	tissue	44.6
Prefrontal cortex	tissue	43.6
Liver	tissue	43.4	high
Temporal cortex	tissue	43.1
Entorhinal cortex	tissue	42.5
Salivary gland	tissue	42.2	high
Amygdala	tissue	41.6
Insular cortex	tissue	40.0
Hippocampus	tissue	39.4	high
Testis	tissue	38.6	medium
Cervix	tissue	38.5	medium
Stomach 1	tissue	35.2	high
Epididymis	tissue	31.8	medium
Caudate putamen	tissue	30.9
Postcentral gyrus	tissue	30.5
Bone marrow	tissue	30.4	low
Gallbladder	tissue	29.9	high
Locus coeruleus	tissue	29.8
Olfactory bulb	tissue	29.3
Cerebellum	tissue	29.1	medium
Choroid plexus	tissue	28.7
Hippocampus	tissue	28.7	medium
Placenta	tissue	28.5	medium
Olfactory bulb	tissue	27.8
Nucleus accumbens	tissue	27.3
Thyroid gland	tissue	27.0	high
Parathyroid gland	tissue	26.8	medium
Skin 1	tissue	26.5	medium
Frontal cortex	tissue	26.5
Stomach 1	tissue	25.7
Breast	tissue	25.1	medium
Postcentral gyrus	tissue	25.1
Cerebral cortex	tissue	24.8	high

Brain sub-regions (HPA Brain Atlas): detected in 383; highest nTPM — White matter (175.0), Ventral spinal cord (143.7), Dorsal spinal cord (123.2), Dorsal hippocampus (71.6), Parieto-temporal junction (white matter) (64.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CPD by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 233 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4262	100.00	73.26	3931
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-4747-5P	100.00	67.90	2681
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478

Functional genomics

gnomAD constraint: pLI 7.75e-07, LOEUF 0.627, missense Z 1.99 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000225719 splits into 6 regions with different missense tolerance; 1 is missense-constrained (≈1% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:30,378,981–30,420,846	484 / 477.2	1.01	no
17:30,420,847–30,422,874	160 / 197.9	0.81	no
17:30,422,875–30,422,915	1 / 17.1	0.06	yes (p 1.0e-04)
17:30,422,916–30,445,715	297 / 405.3	0.73	no
17:30,445,716–30,446,014	124 / 117.0	1.06	no
17:30,446,015–30,464,811	366 / 518.8	0.71	no

Literature-anchored findings (GeneRIF, showing 12)

• CPD releases C-terminal Arg from peptides to provide the precursor substrate for inducible nitric oxide synthase, which enhances nitric oxide synthesis in macrophages. (PMID:11306718)
• Palmitoylation of carboxypeptidase D has a role in intracellular trafficking (PMID:12643288)
• The isolation and characterization of CPD from several haematopoietic tumour cells are reported. (PMID:15918796)
• First report to demonstrate carboxypeptidase D as part of the transforming growth factor (TGF)-beta pathway as a TGF-beta target gene implicated in the pathogenesis of lupus erythematosus. (PMID:17641957)
• prolactin or E2 up-regulated CPD mRNA and protein expression in MCF-7 breast cancer cells promoting their survival (PMID:18535109)
• Either high glucose or insulin (with low glucose) up-regulates beta-cell CPD (but not CPE). (PMID:21628999)
• Carboxypeptidase D (CPD) is frequently upregulated in hepatocellular carcinoma; targeting CPD inhibits hepatocellular carcinoma cell proliferation through induction of G1 cell-cycle arrest and apoptosis. (PMID:23589395)
• Prolactin and R1881, acting through Stat5 and androgen receptor, act cooperatively to stimulate CPD gene transcription in breast cancer cells. (PMID:24433040)
• CPD immunostaining and testosterone/prolactin-stimulated CPD expression were higher in prostate cancer than benign tissues/cells. Elevated CPD increased NO production, which was abolished when both androgen and prolactin receptors were inhibited. (PMID:24615730)
• The human carboxypeptidase D transthyretin-like domain forms amyloid under physiological conditions. (PMID:25294878)
• Carboxypeptidase-D (CPD) overexpression coincides with high-grade lung cancer and the CPD overexpression could reverse the inhibitory effects of miR-214 (PMID:27494742)
• prolactin induction of VEGF-C and Runx2 was inhibited partly by Carboxypeptidase-D inhibitors, implicating nitric oxide , produced by PRL-regulated Carboxypeptidase-D, in breast cancer progression (PMID:28364216)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cpdb	ENSDARG00000053877
danio_rerio	cpda	ENSDARG00000055648
mus_musculus	Cpd	ENSMUSG00000020841
rattus_norvegicus	Cpd	ENSRNOG00000003873
drosophila_melanogaster	svr	FBGN0004648
caenorhabditis_elegans	cpd-1	WBGENE00019074

Paralogs (7): CPXM1 (ENSG00000088882), AEBP1 (ENSG00000106624), CPE (ENSG00000109472), CPZ (ENSG00000109625), CPN1 (ENSG00000120054), CPXM2 (ENSG00000121898), CPM (ENSG00000135678)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:107265) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal embryo size	1
pallor	1
abnormal cholesterol homeostasis	1
impaired glucose tolerance	1
increased circulating aspartate transaminase level	1
increased circulating creatinine level	1
preweaning lethality, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Lophonetta specularioides	P83852	100.0%	Diamond
Anas platyrhynchos	Q90240	100.0%	Diamond
Coccidioides posadasii C735 delta SOWgp	C5PHW9	99.8%	Diamond
Coccidioides posadasii str. Silveira	E9DD69	99.8%	Diamond
Pan troglodytes	A5A6K7	99.4%	Diamond
Macaca fascicularis	Q4R4M3	99.2%	Diamond
Pongo abelii	Q5RFD6	98.9%	Diamond
Aspergillus fischeri NRRL 181	A1DGH9	94.9%	Diamond
Bos taurus	P04836	92.9%	Diamond
Lophius americanus	P37892	83.4%	Diamond
Gallus gallus	Q8QGP3	65.2%	Diamond
Plenodomus lingam JN3	E5A0U8	58.9%	Diamond
Saccharothrix mutabilis subsp. capreolus	P39041	47.6%	Diamond
Arabidopsis thaliana	Q9M9H7	45.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TMIGD1	protein-coding	388364
GOSR1	protein-coding	9527

Protein

Protein identifiers

Carboxypeptidase D — O75976 (reviewed: O75976)

Alternative names: Metallocarboxypeptidase D, gp180

All UniProt accessions (3): O75976, J3QRJ9, K7ELF0

UniProt curated annotations — full annotation on UniProt →

Function. Functions in the processing of proteins and peptides in the secretory pathway. Mechanistically, cleaves exclusively C-terminal basic residues. By removing terminal residues, can modulate the activity, stability, and receptor-binding properties of bioactive peptides. (Microbial infection) Acts as an alternative entry receptor for adeno-associated virus (AAV).

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in placenta, pancreas and hepatoma cells. Lower levels found in skeletal muscle, heart and colon carcinoma and melanoma cell lines.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Domain organisation. There are 3 carboxypeptidase-like domains. Only the first two domains seem to have kept a catalytic activity.

Similarity. Belongs to the peptidase M14 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75976-1	1	yes
O75976-2	2

RefSeq proteins (2): NP_001186704, NP_001295* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000834	Peptidase_M14	Domain
IPR008969	CarboxyPept-like_regulatory	Homologous_superfamily
IPR033848	M14_CPD_III	Domain
IPR034224	M14_CPD_II	Domain
IPR050753	Peptidase_M14_domain	Family
IPR057246	CARBOXYPEPT_ZN_1	Binding_site
IPR057247	CARBOXYPEPT_ZN_2	Binding_site

Pfam: PF00246, PF13620

Enzyme classification (BRENDA)

• EC 3.4.17.22 — metallocarboxypeptidase D (BRENDA: 10 organisms, 25 substrates, 24 inhibitors, 37 Km, 25 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
DANSYL-PHE-ALA-ARG	0.012–0.844	12
DANSYL-PRO-ALA-ARG	0.0092–0.054	7
DANSYL-LEU-ALA-ARG	0.056–0.065	3
DANSYL-PHE-PHE-ARG	0.016–0.1	3
DANSYL-ALA-ARG	0.063–0.132	2
DANSYL-PHE-GLY-ARG	0.047–0.15	2
DANSYL-PHE-LEU-ARG	0.042–0.048	2
DANSYL-LEU-ARG	0.25	1
DANSYL-PHE-ILE-ARG	0.085	1
DANSYL-PHE-PRO-ARG	0.11	1
TYR-GLY-GLY-PHE-LEU-ARG	0.115	1
TYR-GLY-GLY-PHE-LEU-LYS	0.0305	1

UniProt features (92 total): strand 17, glycosylation site 15, helix 12, binding site 6, modified residue 6, turn 5, sequence variant 4, sequence conflict 4, region of interest 3, lipid moiety-binding region 3, domain 3, compositionally biased region 2, active site 2, topological domain 2, splice variant 2, mutagenesis site 2, signal peptide 1, chain 1, short sequence motif 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
5AQ0	The structure of the Transthyretin-like domain of the first catalytic domain of the HUMAN …	X-RAY DIFFRACTION	0.95
9J7L	Structure of AAV8 capsid in complex with receptor	ELECTRON MICROSCOPY	2.89
9J6Z	Structure of AAV8 in complex with its receptor	ELECTRON MICROSCOPY	3.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75976-F1	83.14	0.57

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Ear disease

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH uncertain · IF supported

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)

Position	Role
350	proton donor/acceptor
762	proton donor/acceptor

Ligand- & substrate-binding residues (6)

Position	Role
139	Zn(2+)
142	Zn(2+)
257	Zn(2+)
564	Zn(2+)
567	Zn(2+)
671	Zn(2+)

Post-translational modifications (9)

Type	Positions
Phosphotyrosine	265
Phosphoserine	270, 1358, 1361
Phosphothreonine	1368, 1370
S-palmitoyl cysteine	1317, 1321, 1323

Glycosylation sites (15)

Type	Positions
N-linked (glcnac…) asparagine	172, 217, 399, 410, 429, 522, 626, 811, 855, 867, 879, 955, 978, 1070, 1142

Mutagenesis-validated functional residues (2)

Position	Phenotype
350	enzymatically inactive; when associated with q-762.
762	enzymatically inactive; when associated with q-350.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-432722	Golgi Associated Vesicle Biogenesis	curated
R-HSA-9696273	RND1 GTPase cycle	curated
R-HSA-9696264	RND3 GTPase cycle	curated
R-HSA-199991	Membrane Trafficking	—
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-162582	Signal Transduction	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—
R-HSA-5653656	Vesicle-mediated transport	—
R-HSA-199992	trans-Golgi Network Vesicle Budding	—

MSigDB gene sets: 381 (showing top): KOBAYASHI_EGFR_SIGNALING_24HR_UP, ACTACCT_MIR196A_MIR196B, GOMF_METALLOPEPTIDASE_ACTIVITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, MODULE_45, AAGCCAT_MIR135A_MIR135B, DITTMER_PTHLH_TARGETS_UP, IVANOVA_HEMATOPOIESIS_MATURE_CELL, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, REACTOME_MEMBRANE_TRAFFICKING, MODULE_16, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, chr17q11, TTGGGAG_MIR150, PATIL_LIVER_CANCER

GO Biological Process (3): peptide metabolic process (GO:0006518), protein processing (GO:0016485), proteolysis (GO:0006508)

GO Molecular Function (8): metallocarboxypeptidase activity (GO:0004181), serine-type carboxypeptidase activity (GO:0004185), 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 (3): plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

7 top-level categories:

Category	Pathways
RHO GTPase cycle	2
trans-Golgi Network Vesicle Budding	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Vesicle-mediated transport	1
Membrane Trafficking	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

18 GO namespaces:

Category	Terms
carboxypeptidase activity	2
metabolic process	1
proteolysis	1
protein maturation	1
protein metabolic process	1
metalloexopeptidase activity	1
serine-type exopeptidase 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
membrane	1
cell periphery	1
cellular anatomical structure	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 15 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 654 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPD	SLC26A5	P58743	836
CPD	PACS1	Q6VY07	527
CPD	FAM91A1	Q658Y4	525
CPD	SLC6A4	P31645	507
CPD	KIAA0319L	Q8IZA0	494
CPD	CD1D	P15813	493
CPD	FURIN	P09958	480
CPD	PRSS36	Q5K4E3	471
CPD	EIPR1	Q53HC9	460
CPD	GOSR1	O95249	456
CPD	TBC1D23	Q9NUY8	451
CPD	TGOLN2	O43493	442
CPD	CCDC186	Q7Z3E2	442
CPD	OVCA2	Q8WZ82	438
CPD	TSLIG3B	Q52LJ0	437

IntAct

Human interaction partners of CPD in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
AP1M1	association	0.530	1
AATF	physical association	0.370	1
FOXK2	association	0.350	1
IFNA21	association	0.350	1
PRTN3	association	0.350	1
SLC10A3	association	0.350	1
SLC39A1	association	0.350	1
DISC1	physical association	0.000	1

BioGRID (273 interactions; top human partners by supporting records): KRAS (Proximity Label-MS; 3 records), LAMP1 (Affinity Capture-MS; 3 records), TNF (Affinity Capture-MS; 3 records), ANPEP (Affinity Capture-MS; 2 records), AP1M1 (Affinity Capture-MS; 2 records), BSG (Affinity Capture-MS; 2 records), CANX (Proximity Label-MS; 2 records), CDC42 (Affinity Capture-MS; 2 records), CLEC4D (Affinity Capture-MS; 2 records), CLEC4E (Affinity Capture-MS; 2 records), CTSL (Affinity Capture-MS; 2 records), CTSS (Affinity Capture-MS; 2 records), DEFA1 (Affinity Capture-MS; 2 records), DPP4 (Affinity Capture-MS; 2 records), EPHA2 (Proximity Label-MS; 2 records)

Disease & clinical

Genetic variants

Variant evidence for CPD: 175 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	145
Likely benign	9
Benign	4

AlphaMissense

3,461 missense substitutions predicted likely pathogenic (of 9,047 scored), across 815 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M334	9	0.967	0.996
M302	9	0.956	0.996
M746	9	0.918	0.988
M714	9	0.910	0.981
M563	9	0.905	0.992
M138	9	0.891	0.987
H257	8	0.996	0.999
D336	8	0.996	0.999
H564	8	0.995	0.998
D268	8	0.994	0.998
D632	8	0.994	0.999
H671	8	0.993	0.999
N607	8	0.992	1.000
D748	8	0.992	0.998
D682	8	0.988	0.997
F220	8	0.987	0.998
D609	8	0.984	0.997
N627	8	0.981	0.999
D185	8	0.980	0.994
D215	8	0.980	0.992

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Prostate Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	favorable	2.59e-05
Lung Adenocarcinoma (validation)	unfavorable	0.000688

Disease associations

OMIM: gene MIM:603102 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523154 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M14: Carboxypeptidase A

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression, increases expression, affects expression	3
bisphenol A	increases expression	2
trichostatin A	decreases expression, affects cotreatment	2
sodium arsenite	increases abundance, increases expression, decreases expression	2
Fluorouracil	decreases expression, affects response to substance, affects reaction	2
Valproic Acid	increases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
sulforaphane	increases expression	1
butyraldehyde	decreases expression	1
ochratoxin A	increases expression	1
nivalenol	decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects expression	1
jinfukang	decreases expression	1
gardiquimod	decreases reaction, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Zoledronic Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4413966	Binding	Inhibition of human CPD at 1 nM to 1 mM using AAFA as substrate preincubated for 45 mins to 2 hrs measured at 30 sec intervals for 15 mins by UV/vis-spectrophotometry	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)

Via MONDO — disease-level, not drug-specific.