MEP1B

Summary

MEP1B (meprin A subunit beta, HGNC:7020) is a protein-coding gene on chromosome 18q12.1, encoding Meprin A subunit beta (Q16820). Membrane metallopeptidase that sheds many membrane-bound proteins.

Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes, and in leukocytes and certain cancer cells. They are involved in the hydrolysis of a variety of peptide and protein substrates, and have been implicated in cancer and intestinal inflammation. Mature meprins are oligomers of evolutionarily related, but separately encoded alpha and/or beta subunits. Homooligomers of alpha subunit are secreted, whereas, oligomers containing the beta subunit are plasma membrane-bound. This gene encodes the beta subunit. Targeted disruption of this gene in mice affects embryonic viability, renal gene expression profiles, and distribution of the membrane-associated alpha subunit in kidney and intestine.

Source: NCBI Gene 4225 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 96 total
• Druggable target: yes
• MANE Select transcript: NM_005925

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7020
Approved symbol	MEP1B
Name	meprin A subunit beta
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141434
Ensembl biotype	protein_coding
OMIM	600389
Entrez	4225

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000269202, ENST00000579919, ENST00000581184, ENST00000581447

RefSeq mRNA: 2 — MANE Select: NM_005925 NM_001308171, NM_005925

CCDS: CCDS45846, CCDS77173

Canonical transcript exons

ENST00000269202 — 15 exons

Exon	Start	End
ENSE00000948528	32190039	32190133
ENSE00000948535	32202893	32203010
ENSE00000948537	32204182	32204360
ENSE00000948538	32207252	32207470
ENSE00000948539	32208119	32208271
ENSE00000948540	32210501	32210716
ENSE00000948541	32213116	32213559
ENSE00000948543	32216991	32217117
ENSE00001273196	32217761	32217965
ENSE00001273212	32215082	32215261
ENSE00002697490	32220231	32220404
ENSE00003513859	32195407	32195485
ENSE00003627479	32192774	32192817
ENSE00003654543	32192646	32192690
ENSE00003660395	32191822	32191840

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 99.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.4915 / max 1838.2269, expressed in 13 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169870	1.2804	12
169869	0.2111	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.54	gold quality
ileal mucosa	UBERON:0000331	99.12	gold quality
ileum	UBERON:0002116	99.07	silver quality
duodenum	UBERON:0002114	95.46	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.37	gold quality
small intestine	UBERON:0002108	87.42	gold quality
mucosa of transverse colon	UBERON:0004991	87.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.48	gold quality
jejunum	UBERON:0002115	73.16	gold quality
rectum	UBERON:0001052	70.02	gold quality
transverse colon	UBERON:0001157	69.89	gold quality
intestine	UBERON:0000160	69.17	gold quality
mucosa of stomach	UBERON:0001199	67.13	gold quality
islet of Langerhans	UBERON:0000006	65.77	gold quality
smooth muscle tissue	UBERON:0001135	64.53	gold quality
colon	UBERON:0001155	63.74	gold quality
large intestine	UBERON:0000059	63.47	gold quality
left uterine tube	UBERON:0001303	63.32	gold quality
sural nerve	UBERON:0015488	63.03	silver quality
cerebellar hemisphere	UBERON:0002245	62.69	gold quality
cerebellar cortex	UBERON:0002129	62.54	gold quality
metanephros cortex	UBERON:0010533	61.93	gold quality
right adrenal gland cortex	UBERON:0035827	61.77	gold quality
tibial nerve	UBERON:0001323	61.69	gold quality
diaphragm	UBERON:0001103	61.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.17	gold quality
right lobe of liver	UBERON:0001114	60.95	gold quality
cerebellum	UBERON:0002037	60.74	gold quality
right ovary	UBERON:0002118	60.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETV4, HNF1B

miRNA regulators (miRDB)

11 targeting MEP1B, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-4436B-5P	96.71	68.37	1346

Literature-anchored findings (GeneRIF, showing 25)

• results show that the O-linked carbohydrate side chains in hmeprinbeta are clustered around a 13 amino acid sequence that contains the main cleavage site for proteolytic processing of the subunit (PMID:12387727)
• two different metalloprotease activities are responsible for the constitutive and the PMA-stimulated hmeprinbeta shedding (PMID:12941954)
• Mephrin beta induced a dramatic change in cell morphology and reduced the cell number, indicating a function in terminal differentiation, whereas meprin alpha did not affect cell viability, and may play a role in basal keratinocyte proliferation. (PMID:17195012)
• data indicate that, at least under pathological conditions, meprinbeta might attack specific functional sites in tenascin-C that are important for its oligomerization and anti-adhesive activity (PMID:19748582)
• meprins could be important players in several remodeling processes involving collagen fiber deposition (PMID:20631730)
• Cystatin C was an inhibitor for human meprin alpha(K(i) = 8.5 x 10(-6) M) but, interestingly, not for meprin beta. (PMID:20806899)
• Demonstrate that the metalloprotease meprin beta and gamma-ENaC associate directly through cytoplasmic domains. (PMID:20953144)
• Processing of APP by meprin beta was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin beta(-/-) mouse brain lysates (PMID:21646356)
• metalloprotease meprin beta generates amino terminal-truncated amyloid beta peptide species (PMID:22879596)
• of the 151 new extracellular substrates identified, it was notable that ADAM10 the constitutive alpha-secretase-is activated by meprin beta through cleavage of the propeptide (PMID:22940918)
• Overexpression of MEP1B is associated with pancreatic neuroendocrine tumors. (PMID:24114056)
• promotes inflammation in macrophages via ADAM-10 dependent pathway (PMID:24239627)
• Suggest role for in meprin-beta-Fra2 axis in mediating vascular remodelling in pulmonary hypertension. (PMID:24258247)
• Meprin metalloproteases A and B inactivate interleukin 6 (PMID:24474695)
• n conclusion, we show that the concept of cleavable linkers specific for meprin beta is feasible, as the peptides are rapidly cleaved by the enzyme while retaining their biological properties (PMID:25855967)
• Meprin Beta was found to be activated at the cell surface by matriptase-2. (PMID:26251449)
• TSPAN8 might be important for the orchestration of meprin beta at the cell surface with impact on certain proteolytic processes (PMID:27180358)
• Results provide evidence that meprin beta is involved in collagen deposition in vivo in the lung of bleomycin treated mice and it localized in region with immature collagen. This suggests that meprin beta can favor the progression of the fibrotic process enhancing collagen processing and deposition. (PMID:28059112)
• For meprin beta a reduction and for BMP-1 an increase in activity was reported under increasing calcium concentrations. (PMID:28365001)
• In this review we report on recent findings that summarize the complex molecular regulation of meprins, particular folding, activation and shedding. Dysregulation of meprin alpha and meprin beta is often associated with pathological conditions such as neurodegeneration, inflammatory bowel disease and fibrosis (PMID:28502593)
• This secreted cysteine protease potently converts membrane-bound meprin beta into its active form, impairing meprin beta shedding and its function as a mucus-detaching protease (PMID:29166602)
• The authors found that increased meprin beta G32R activity at the cell surface reduces cell proliferation, but increases cell invasion. (PMID:31076514)
• As meprin beta cleavage of APP has been shown to result in formation of highly aggregation-prone, truncated Abeta2-40/42 peptides, enhanced APP processing by this enzyme could contribute to Alzheimer’s disease pathology. (PMID:31604820)
• Structure and Dynamics of Meprin beta in Complex with a Hydroxamate-Based Inhibitor. (PMID:34073350)
• The putative pleiotropic functions of meprin beta in gastric cancer. (PMID:36976399)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mep1ba	ENSDARG00000037533
danio_rerio	mep1bb	ENSDARG00000040683
mus_musculus	Mep1b	ENSMUSG00000024313
rattus_norvegicus	Mep1b	ENSRNOG00000049345

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Meprin A subunit beta — Q16820 (reviewed: Q16820)

Alternative names: Endopeptidase-2, Meprin B, N-benzoyl-L-tyrosyl-P-amino-benzoic acid hydrolase subunit beta, PABA peptide hydrolase, PPH beta

All UniProt accessions (2): Q16820, J3QKX5

UniProt curated annotations — full annotation on UniProt →

Function. Membrane metallopeptidase that sheds many membrane-bound proteins. Exhibits a strong preference for acidic amino acids at the P1’ position. Known substrates include: FGF19, VGFA, IL1B, IL18, procollagen I and III, E-cadherin, KLK7, gastrin, ADAM10, tenascin-C. The presence of several pro-inflammatory cytokine among substrates implicate MEP1B in inflammation. It is also involved in tissue remodeling due to its capability to degrade extracellular matrix components. Also cleaves the amyloid precursor protein/APP, thereby releasing neurotoxic amyloid beta peptides.

Subunit / interactions. Homotetramer consisting of disulfide-linked beta subunits, or heterotetramer of two alpha and two beta subunits formed by non-covalent association of two disulfide-linked heterodimers. Interacts with MBL2 through its carbohydrate moiety. This interaction may inhibit its catalytic activity. Interacts with TSPAN8.

Subcellular location. Cell membrane. Secreted.

Tissue specificity. The major site of expression is the brush border membrane of small intestinal and kidney epithelial cells.

Post-translational modifications. Phosphorylated by PKC at multiple sites of its cytoplasmic part. Phosphorylation dcreases activity at the cell surface, leading to diminished substrate cleavage. N-glycosylated; contains high mannose and/or complex biantennary structures. O-glycosylation protect the C-terminal region from proteolytic cleavage and diminish secretion, this seems to be specific to human. Proteolytically activated by trypsin in the intestinal lumen and kallikrein-related peptidases in other tissues.

Activity regulation. Strongly inhibited by fetuin-A/AHSG.

Cofactor. Binds 1 zinc ion per subunit.

RefSeq proteins (2): NP_001295100, NP_005916* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR000998	MAM_dom	Domain
IPR001506	Peptidase_M12A	Domain
IPR002083	MATH/TRAF_dom	Domain
IPR006026	Peptidase_Metallo	Domain
IPR008294	Meprin	Family
IPR008974	TRAF-like	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR034038	ZnMP_meprin	Domain

Pfam: PF00629, PF01400, PF22486

Enzyme classification (BRENDA):

• EC 3.4.24.18 — meprin A (BRENDA: 6 organisms, 243 substrates, 90 inhibitors, 44 Km, 40 kcat entries)
• EC 3.4.24.63 — meprin B (BRENDA: 4 organisms, 134 substrates, 146 inhibitors, 27 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BRADYKININ	0.0121–0.224	5
CHOLECYSTOKININ 8-SULFATE	0.11–0.49	4
GASTRIN 17	0.001–0.0296	4
SUBSTANCE P	0.0306–0.118	3
ALPHA-MSH	0.0223–0.292	2
KKGYVADAP-4-NITROANILIDE	0.024	2
LUTEINIZING HORMONE RELEASING HORMONE LHRH	0.0565–0.156	2
PROTEIN PTH12-34	0.018–0.0672	2
SECRETIN	0.0339–0.111	2
CHOLECYSTOKININ 8 SULFATE	0.211–0.22	2
KKGYVADAP-4-NITROANILIDE	0.184	2
KKGYVADAP-7-AMIDO-4-METHYLCOUMARIN	0.074	2
2-AMINOBENZOYL-ARG-GLY-PRO-PHE-SER-PRO-(4-NITRO)	0.22	1
2-AMINOBENZOYL-ARG-HYP-GLY-PHE-SER-PRO-(4-NITRO)	0.183	1
2-AMINOBENZOYL-ARG-PRO-GLY-ALA-SER-PRO-(4-NITRO)	1.38	1

UniProt features (108 total): strand 37, helix 17, glycosylation site 12, disulfide bond 9, turn 5, mutagenesis site 4, sequence conflict 4, domain 4, binding site 3, sequence variant 3, topological domain 2, signal peptide 1, propeptide 1, region of interest 1, active site 1, site 1, modified residue 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4GWM	X-RAY DIFFRACTION	1.85
7AQ1	X-RAY DIFFRACTION	2.41
7AUW	X-RAY DIFFRACTION	2.8
4GWN	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16820-F1	90.06	0.76

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): 153; 238 (mediates preference for acidic residues at subsite p1')

Ligand- & substrate-binding residues (3): 152; 156; 162

Post-translational modifications (1): 694

Disulfide bonds (9): 103–255, 124–144, 265–427, 273, 305, 492, 608–619, 613–628, 630–643

Glycosylation sites (12): 218, 254, 370, 421, 436, 445, 547, 592, 593, 594, 599, 603

Mutagenesis-validated functional residues (4):

Position	Phenotype
153	complete loss of activity.
248	decreased activity toward gastrin.
595–607	abolishes secretion.
694	almost complete loss of phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 63 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE, chr18q12, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM3, PID_AJDISS_2PATHWAY, SANSOM_APC_TARGETS_DN, BROWN_MYELOID_CELL_DEVELOPMENT_DN, SABATES_COLORECTAL_ADENOMA_DN, VECCHI_GASTRIC_CANCER_EARLY_DN, KAYO_AGING_MUSCLE_UP, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, YOSHIMURA_MAPK8_TARGETS_UP

GO Biological Process (2): proteolysis (GO:0006508), inflammatory response (GO:0006954)

GO Molecular Function (8): metalloendopeptidase activity (GO:0004222), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), meprin A complex (GO:0017090), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
defense response	1
endopeptidase activity	1
metallopeptidase activity	1
transition metal ion binding	1
protein binding	1
binding	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
membrane protein complex	1

Protein interactions and networks

STRING

854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MEP1B	PTPRU	P78399	766
MEP1B	PTPRS	Q13332	648
MEP1B	NTS	P30990	606
MEP1B	GSTA2	P09210	586
MEP1B	ACE2	Q9BYF1	547
MEP1B	MGAM2	Q2M2H8	507
MEP1B	KNG1	P01042	501
MEP1B	PTS	Q03393	495
MEP1B	GFOD2	Q3B7J2	494
MEP1B	IL18	Q14116	480
MEP1B	MGAM	O43451	477
MEP1B	XPNPEP2	O43895	464
MEP1B	TTR	P02766	461
MEP1B	SI	P14410	461
MEP1B	OS9	Q13438	459

IntAct

50 interactions, top by confidence:

A	B	Type	Score
MEP1B	MEP1B	psi-mi:“MI:0407”(direct interaction)	0.590
MEP1B	MEP1B	psi-mi:“MI:0915”(physical association)	0.590
MEP1B	TSPAN8	psi-mi:“MI:0915”(physical association)	0.560
MMP9	MEP1B	psi-mi:“MI:0194”(cleavage reaction)	0.560
MEP1B	MMP9	psi-mi:“MI:0194”(cleavage reaction)	0.560
APP	MEP1B	psi-mi:“MI:0570”(protein cleavage)	0.440
MEP1B	ARL14	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	AIG1	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	APOC3	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	AQP7	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	ATP5MC3	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	CHPT1	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	CPNE3	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	UTY	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	HLA-A	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	HLA-DMA	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	IFITM1	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	IL32	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	SPINT2	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	LEPROT	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	PDZK1IP1	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	PRAP1	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	FAM3B	psi-mi:“MI:0915”(physical association)	0.370
MEP1B	NKG7	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (7): PYY (Biochemical Activity), GAST (Biochemical Activity), FN1 (Biochemical Activity), TSPAN8 (Co-fractionation), TSPAN8 (Two-hybrid), TSPAN8 (Affinity Capture-Luminescence), MEP1B (Affinity Capture-MS)

ESM2 similar proteins: A0A0N9E2K8, A0A1D5NSK0, A0A8M9PFP2, G5ECS8, G5EFD9, O15072, O18767, O43909, O60882, O62806, O77656, O93470, P07152, P22003, P23097, P28825, P29788, P33435, P49003, P57748, P79287, Q10835, Q11005, Q14703, Q16819, Q16820, Q19791, Q24025, Q3U435, Q568B8, Q61847, Q64230, Q6GQB9, Q6NP60, Q8CGD2, Q8K3F2, Q8N119, Q8R4K8, Q8VDA1, Q90YC2

Diamond homologs: A0A0C5PRQ1, A0FKN6, A8Q2D1, C9D7R2, C9D7R3, D2KBH9, D5FM34, D5FM37, D5FM38, K7Z9Q9, O16977, O17264, O43897, O57382, O57460, O62243, P07584, P0DM61, P0DM62, P13497, P28825, P28826, P31579, P31580, P31581, P42674, P55112, P55113, P55114, P55115, P84748, P91137, P98060, P98061, P98063, P98068, P98069, P98070, Q16819, Q16820

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PRKCD	“down-regulates quantity”	MEP1B	phosphorylation
PRKCA	“down-regulates quantity”	MEP1B	phosphorylation
PRKCB	“down-regulates quantity”	MEP1B	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1792 predictions. Top by Δscore:

Variant	Effect	Δscore
18:32192638:A:AG	acceptor_gain	1.0000
18:32204167:A:AG	acceptor_gain	1.0000
18:32204168:A:G	acceptor_gain	1.0000
18:32207401:G:GT	donor_gain	1.0000
18:32207422:GATT:G	donor_gain	1.0000
18:32207429:G:GG	donor_gain	1.0000
18:32207449:T:G	donor_gain	1.0000
18:32207468:GCT:G	donor_gain	1.0000
18:32207471:G:GG	donor_gain	1.0000
18:32208278:GGA:G	donor_gain	1.0000
18:32208279:GAG:G	donor_gain	1.0000
18:32210661:G:GT	donor_gain	1.0000
18:32210712:AAAAG:A	donor_loss	1.0000
18:32210713:AAAGG:A	donor_loss	1.0000
18:32210714:AAGGT:A	donor_loss	1.0000
18:32210715:AGGTA:A	donor_loss	1.0000
18:32210716:GGTAC:G	donor_loss	1.0000
18:32210717:G:T	donor_loss	1.0000
18:32210718:T:A	donor_loss	1.0000
18:32216990:GACAT:G	acceptor_gain	1.0000
18:32217753:A:G	acceptor_gain	1.0000
18:32217756:TGCA:T	acceptor_loss	1.0000
18:32217757:GCAG:G	acceptor_loss	1.0000
18:32217759:A:AG	acceptor_gain	1.0000
18:32217760:G:GG	acceptor_gain	1.0000
18:32217966:G:GG	donor_gain	1.0000
18:32220230:GCA:G	acceptor_gain	1.0000
18:32190129:GCTTG:G	donor_gain	0.9900
18:32190133:GGTA:G	donor_loss	0.9900
18:32190134:G:C	donor_loss	0.9900

AlphaMissense

4664 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:32195448:G:C	W71C	0.997
18:32195448:G:T	W71C	0.997
18:32195446:T:A	W71R	0.996
18:32195446:T:C	W71R	0.996
18:32213450:G:C	W490C	0.996
18:32213450:G:T	W490C	0.996
18:32204319:G:C	R169P	0.995
18:32213328:A:C	S450R	0.995
18:32213330:C:A	S450R	0.995
18:32213330:C:G	S450R	0.995
18:32204183:T:A	C124S	0.994
18:32204184:G:C	C124S	0.994
18:32204243:T:A	C144S	0.994
18:32204244:G:C	C144S	0.994
18:32204245:T:G	C144W	0.994
18:32213448:T:A	W490R	0.994
18:32213448:T:C	W490R	0.994
18:32204244:G:A	C144Y	0.993
18:32204244:G:T	C144F	0.993
18:32204279:C:G	H156D	0.993
18:32207266:T:C	F188L	0.993
18:32207268:T:A	F188L	0.993
18:32207268:T:G	F188L	0.993
18:32207350:T:C	F216L	0.993
18:32207352:C:A	F216L	0.993
18:32207352:C:G	F216L	0.993
18:32208207:G:C	W285C	0.993
18:32208207:G:T	W285C	0.993
18:32204310:G:C	R166P	0.992
18:32204185:C:G	C124W	0.991

dbSNP variants (sampled 300 via entrez): RS1000350211 (18:32191116 C>T), RS1000498119 (18:32215918 A>C), RS1000760336 (18:32189269 G>T), RS1000821456 (18:32197849 A>G), RS1000822922 (18:32190926 T>C), RS1000914932 (18:32196096 G>A), RS1000962427 (18:32209544 G>A), RS1001126605 (18:32201564 G>C), RS1001205142 (18:32198532 G>A), RS1001229856 (18:32191628 A>T), RS1001256537 (18:32203188 C>G,T), RS1001284465 (18:32196210 C>A,T), RS1001312509 (18:32205238 T>C), RS1001448187 (18:32204654 C>T), RS1001448931 (18:32200497 T>C)

Disease associations

OMIM: gene MIM:600389 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004424_45	TRAIL levels	8.000000e-175
GCST009391_1257	Metabolite levels	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008300	TNF-related apoptosis-inducing ligand measurement
EFO:0004761	uric acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105879 (SINGLE PROTEIN)

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

ChEMBL bioactivities

65 potent at pChembl≥5 of 94 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.10	Ki	8	nM	CHEMBL4096803
7.66	Ki	22	nM	CHEMBL1253351
7.64	IC50	23	nM	CHEMBL4209993
7.62	IC50	24	nM	CHEMBL4205925
7.31	IC50	49	nM	CHEMBL4216076
7.24	IC50	57	nM	CHEMBL4078433
7.22	IC50	60	nM	CHEMBL4078433
7.22	IC50	60	nM	CHEMBL4105563
7.12	IC50	76	nM	CHEMBL4206683
7.11	IC50	77	nM	CHEMBL4217240
6.75	IC50	177	nM	CHEMBL4207946
6.68	IC50	207	nM	CHEMBL4204835
6.66	IC50	220	nM	CHEMBL4099123
6.57	IC50	270	nM	CHEMBL4102689
6.57	IC50	272	nM	CHEMBL4206728
6.54	IC50	285	nM	CHEMBL4215019
6.51	IC50	310	nM	CHEMBL4083600
6.50	IC50	320	nM	CHEMBL4087683
6.50	IC50	320	nM	CHEMBL4207739
6.47	IC50	340	nM	CHEMBL4072148
6.46	IC50	347	nM	CHEMBL4218599
6.43	IC50	375	nM	CHEMBL4204272
6.42	IC50	377	nM	CHEMBL4210875
6.41	IC50	386	nM	CHEMBL4208444
6.40	IC50	400	nM	CHEMBL4096428
6.39	IC50	410	nM	CHEMBL4101604
6.37	IC50	430	nM	CHEMBL4063534
6.28	IC50	524	nM	CHEMBL4209047
6.26	IC50	548	nM	CHEMBL4206648
6.25	IC50	559	nM	CHEMBL4214841
6.19	IC50	650	nM	CHEMBL4067530
6.19	IC50	643	nM	CHEMBL4216704
6.18	IC50	654	nM	CHEMBL4214445
6.16	IC50	700	nM	CHEMBL4083361
6.13	IC50	742	nM	CHEMBL4218003
6.12	IC50	768	nM	CHEMBL4209523
6.01	IC50	980	nM	CHEMBL4079395
5.97	IC50	1080	nM	CHEMBL4071300
5.97	IC50	1060	nM	CHEMBL4098334
5.97	IC50	1060	nM	CHEMBL4207129
5.89	IC50	1280	nM	CHEMBL4213564
5.89	IC50	1285	nM	CHEMBL4205822
5.88	IC50	1325	nM	CHEMBL4210373
5.71	IC50	1930	nM	CHEMBL4061533
5.70	Ki	2000	nM	ACTINONIN
5.65	IC50	2250	nM	CHEMBL4211738
5.59	IC50	2550	nM	CHEMBL4097429
5.54	IC50	2905	nM	CHEMBL4211265
5.54	IC50	2910	nM	CHEMBL4207661
5.42	IC50	3850	nM	CHEMBL550148

PubChem BioAssay actives

65 with measured affinity, of 94 total; 50 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
tetrasodium;3-[[4-carboxy-5-hydroxy-6-methyl-3-(phosphonatooxymethyl)-2-pyridinyl]diazenyl]-7-nitronaphthalene-1,5-disulfonate	1450127: Inhibition of recombinant human meprin beta expressed in baculovirus infected Sf9 insect cells using (MCA)-EDEDED-(K-epsilon-dnp) as substrate by fluorescence assay	ki	0.0080	uM
octasodium;4-[[3-[[3,5-bis[(2,4-disulfonatophenyl)carbamoyl]phenyl]carbamoylamino]-5-[(2,4-disulfonatophenyl)carbamoyl]benzoyl]amino]benzene-1,3-disulfonate	1450127: Inhibition of recombinant human meprin beta expressed in baculovirus infected Sf9 insect cells using (MCA)-EDEDED-(K-epsilon-dnp) as substrate by fluorescence assay	ki	0.0220	uM
2-[bis[(2,4-difluoro-3-hydroxyphenyl)methyl]amino]-N-hydroxyacetamide	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.0230	uM
2-[bis[(4-chloro-2-fluoro-3-hydroxyphenyl)methyl]amino]-N-hydroxyacetamide	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.0240	uM
3-[[(3-carboxyphenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.0490	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-(4-methoxyphenyl)sulfonylamino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.0570	uM
3-[[(3-carboxyphenyl)sulfonyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.0600	uM
3-[[(4-chlorophenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.0760	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-[(4-methoxyphenyl)methyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.0770	uM
3-[[(4-fluorophenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.1770	uM
3-[[(4-carboxyphenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.2070	uM
3-[[3-(hydroxyamino)-3-oxopropyl]sulfamoyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.2200	uM
3-[[1,3-benzodioxol-5-ylsulfonyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.2700	uM
2-[bis[(3,5-difluoro-4-hydroxyphenyl)methyl]amino]-N-hydroxyacetamide	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.2720	uM
3-[[1,3-benzodioxol-5-ylmethyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.2850	uM
3-[[2-(hydroxyamino)-2-oxoethyl]sulfamoyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3100	uM
3-[[(4-cyanophenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3200	uM
3-[[(4-carboxyphenyl)sulfonyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3200	uM
4-[[3-(hydroxyamino)-3-oxopropyl]sulfamoyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3400	uM
3-[[(2,6-difluoro-4-methoxyphenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3470	uM
3-[[(3-fluoro-4-methoxyphenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3750	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3770	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-[(4-methylphenyl)methyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.3860	uM
3-[(3,5-dichloro-4-hydroxyphenyl)sulfonylamino]-N-hydroxypropanamide	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.4000	uM
4-[[2-(hydroxyamino)-2-oxoethyl]sulfamoyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.4100	uM
2-[(3,5-dichloro-4-hydroxyphenyl)sulfonylamino]-N-hydroxyacetamide	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.4300	uM
4-[[(4-carboxyphenyl)methyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.5240	uM
3-[[[(2R)-3-carboxy-1-(hydroxyamino)-1-oxopropan-2-yl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.5480	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-[(3-methoxyphenyl)methyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.5590	uM
3-[[[3-(hydroxyamino)-3-oxopropyl]-[(4-methoxyphenyl)methyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.6430	uM
3-[[(3-fluoro-4-methoxyphenyl)sulfonyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.6500	uM
3-[[[(2S)-4-carboxy-1-(hydroxyamino)-1-oxobutan-2-yl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.6540	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-[4-(trifluoromethoxy)phenyl]sulfonylamino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.7000	uM
3-[[[4-(hydroxyamino)-4-oxobutyl]-[(4-methoxyphenyl)methyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.7420	uM
3-[[[(2R)-4-carboxy-1-(hydroxyamino)-1-oxobutan-2-yl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.7680	uM
4-[[[2-(hydroxyamino)-2-oxoethyl]-(4-methoxyphenyl)sulfonylamino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	0.9800	uM
2-[bis[(4-fluoro-3-hydroxyphenyl)methyl]amino]-N-hydroxyacetamide	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	1.0600	uM
3-[[(4-fluorophenyl)sulfonyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	1.0600	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-(4-phenylphenyl)sulfonylamino]methyl]benzoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	1.0800	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-[(4-phenylphenyl)methyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	1.2800	uM
3-[[benzyl-[2-(hydroxyamino)-2-oxoethyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	1.2850	uM
3-[[[(2S)-3-carboxy-1-(hydroxyamino)-1-oxopropan-2-yl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	1.3250	uM
2-[1,3-benzodioxol-5-ylmethyl-(4-methoxyphenyl)sulfonylamino]-N-hydroxyacetamide	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	1.9300	uM
(2R)-N’-hydroxy-N-[(2S)-1-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-2-pentylbutanediamide	1375470: Inhibition of recombinant human meprin beta expressed in baculovirus infected insect cells using N-benzoyl-L-tyrosyl-p-aminobenzoic acid as substrate	ki	2.0000	uM
3-[[[2-(hydroxyamino)-2-oxoethyl]-[(3-propoxyphenyl)methyl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	2.2500	uM
3-[[2-(hydroxyamino)-2-oxoethyl]-(4-methoxyphenyl)sulfonylamino]propanoic acid	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	2.5500	uM
2-[bis[(2-fluoro-3-hydroxyphenyl)methyl]amino]-N-hydroxyacetamide	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	2.9050	uM
3-[[[(2R)-1-(hydroxyamino)-1-oxo-3-phenylpropan-2-yl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	2.9100	uM
N-hydroxy-2-[(4-phenylphenyl)sulfonylamino]acetamide	1450128: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	3.8500	uM
3-[[[(2S)-1-(hydroxyamino)-1-oxopropan-2-yl]amino]methyl]benzoic acid	1375444: Inhibition of recombinant human meprin beta expressed in yeast using Abz-YVAEAPK(Dnp)G-OH as substrate by fluorescence assay	ic50	4.2000	uM

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	2
methyleugenol	decreases expression	1
testosterone undecanoate	affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Estradiol	decreases expression	1
Levonorgestrel	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4018048	Binding	Inhibition of human meprin beta expressed in baculovirus infected BTI-TN-5B1-4 insect cells using N-benzoyl-L-tyrosylp-aminobenzoic acid as substrate	First insight into structure-activity relationships of selective meprin β inhibitors. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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