CPZ

Summary

CPZ (carboxypeptidase Z, HGNC:2333) is a protein-coding gene on chromosome 4p16.1, encoding Carboxypeptidase Z (Q66K79). Specifically cleaves substrates and peptides with C-terminal basic amino acids, especially those containing C-terminal Arg residues.

This gene encodes a member of the metallocarboxypeptidase family. This enzyme displays carboxypeptidase activity towards substrates with basic C-terminal residues. It is most active at neutral pH and is inhibited by active site-directed inhibitors of metallocarboxypeptidases. Alternative splicing in the coding region results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 8532 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 316 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001014447

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2333
Approved symbol	CPZ
Name	carboxypeptidase Z
Location	4p16.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109625
Ensembl biotype	protein_coding
OMIM	603105
Entrez	8532

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000315782, ENST00000360986, ENST00000382480, ENST00000504070, ENST00000506287, ENST00000513486, ENST00000514602, ENST00000514875, ENST00000515606, ENST00000906052, ENST00000906053, ENST00000906054, ENST00000906055, ENST00000912696, ENST00000912697, ENST00000912698, ENST00000912699, ENST00000912700, ENST00000912701, ENST00000947471, ENST00000947472

RefSeq mRNA: 3 — MANE Select: NM_001014447 NM_001014447, NM_001014448, NM_003652

CCDS: CCDS33953, CCDS3404, CCDS43212

Canonical transcript exons

ENST00000360986 — 11 exons

Exon	Start	End
ENSE00002227785	8592765	8592921
ENSE00003488419	8599453	8599485
ENSE00003500663	8618429	8618528
ENSE00003540868	8619262	8619752
ENSE00003545515	8607267	8607425
ENSE00003559726	8603976	8604188
ENSE00003566430	8612027	8612162
ENSE00003579056	8606737	8606898
ENSE00003582179	8601123	8601497
ENSE00003588583	8614359	8614498
ENSE00003671259	8605989	8606185

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.82.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4534 / max 347.5516, expressed in 690 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46900	5.2365	682
46898	0.1816	67
46899	0.0352	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	97.82	gold quality
right ovary	UBERON:0002118	97.75	gold quality
ovary	UBERON:0000992	97.53	gold quality
placenta	UBERON:0001987	94.54	gold quality
gall bladder	UBERON:0002110	92.08	gold quality
endocervix	UBERON:0000458	91.11	gold quality
lower esophagus mucosa	UBERON:0035834	90.22	gold quality
ectocervix	UBERON:0012249	88.32	gold quality
stromal cell of endometrium	CL:0002255	87.97	gold quality
vagina	UBERON:0000996	87.65	gold quality
uterine cervix	UBERON:0000002	87.36	gold quality
fallopian tube	UBERON:0003889	86.71	gold quality
right uterine tube	UBERON:0001302	86.51	gold quality
left uterine tube	UBERON:0001303	86.22	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.94	gold quality
urinary bladder	UBERON:0001255	81.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.70	gold quality
mucosa of stomach	UBERON:0001199	81.54	gold quality
smooth muscle tissue	UBERON:0001135	80.32	gold quality
omental fat pad	UBERON:0010414	80.16	gold quality
body of uterus	UBERON:0009853	79.47	gold quality
myometrium	UBERON:0001296	78.77	gold quality
mammary gland	UBERON:0001911	78.42	gold quality
thoracic mammary gland	UBERON:0005200	78.42	gold quality
uterus	UBERON:0000995	78.34	gold quality
esophagus mucosa	UBERON:0002469	78.17	gold quality
left lobe of thyroid gland	UBERON:0001120	77.27	gold quality
thyroid gland	UBERON:0002046	77.19	gold quality
skin of abdomen	UBERON:0001416	76.69	gold quality
right lobe of thyroid gland	UBERON:0001119	74.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	66.26
E-ANND-3	yes	9.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting CPZ, 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-1825	99.72	68.11	1089
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-335-5P	97.10	68.12	1022
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-4769-5P	95.37	66.09	570
HSA-MIR-885-3P	95.14	63.08	448

Literature-anchored findings (GeneRIF, showing 3)

• Common variants within CPZ at 4p16 is associated with neuroblastoma. (PMID:28545128)
• CPZ rs3796725 and rs3796727 were not associated with neuroblastoma risk in Chinese children.. (PMID:29653227)
• Substrate Specificity and Structural Modeling of Human Carboxypeptidase Z: A Unique Protease with a Frizzled-Like Domain. (PMID:33217972)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cpz	ENSDARG00000075521
mus_musculus	Cpz	ENSMUSG00000036596
rattus_norvegicus	Cpz	ENSRNOG00000008947

Paralogs (7): CPXM1 (ENSG00000088882), AEBP1 (ENSG00000106624), CPD (ENSG00000108582), CPE (ENSG00000109472), CPN1 (ENSG00000120054), CPXM2 (ENSG00000121898), CPM (ENSG00000135678)

Protein

Protein identifiers

Carboxypeptidase Z — Q66K79 (reviewed: Q66K79)

All UniProt accessions (2): Q66K79, D6RBI5

UniProt curated annotations — full annotation on UniProt →

Function. Specifically cleaves substrates and peptides with C-terminal basic amino acids, especially those containing C-terminal Arg residues. Probably modulates the Wnt signaling pathway, by cleaving some undefined protein. May play a role in cleavage during prohormone processing.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. In placenta, it is present within invasive trophoblasts and in the surrounding extracellular space. Also present in amnion cells, but is not readily apparent in the extracellular matrix of this cell type. Present in normal pituitary gland and neoplastic pituitary gland (especially POMC-, GH- and PRL-producing adenomas) (at protein level). Widely expressed.

Activity regulation. Inhibited by 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA) and guanidinoethylmercaptosuccinic acid (GEMSA). Inhibited by chelating agents such as EDTA and EGTA.

Similarity. Belongs to the peptidase M14 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q66K79-1	1	yes
Q66K79-2	2
Q66K79-3	3

RefSeq proteins (3): NP_001014447, NP_001014448, NP_003643 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000834	Peptidase_M14	Domain
IPR008969	CarboxyPept-like_regulatory	Homologous_superfamily
IPR020067	Frizzled_dom	Domain
IPR034239	M14_CPZ_CPD	Domain
IPR036790	Frizzled_dom_sf	Homologous_superfamily
IPR050753	Peptidase_M14_domain	Family
IPR057247	CARBOXYPEPT_ZN_2	Binding_site

Pfam: PF00246, PF01392, PF13620

UniProt features (25 total): disulfide bond 5, sequence variant 5, sequence conflict 3, binding site 3, splice variant 2, domain 2, signal peptide 1, chain 1, region of interest 1, active site 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q66K79-F1	85.33	0.65

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): 472 (proton donor/acceptor)

Ligand- & substrate-binding residues (3): 248; 251; 380

Disulfide bonds (5): 43–109, 51–102, 93–129, 118–157, 122–146

Glycosylation sites (1): 281

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 85 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, MORF_MSH3, GOMF_METALLOPEPTIDASE_ACTIVITY, MORF_RAD51L3, GOBP_PEPTIDE_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION, chr4p16, YRTCANNRCGC_UNKNOWN, E12_Q6, RICKMAN_TUMOR_DIFFERENTIATED_MODERATELY_VS_POORLY_UP, GOBP_PROTEOLYSIS, GOMF_CARBOXYPEPTIDASE_ACTIVITY, GOMF_METALLOEXOPEPTIDASE_ACTIVITY, GOMF_METALLOCARBOXYPEPTIDASE_ACTIVITY, GOMF_PEPTIDASE_ACTIVITY

GO Biological Process (4): proteolysis (GO:0006508), peptide metabolic process (GO:0006518), Wnt signaling pathway (GO:0016055), protein processing (GO:0016485)

GO Molecular Function (8): carboxypeptidase activity (GO:0004180), metallocarboxypeptidase activity (GO:0004181), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
metabolic process	1
cell surface receptor signaling pathway	1
proteolysis	1
protein maturation	1
exopeptidase activity	1
carboxypeptidase activity	1
metalloexopeptidase activity	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPZ	AFF1	P51825	903
CPZ	OSTF1	Q92882	644
CPZ	POLI	Q9UNA4	607
CPZ	RTN4	Q9NQC3	507
CPZ	STIM2	Q9P246	465
CPZ	FUBP3	Q96I24	445
CPZ	SPCS1	Q9Y6A9	443
CPZ	AGMO	Q6ZNB7	423
CPZ	SPIC	Q8N5J4	385
CPZ	AGBL3	Q8NEM8	370
CPZ	LNP1	A1A4G5	357
CPZ	AGBL2	Q5U5Z8	348
CPZ	GABRB3	P28472	347
CPZ	SFTPD	P35247	347
CPZ	TIGD4	Q8IY51	337

IntAct

3 interactions, top by confidence:

A	B	Type	Score
GSK3A	PRSS37	psi-mi:“MI:0914”(association)	0.350
CPZ	HSPA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): CCT6A (Affinity Capture-MS), L3HYPDH (Affinity Capture-MS), BAG1 (Affinity Capture-MS), L3HYPDH (Affinity Capture-MS), BAG1 (Affinity Capture-MS), CPZ (Affinity Capture-MS), BAG1 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), L3HYPDH (Affinity Capture-MS)

ESM2 similar proteins: A2RUV9, F8W3R9, O18738, O43278, O54858, O88393, O97827, P00734, P00735, P0C5J5, P12259, P18292, P26342, P35054, P51511, Q08629, Q08E66, Q09101, Q14118, Q24567, Q24568, Q28685, Q29243, Q5R537, Q5RD69, Q62165, Q62288, Q640N1, Q66K79, Q701R2, Q7TQN3, Q80TS3, Q8BKV0, Q8IUX7, Q8N436, Q8R4V4, Q8TEU8, Q91ZV2, Q91ZV3, Q92563

Diamond homologs: A2RUV9, A5A6K7, O14786, O17754, O18806, O35276, O35375, O35474, O43854, O54858, O54991, O60462, O75976, O88783, O89001, P00451, P02886, P02887, P02888, P04836, P12259, P12263, P14384, P15087, P15169, P16870, P21956, P28824, P29068, P37892, P39041, P42787, P70490, P78357, P79385, P79795, P83852, P97333, P97846, P98092

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	233
Likely benign	27
Benign	31

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
831637	NC_000004.11:g.(?8613754)(8873340_?)del	Pathogenic
599479	NM_001014447.3(CPZ):c.493C>T (p.Arg165Trp)	Likely pathogenic

SpliceAI

2457 predictions. Top by Δscore:

Variant	Effect	Δscore
4:8601495:GGG:G	donor_gain	1.0000
4:8601496:GG:G	donor_gain	1.0000
4:8601496:GGG:G	donor_gain	1.0000
4:8601497:GG:G	donor_gain	1.0000
4:8601497:GGTA:G	donor_loss	1.0000
4:8601498:G:GG	donor_gain	1.0000
4:8601498:G:T	donor_loss	1.0000
4:8601499:T:G	donor_loss	1.0000
4:8603975:GGA:G	acceptor_gain	1.0000
4:8604150:TCATC:T	donor_gain	1.0000
4:8604184:GCTGA:G	donor_gain	1.0000
4:8604185:C:G	donor_gain	1.0000
4:8604185:CTGA:C	donor_gain	1.0000
4:8604186:TGA:T	donor_gain	1.0000
4:8604187:GA:G	donor_gain	1.0000
4:8604187:GAG:G	donor_gain	1.0000
4:8604188:AG:A	donor_loss	1.0000
4:8604189:G:GG	donor_gain	1.0000
4:8605985:CCA:C	acceptor_loss	1.0000
4:8605986:CAGTG:C	acceptor_loss	1.0000
4:8605987:A:AC	acceptor_loss	1.0000
4:8605987:A:AG	acceptor_gain	1.0000
4:8605987:AGT:A	acceptor_gain	1.0000
4:8605987:AGTG:A	acceptor_gain	1.0000
4:8605988:G:GT	acceptor_gain	1.0000
4:8605988:GT:G	acceptor_gain	1.0000
4:8605988:GTG:G	acceptor_gain	1.0000
4:8605988:GTGG:G	acceptor_gain	1.0000
4:8605988:GTGGA:G	acceptor_gain	1.0000
4:8606184:AGG:A	donor_loss	1.0000

AlphaMissense

4262 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:8606155:C:A	N292K	0.999
4:8606155:C:G	N292K	0.999
4:8606798:G:C	R323P	0.999
4:8606021:C:G	H248D	0.998
4:8606025:G:A	G249D	0.998
4:8606025:G:T	G249V	0.998
4:8606029:C:A	N250K	0.998
4:8606029:C:G	N250K	0.998
4:8606803:T:C	F325L	0.998
4:8606805:C:A	F325L	0.998
4:8606805:C:G	F325L	0.998
4:8612146:G:C	W449C	0.998
4:8612146:G:T	W449C	0.998
4:8619560:G:C	W634C	0.998
4:8619560:G:T	W634C	0.998
4:8601421:G:C	W140C	0.997
4:8601421:G:T	W140C	0.997
4:8606017:C:A	N246K	0.997
4:8606017:C:G	N246K	0.997
4:8606024:G:T	G249C	0.997
4:8606031:A:T	E251V	0.997
4:8606142:T:C	L288P	0.997
4:8606768:G:C	R313T	0.997
4:8606796:C:A	N322K	0.997
4:8606796:C:G	N322K	0.997
4:8606802:T:A	N324K	0.997
4:8606802:T:G	N324K	0.997
4:8607297:T:A	W367R	0.997
4:8607297:T:C	W367R	0.997
4:8607324:T:C	S376P	0.997

dbSNP variants (sampled 300 via entrez): RS1000018340 (4:8611087 T>C,G), RS1000081859 (4:8617085 G>A,C), RS1000095056 (4:8618129 G>A), RS1000197796 (4:8616438 G>C), RS1000208259 (4:8593553 G>A,T), RS1000244395 (4:8593341 C>A,T), RS1000347142 (4:8608562 T>C), RS1000450300 (4:8611777 T>C), RS1000529184 (4:8617706 C>A,G), RS1000539657 (4:8597266 T>G), RS1000540647 (4:8594496 C>T), RS1000572047 (4:8607796 G>A,C,T), RS1000608618 (4:8614991 C>G), RS1000644417 (4:8617170 G>A,T), RS10006470 (4:8602779 G>A)

Disease associations

OMIM: gene MIM:603105 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004510_9	Sporadic neuroblastoma	1.000000e-12
GCST006585_2228	Blood protein levels	9.000000e-09
GCST007293_24	Body fat distribution (arm fat ratio)	8.000000e-07
GCST007294_17	Body fat distribution (trunk fat ratio)	4.000000e-13
GCST007294_36	Body fat distribution (trunk fat ratio)	5.000000e-12
GCST007295_176	Body fat distribution (leg fat ratio)	1.000000e-07
GCST007295_55	Body fat distribution (leg fat ratio)	2.000000e-07
GCST008163_138	Height	8.000000e-06
GCST008839_391	Height	6.000000e-24
GCST009218_49	Lateral ventricle temporal horn volume	3.000000e-06
GCST009391_30	Metabolite levels	4.000000e-06
GCST010002_448	Refractive error	2.000000e-08
GCST010397_85	Gut microbiota (bacterial taxa, rank normal transformation method)	8.000000e-06
GCST90000025_257	Appendicular lean mass	3.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0010350	cholesteryl ester 22:6 measurement
EFO:0007874	gut microbiome measurement
EFO:0004980	appendicular lean mass

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 — M14: Carboxypeptidase A

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	3
bisphenol A	affects methylation, affects cotreatment, increases methylation, increases expression	2
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	increases expression	1
mono(carboxy-isooctyl)phthalate	affects expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Calcitriol	decreases expression	1
Cytarabine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Malathion	decreases expression	1
Mercury	increases expression	1
Methapyrilene	increases methylation	1
Progesterone	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Mifepristone	increases expression	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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