LGMN

Summary

LGMN (legumain, HGNC:9472) is a protein-coding gene on chromosome 14q32.12, encoding Legumain (Q99538). Has a strict specificity for hydrolysis of asparaginyl bonds.

This gene encodes a cysteine protease that has a strict specificity for hydrolysis of asparaginyl bonds. This enzyme may be involved in the processing of bacterial peptides and endogenous proteins for MHC class II presentation in the lysosomal/endosomal systems. Enzyme activation is triggered by acidic pH and appears to be autocatalytic. Protein expression occurs after monocytes differentiate into dendritic cells. A fully mature, active enzyme is produced following lipopolysaccharide expression in mature dendritic cells. Overexpression of this gene may be associated with the majority of solid tumor types. This gene has a pseudogene on chromosome 13. Several alternatively spliced transcript variants have been described, but the biological validity of only two has been determined. These two variants encode the same isoform.

Source: NCBI Gene 5641 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 107 total
• Druggable target: yes
• MANE Select transcript: NM_005606

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9472
Approved symbol	LGMN
Name	legumain
Location	14q32.12
Locus type	gene with protein product
Status	Approved
Aliases	LGMN1
Ensembl gene	ENSG00000100600
Ensembl biotype	protein_coding
OMIM	602620
Entrez	5641

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 36 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000334869, ENST00000393218, ENST00000553371, ENST00000553802, ENST00000553918, ENST00000554080, ENST00000554189, ENST00000554397, ENST00000554919, ENST00000555169, ENST00000555699, ENST00000556097, ENST00000556790, ENST00000557034, ENST00000557315, ENST00000557434, ENST00000557609, ENST00000557694, ENST00000557725, ENST00000862021, ENST00000862022, ENST00000862023, ENST00000862024, ENST00000862025, ENST00000862026, ENST00000862027, ENST00000862028, ENST00000862029, ENST00000862030, ENST00000862031, ENST00000862032, ENST00000862033, ENST00000862034, ENST00000862035, ENST00000862036, ENST00000862037, ENST00000926650, ENST00000926651, ENST00000926652, ENST00000952377, ENST00000952378, ENST00000952379, ENST00000952380, ENST00000952381

RefSeq mRNA: 4 — MANE Select: NM_005606 NM_001008530, NM_001363696, NM_001363699, NM_005606

CCDS: CCDS86423, CCDS86424, CCDS9904

Canonical transcript exons

ENST00000334869 — 14 exons

Exon	Start	End
ENSE00001550662	92748489	92748627
ENSE00002439536	92703809	92704361
ENSE00003466591	92709672	92709872
ENSE00003499032	92716136	92716221
ENSE00003523418	92711659	92711748
ENSE00003542398	92714376	92714451
ENSE00003562228	92717380	92717461
ENSE00003566599	92706483	92706653
ENSE00003609109	92712805	92712871
ENSE00003618144	92704640	92704707
ENSE00003642923	92713823	92713885
ENSE00003676696	92732649	92732815
ENSE00003691825	92711837	92711955
ENSE00003791195	92718747	92718844

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.8856 / max 4041.4329, expressed in 1717 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144601	91.1850	1704
144602	5.3904	1549
144596	0.1970	76
144597	0.1132	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
synovial joint	UBERON:0002217	99.50	gold quality
gall bladder	UBERON:0002110	98.84	gold quality
layer of synovial tissue	UBERON:0007616	98.72	gold quality
right coronary artery	UBERON:0001625	98.34	gold quality
left lobe of thyroid gland	UBERON:0001120	98.08	gold quality
placenta	UBERON:0001987	98.05	gold quality
rectum	UBERON:0001052	98.02	gold quality
right lobe of thyroid gland	UBERON:0001119	97.96	gold quality
thyroid gland	UBERON:0002046	97.92	gold quality
spleen	UBERON:0002106	97.89	gold quality
oocyte	CL:0000023	97.67	gold quality
upper lobe of left lung	UBERON:0008952	97.42	gold quality
colonic epithelium	UBERON:0000397	97.36	gold quality
lymph node	UBERON:0000029	97.28	gold quality
adult mammalian kidney	UBERON:0000082	97.27	gold quality
upper lobe of lung	UBERON:0008948	97.25	gold quality
urethra	UBERON:0000057	97.15	gold quality
penis	UBERON:0000989	97.12	gold quality
coronary artery	UBERON:0001621	97.12	gold quality
descending thoracic aorta	UBERON:0002345	97.06	gold quality
left coronary artery	UBERON:0001626	97.05	gold quality
mucosa of urinary bladder	UBERON:0001259	97.01	gold quality
right lung	UBERON:0002167	96.94	gold quality
omental fat pad	UBERON:0010414	96.94	gold quality
peritoneum	UBERON:0002358	96.91	gold quality
mucosa of stomach	UBERON:0001199	96.88	gold quality
thoracic aorta	UBERON:0001515	96.75	gold quality
vermiform appendix	UBERON:0001154	96.74	gold quality
ascending aorta	UBERON:0001496	96.74	gold quality
decidua	UBERON:0002450	96.64	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	3168.33
E-HCAD-36	yes	2367.04
E-MTAB-8322	yes	1990.26
E-CURD-112	yes	967.53
E-GEOD-89232	yes	562.28
E-MTAB-6701	yes	54.96
E-HCAD-10	yes	54.37
E-MTAB-10553	yes	45.46
E-MTAB-10287	yes	44.82
E-HCAD-6	yes	33.58
E-HCAD-9	yes	17.89
E-MTAB-9067	yes	15.64
E-CURD-122	yes	13.26
E-MTAB-10042	yes	10.09
E-MTAB-9801	yes	6.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CCNE1	Repression

Upstream regulators (CollecTRI, top): AP1, APOE

miRNA regulators (miRDB)

15 targeting LGMN, 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-95-5P	99.89	72.17	3973
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-3611	98.76	68.76	1290
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-152-5P	96.42	66.59	960
HSA-MIR-3943	95.87	64.57	523
HSA-MIR-4268	94.45	64.09	819

Literature-anchored findings (GeneRIF, showing 40)

• human monocyte-derived dendritic cells harbor inactive proforms of AEP (legumain) that become activated upon maturation of dendritic cells with lipopolysaccharide (PMID:12860980)
• Freshly isolated human B lymphocytes lack significant asparagine-specific endoprotease (AEP/legumain) activity; cleavage by AEP is dispensable for proteolytic processing of myelin basic protein in this type of cell. (PMID:15100291)
• Increased legumain expression is associated with primary colorectal cancer (PMID:15788679)
• AEP may be a proteinases activated by acidosis triggering neuronal injury during neuroexcitotoxicity or ischemia. (PMID:18374643)
• Legumain is expressed in both murine and human atherosclerotic lesions, may play a functional role in atherogenesis (PMID:18377911)
• GARP is a key receptor controlling FOXP3 in T(reg) cells following T-cell activation in a positive feedback loop assisted by LGALS3 and LGMN (PMID:19453521)
• the level of cystatin E/M regulates legumain activity and hence the invasive potential of human melanoma cells (PMID:20074384)
• The Lgmn can serve as novel target in diabetes mellitus genetic therapy. (PMID:20536387)
• Accepting asparagines and, to lesser extent, aspartic acid in P1, super-activated legumain exhibits a marked pH dependence that is governed by the P1 residue of its substrate and conformationally stabilizing factors such as temperature or ligands (PMID:22232165)
• Increased legumain expression was validated by real-time PCR and Western blots, correlated positively with an increased malignancy of ovarian tumors. (PMID:22441772)
• TDP-43 is cleaved by AEP in brain. (PMID:22718532)
• Data show a regulatory role of cystatin E/M in controlling both intra- and extracellular legumain activity. (PMID:22902879)
• Prostate cancer with a vesicular staining pattern of legumain had the potential of being highly invasive and aggressive in patients treated with radical prostatectomy. This suggests that legumain might contribute to the invasiveness and aggressiveness. (PMID:23124822)
• glycosaminoglycans accelerated the autocatalytic activation of prolegumain (PMID:23160071)
• In the HCT116 and SW620 cell lines nuclear Data indicate that legumain was found to make up approximately 13% and 17% of the total legumain, respectively. (PMID:23326369)
• Involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and the asparaginyl endopeptidase-I2(PP2A)-protein phosphatase 2A-Tau hyperphosphorylation pathway. (PMID:23640887)
• The multibranched and context-dependent activation process of legumain illustrates how proteases can act not only as signal transducers but as decision makers. (PMID:23776206)
• HCT116 cells were transfected with p53 siRNA and the effect of knockdown of p53 expression on legumain expression was examined. The results showed that expression levels of both legumain mRNA and protein were decreased in the siRNA-treated cells. (PMID:23942113)
• the relationship among Legumain expression, clinicopathologic, biological variables and patient prognosis in gastric carcinoma (PMID:24023813)
• This unique feature was confirmed by the crystal structure of AEPpH4.5 (AEP was matured at pH 4.5 and crystallized at pH 8.5), in which the broken peptide bonds were religated and the structure was transformed back to its proenzyme form. (PMID:24407422)
• Identified an alternative oncogenic pathway for TRAF6 that uses AEP as its substrate. AEP and TRAF6 protein levels may have prognostic implications in breast cancer patients. Thus, AEP may serve as a biomarker as well as new therapeutic target (PMID:24610907)
• High legumain activity is associated with breast cancer. (PMID:24742492)
• AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. (PMID:25326800)
• High legumain expression is associated with breast cancer. (PMID:25605174)
• Studies indicate that legumain, usually in lysosomes, is also found extracellularly and even translocates to the cytosol and the nucleus. (PMID:26403494)
• AEP acts as a delta-secretase, cleaving APP at N373 and N585 residues, selectively influencing the amyloidogenic fragmentation of APP. AEP contributes to the age-dependent pathogenic mechanisms in Alzheimer disease. (PMID:26549211)
• Legumain appears to be involved in tumor development and deterioration. (PMID:26607955)
• legumain might play an important role in cervical cancer cell migration and invasion. (PMID:26802645)
• upregulation of legumain is associated with malignant behavior of uveal melanoma. (PMID:26846877)
• These results showed that Asparaginyl endopeptidase could promote invasion and metastasis by modulating epithelial-to-mesenchymal transition. (PMID:27102302)
• our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL. (PMID:27464733)
• AEP promotes activation of the PI3K-AKT signaling pathway in prostate cancer cells. (PMID:27590439)
• MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain expression, promoting cell migration/neoplasm invasiveness. (PMID:27793040)
• Legumain is increased in both plasma and plaques of patients with carotid stenosis and might be a new and early biomarker of atherosclerosis. (PMID:27940038)
• Studies identified Legumain (LGMN) as a new target which is highly expressed in the tumor microenvironment and in tumor cells. [review] (PMID:27993111)
• Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis. (PMID:28162997)
• Data suggest that melanoma cells internalize/absorb cystatin C from culture media, leading to increased intracellular cystatin C levels; cystatin E/M is internalized as well but at modest rate due to down-regulation of cell migration; however, the effect of intracellular cystatin E/M on down-regulation of legumain activity is pronounced. (PMID:28630039)
• AEP is activated and cleaves human alpha-synuclein at N103 in an age-dependent manner. (PMID:28671665)
• Legumain regulates oxLDL-induced macrophage apoptosis by enhancing the autophagy pathway. (PMID:29414692)
• Study in different human cell lines and postmortem neurodegenerative diseases brain samples shows that BDNF-mediated Akt directly phosphorylates AEP on T322 and blocks AEP activation, sequestering it in lysosomes. BDNF reduction in neurodegenerative diseases elicits reduction of p-AEP T322, AEP cytoplasmic translocation, and subsequent activation, escalating its autocleavage and pathological substrate truncation. (PMID:30135302)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lgmn	ENSDARG00000039150
mus_musculus	Lgmn	ENSMUSG00000021190
rattus_norvegicus	Lgmn	ENSRNOG00000007089
caenorhabditis_elegans		WBGENE00012144

Paralogs (1): PIGK (ENSG00000142892)

Protein

Protein identifiers

Legumain — Q99538 (reviewed: Q99538)

Alternative names: Asparaginyl endopeptidase, Protease, cysteine 1

All UniProt accessions (10): Q99538, G3V263, G3V2E9, G3V2T4, G3V3Z4, G3V4E4, G3V4P5, G3V5B2, H0YJN9, Q53XC6

UniProt curated annotations — full annotation on UniProt →

Function. Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. Involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system. Also involved in MHC class I antigen presentation in cross-presenting dendritic cells by mediating cleavage and maturation of Perforin-2 (MPEG1), thereby promoting antigen translocation in the cytosol. Required for normal lysosomal protein degradation in renal proximal tubules. Required for normal degradation of internalized EGFR. Plays a role in the regulation of cell proliferation via its role in EGFR degradation.

Subunit / interactions. Homodimer before autocatalytic removal of the propeptide. Monomer after autocatalytic processing. May interact with integrins.

Subcellular location. Lysosome.

Tissue specificity. Ubiquitous. Particularly abundant in kidney, heart and placenta.

Post-translational modifications. Activated by autocatalytic processing at pH 4.

Activity regulation. Inhibited by CST6.

Domain organisation. In the zymogen form, the uncleaved propeptide blocks access to the active site.

Similarity. Belongs to the peptidase C13 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99538-1	1	yes
Q99538-2	2
Q99538-3	3

RefSeq proteins (4): NP_001008530, NP_001350625, NP_001350628, NP_005597* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001096	Peptidase_C13	Family
IPR043577	AE	Family
IPR046427	Legumain_prodom_sf	Homologous_superfamily
IPR048501	Legum_prodom	Domain

Pfam: PF01650, PF20985

Enzyme classification (BRENDA):

• EC 3.4.22.34 — Legumain (BRENDA: 43 organisms, 293 substrates, 339 inhibitors, 13 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-ALA-ALA-ASN-4-METHYLCOUMARIN-7	0.05–0.67	4
ACETYL-PRO-THR-ASN-4-METHYLCOUMARIN-7-AMIDE	0.122–0.286	2
ACETYL-THR-ALA-ASN-4-METHYLCOUMARIN-7-AMIDE	0.07–0.128	2
DINITROPHENYL-PRO-GLU-ALA-ASN-NH2	0.023–0.033	2
BENZYLOXYCARBONYL-ALA-ALA-ASN-7-AMIDO-4-METHYLCO	0.052	1
BENZYLOXYCARBONYL-ILE-SER-ASN-4-METHYLCOUMARIN-7	0.05	1

UniProt features (45 total): helix 12, strand 11, glycosylation site 4, splice variant 3, turn 3, disulfide bond 2, mutagenesis site 2, active site 2, signal peptide 1, chain 1, sequence variant 1, sequence conflict 1, propeptide 1, site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
7FQI	X-RAY DIFFRACTION	1.45
7FQJ	X-RAY DIFFRACTION	1.7
8AE4	X-RAY DIFFRACTION	1.79
4N6O	X-RAY DIFFRACTION	1.8
4N6N	X-RAY DIFFRACTION	1.87
7O50	X-RAY DIFFRACTION	1.9
5LU8	X-RAY DIFFRACTION	1.95
7FQK	X-RAY DIFFRACTION	1.97
5LUA	X-RAY DIFFRACTION	2
5LUB	X-RAY DIFFRACTION	2.1
7FQH	X-RAY DIFFRACTION	2.18
4AW9	X-RAY DIFFRACTION	2.2
5LU9	X-RAY DIFFRACTION	2.27
8AE5	X-RAY DIFFRACTION	2.29
4AWA	X-RAY DIFFRACTION	2.5
7FQL	X-RAY DIFFRACTION	2.53
4AWB	X-RAY DIFFRACTION	2.7
4FGU	X-RAY DIFFRACTION	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99538-F1	94.31	0.91

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 (3): 148; 189 (nucleophile); 323–324 (cleavage; by autolysis)

Disulfide bonds (2): 378–412, 390–429

Glycosylation sites (4): 91, 167, 263, 272

Mutagenesis-validated functional residues (2):

Position	Phenotype
190	increases catalytic activity at ph 5.5.
323	loss of autoactivation.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1679131	Trafficking and processing of endosomal TLR
R-HSA-196791	Vitamin D (calciferol) metabolism
R-HSA-2132295	MHC class II antigen presentation
R-HSA-1280218	Adaptive Immune System
R-HSA-1430728	Metabolism
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 427 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, MODULE_172, GOBP_MEMORY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_CHEMOTAXIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, KAAB_FAILED_HEART_ATRIUM_DN

GO Biological Process (26): antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent (GO:0002479), renal system process (GO:0003014), proteolysis (GO:0006508), vacuolar protein processing (GO:0006624), memory (GO:0007613), positive regulation of cell population proliferation (GO:0008284), associative learning (GO:0008306), response to acidic pH (GO:0010447), negative regulation of gene expression (GO:0010629), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), receptor catabolic process (GO:0032801), cellular response to hepatocyte growth factor stimulus (GO:0035729), negative regulation of multicellular organism growth (GO:0040015), vitamin D metabolic process (GO:0042359), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of mitotic cell cycle (GO:0045931), obsolete proteolysis involved in protein catabolic process (GO:0051603), protein maturation (GO:0051604), cellular response to calcium ion (GO:0071277), positive regulation of monocyte chemotaxis (GO:0090026), dendritic spine organization (GO:0097061), positive regulation of long-term synaptic potentiation (GO:1900273), negative regulation of ERBB signaling pathway (GO:1901185), cellular response to amyloid-beta (GO:1904646), positive regulation of endothelial cell chemotaxis (GO:2001028), antigen processing and presentation of exogenous peptide antigen via MHC class I (GO:0042590)

GO Molecular Function (6): cysteine-type endopeptidase activity (GO:0004197), peptidase activity (GO:0008233), tau protein binding (GO:0048156), endopeptidase activator activity (GO:0061133), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (9): extracellular region (GO:0005576), cytoplasm (GO:0005737), lysosome (GO:0005764), late endosome (GO:0005770), endolysosome lumen (GO:0036021), lysosomal lumen (GO:0043202), apical part of cell (GO:0045177), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Immune System	2
Toll-like Receptor Cascades	1
Metabolism of steroids	1
Adaptive Immune System	1
Innate Immune System	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein metabolic process	2
gene expression	2
endopeptidase activity	2
antigen processing and presentation of exogenous peptide antigen via MHC class I	1
system process	1
vacuole	1
protein processing	1
learning or memory	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
learning	1
response to pH	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
macromolecule catabolic process	1
receptor metabolic process	1
response to hepatocyte growth factor	1
cellular response to growth factor stimulus	1
multicellular organism growth	1
regulation of multicellular organism growth	1
negative regulation of developmental growth	1
negative regulation of multicellular organismal process	1
steroid metabolic process	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
positive regulation of cell cycle	1
response to calcium ion	1
cellular response to metal ion	1
monocyte chemotaxis	1
positive regulation of leukocyte chemotaxis	1
positive regulation of mononuclear cell migration	1
regulation of monocyte chemotaxis	1
cysteine-type peptidase activity	1

Protein interactions and networks

STRING

1444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LGMN	CST6	Q15828	954
LGMN	CTSS	P25774	877
LGMN	CTSB	P07858	871
LGMN	CTSL	P07711	839
LGMN	TGM3	Q08188	826
LGMN	CTSH	P09668	778
LGMN	AGAP2	Q99490	729
LGMN	SET	Q01105	684
LGMN	CST7	O76096	673
LGMN	EPB41L1	Q9H4G0	647
LGMN	CTSC	P53634	646
LGMN	CTSZ	Q9UBR2	627
LGMN	LORICRIN	P23490	619
LGMN	CTSF	Q9UBX1	617
LGMN	CTSD	P07339	602

IntAct

41 interactions, top by confidence:

A	B	Type	Score
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
LGMN	ATG7	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
CST6	CTSV	psi-mi:“MI:0914”(association)	0.530
LGMN	CSTA	psi-mi:“MI:0570”(protein cleavage)	0.440
LGMN	CSTB	psi-mi:“MI:0570”(protein cleavage)	0.440
LGMN	PRKAR1B	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
LGMN		psi-mi:“MI:0915”(physical association)	0.370
LAMC3	LGMN	psi-mi:“MI:0915”(physical association)	0.370
Dctn3		psi-mi:“MI:0914”(association)	0.350
PPP2R3C	OFD1	psi-mi:“MI:0914”(association)	0.350
RNASEH2A	PHF20L1	psi-mi:“MI:0914”(association)	0.350
SOD1	FAAP20	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
USP17L24	USP17L7	psi-mi:“MI:0914”(association)	0.350
JAK3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
LIMK1	ILVBL	psi-mi:“MI:0914”(association)	0.350
GABARAPL1		psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
ACTL6B	HSPA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): LGMN (Biochemical Activity), USP17L2 (Co-fractionation), USP17L2 (Affinity Capture-Western), LGMN (Co-fractionation), PDIA5 (Affinity Capture-MS), ATG7 (Affinity Capture-MS), HNRNPH2 (Co-fractionation), LGMN (Affinity Capture-MS), LGMN (Affinity Capture-MS), LGMN (Affinity Capture-MS), LGMN (Affinity Capture-MS), LGMN (Affinity Capture-MS), PDIA5 (Affinity Capture-MS), LGMN (Affinity Capture-MS), ATG7 (Affinity Capture-MS)

ESM2 similar proteins: B8ASK4, O24325, O24326, O64481, O89017, P08478, P09841, P10537, P10731, P10743, P12890, P14925, P16098, P19021, P25853, P42665, P49018, P49042, P49043, P49044, P49045, P49046, P49047, P49048, P50282, P82993, P93594, P97467, Q0IZZ8, Q39044, Q39119, Q4R4T8, Q5R5D9, Q5R6L8, Q765H6, Q84LM2, Q84R49, Q8GS39, Q8L7E3, Q8QGP3

Diamond homologs: B8ASK4, O24325, O24326, O89017, P09841, P42665, P49042, P49043, P49044, P49045, P49046, P49047, Q39044, Q39119, Q4R4T8, Q5R5D9, Q84LM2, Q8GS39, Q8T4E1, Q95M12, Q99538, Q9LJX8, Q9R0J8, P49018, P49048, P80527, Q3MHZ7, Q4KRV1, Q5R6L8, Q92643, Q9CXY9, Q9USP5, P80530

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TRAF6	“up-regulates quantity by stabilization”	LGMN	polyubiquitination
USP17L2	“down-regulates quantity by destabilization”	LGMN	deubiquitination
HSP90AA1	“up-regulates quantity by stabilization”	LGMN	binding
SRPK2	“up-regulates activity”	LGMN	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2483 predictions. Top by Δscore:

Variant	Effect	Δscore
14:92704360:TC:T	acceptor_gain	1.0000
14:92704361:CC:C	acceptor_gain	1.0000
14:92704362:C:CC	acceptor_gain	1.0000
14:92704704:CGTA:C	acceptor_gain	1.0000
14:92704708:C:CC	acceptor_gain	1.0000
14:92706649:CTGGC:C	acceptor_gain	1.0000
14:92706652:GC:G	acceptor_gain	1.0000
14:92706653:CC:C	acceptor_gain	1.0000
14:92706654:C:CC	acceptor_gain	1.0000
14:92709665:TAC:T	donor_loss	1.0000
14:92709666:ACT:A	donor_loss	1.0000
14:92709667:CTC:C	donor_loss	1.0000
14:92709669:CACAT:C	donor_loss	1.0000
14:92709670:A:AC	donor_gain	1.0000
14:92709670:ACAT:A	donor_gain	1.0000
14:92709671:C:CC	donor_gain	1.0000
14:92709671:CAT:C	donor_gain	1.0000
14:92709671:CATC:C	donor_gain	1.0000
14:92711655:TCA:T	donor_loss	1.0000
14:92711656:CA:C	donor_loss	1.0000
14:92711657:A:AC	donor_gain	1.0000
14:92711658:C:CT	donor_gain	1.0000
14:92711658:CT:C	donor_gain	1.0000
14:92711658:CTT:C	donor_gain	1.0000
14:92711658:CTTT:C	donor_gain	1.0000
14:92711658:CTTTG:C	donor_gain	1.0000
14:92711670:A:AC	donor_gain	1.0000
14:92711671:C:CC	donor_gain	1.0000
14:92711744:TCTTC:T	acceptor_loss	1.0000
14:92711745:CTTC:C	acceptor_gain	1.0000

AlphaMissense

2881 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:92711857:A:G	W237R	0.999
14:92711857:A:T	W237R	0.999
14:92711864:G:C	S234R	0.999
14:92711864:G:T	S234R	0.999
14:92711866:T:G	S234R	0.999
14:92718844:C:G	A47P	0.999
14:92732656:C:A	R44M	0.999
14:92732656:C:G	R44T	0.999
14:92711845:A:G	S241P	0.998
14:92711878:C:A	G230W	0.998
14:92711938:C:G	A210P	0.998
14:92711683:G:C	S265R	0.997
14:92711683:G:T	S265R	0.997
14:92711685:T:G	S265R	0.997
14:92711855:C:A	W237C	0.997
14:92711855:C:G	W237C	0.997
14:92732655:C:A	R44S	0.997
14:92732655:C:G	R44S	0.997
14:92711865:C:A	S234I	0.996
14:92711877:C:T	G230E	0.996
14:92711919:G:A	S216F	0.996
14:92711940:G:T	A209D	0.996
14:92712843:G:A	S191F	0.996
14:92712853:C:G	A188P	0.996
14:92712855:T:A	E187V	0.996
14:92714412:A:C	H148Q	0.996
14:92714412:A:T	H148Q	0.996
14:92717434:G:C	N88K	0.996
14:92717434:G:T	N88K	0.996
14:92718826:A:C	Y53D	0.996

dbSNP variants (sampled 300 via entrez): RS1000000467 (14:92743345 C>A), RS1000045076 (14:92709878 G>A), RS1000289219 (14:92749556 A>G), RS1000325171 (14:92715347 C>G,T), RS1000423968 (14:92727631 G>A), RS1000564088 (14:92720976 G>A,C), RS1000606380 (14:92744798 T>C), RS1000801303 (14:92725959 G>A,C), RS1000925992 (14:92733498 A>T), RS1000927216 (14:92731679 T>C), RS1000966732 (14:92727291 G>A,T), RS1001000320 (14:92743551 G>A,C), RS1001062819 (14:92705273 A>C), RS1001110131 (14:92727866 C>T), RS1001149110 (14:92742585 C>T)

Disease associations

OMIM: gene MIM:602620 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004025_24	Systemic juvenile idiopathic arthritis	5.000000e-06
GCST006585_2356	Blood protein levels	4.000000e-09
GCST009239_2	Change in serum metabolite levels (CMS)	4.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4244 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C13: Legumain

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 7u [PMID: 24775305]	Inhibition	9.05	pIC50
compound 18 [PMID: 38090813]	Inhibition	8.11	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3S)-3-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-5-(2,6-dimethylbenzoyl)oxy-4-oxopentanoic acid	IC50	11.5 nM	US-9345789: Specific inhibitors and active site probes for legumain

ChEMBL bioactivities

223 potent at pChembl≥5 of 225 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL5413711
10.00	IC50	0.1	nM	CHEMBL5420042
9.92	IC50	0.12	nM	CHEMBL4545652
9.70	IC50	0.2	nM	CHEMBL5425743
9.70	IC50	0.2	nM	CHEMBL5394077
9.70	IC50	0.2	nM	CHEMBL5402221
9.70	IC50	0.2	nM	CHEMBL5402155
9.70	IC50	0.2	nM	CHEMBL5412556
9.70	IC50	0.2	nM	CHEMBL5427662
9.59	IC50	0.26	nM	CHEMBL4438891
9.52	IC50	0.3	nM	CHEMBL5418321
9.52	IC50	0.3	nM	CHEMBL5415768
9.40	IC50	0.4	nM	CHEMBL5417499
9.33	IC50	0.47	nM	CHEMBL4556228
9.30	IC50	0.5	nM	CHEMBL5399304
9.22	IC50	0.6	nM	CHEMBL5419921
9.10	IC50	0.8	nM	CHEMBL5406157
9.10	IC50	0.8	nM	CHEMBL5409889
9.05	IC50	0.9	nM	CHEMBL3264590
9.05	IC50	0.9	nM	CHEMBL5407269
9.00	IC50	1	nM	CHEMBL5427707
9.00	IC50	1	nM	CHEMBL5436295
9.00	IC50	1	nM	CHEMBL5424838
9.00	IC50	1	nM	CHEMBL5396516
8.89	IC50	1.3	nM	CHEMBL4549828
8.89	IC50	1.3	nM	CHEMBL5398959
8.85	IC50	1.4	nM	CHEMBL4547118
8.85	IC50	1.4	nM	CHEMBL5415015
8.77	IC50	1.7	nM	CHEMBL5415184
8.74	IC50	1.8	nM	CHEMBL5424036
8.74	IC50	1.8	nM	CHEMBL5404830
8.74	IC50	1.8	nM	CHEMBL5430648
8.66	IC50	2.2	nM	CHEMBL5419035
8.55	IC50	2.8	nM	CHEMBL5406826
8.55	IC50	2.8	nM	CHEMBL5416023
8.52	IC50	3	nM	CHEMBL5424558
8.49	IC50	3.2	nM	CHEMBL3264589
8.47	IC50	3.4	nM	CHEMBL5431473
8.44	IC50	3.6	nM	CHEMBL4474978
8.41	IC50	3.9	nM	CHEMBL5399092
8.38	IC50	4.2	nM	CHEMBL5434439
8.37	IC50	4.3	nM	CHEMBL5425068
8.30	IC50	5	nM	CHEMBL3264578
8.30	IC50	5	nM	CHEMBL3741471
8.26	IC50	5.5	nM	CHEMBL4472825
8.24	IC50	5.7	nM	CHEMBL5416023
8.24	IC50	5.7	nM	CHEMBL5406826
8.22	IC50	6	nM	CHEMBL3740153
8.22	IC50	6	nM	CHEMBL3740378
8.19	IC50	6.4	nM	CHEMBL5401961

PubChem BioAssay actives

220 with measured affinity, of 368 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
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-2,2-dimethyl-3-[4-(1-methylindazol-7-yl)phenyl]sulfonylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0001	uM
(1S)-N-[(3S)-5-amino-1-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxopent-1-yn-3-yl]-2-[1-(4-chlorophenyl)cyclopropanecarbonyl]-1,3-dihydroisoindole-1-carboxamide	2007007: Inhibition of human 8His tagged AEP using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as fluorogenic substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0001	uM
(1S)-N-[(3S)-5-amino-5-oxo-1-pyrimidin-4-ylpent-1-yn-3-yl]-2-[1-(4-chlorophenyl)cyclopropanecarbonyl]-1,3-dihydroisoindole-1-carboxamide	2007007: Inhibition of human 8His tagged AEP using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as fluorogenic substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0001	uM
2-[(2-chloroacetyl)-[[(2S)-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carbonyl]amino]amino]acetamide	2015449: Inhibition of human 8His-tagged AEP (V18 to Y433 residues) using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as substrate incubated for 30 mins followed by substrate addition by fluorescence based microplate reader analysis	ic50	0.0002	uM
(1S)-N-[(3S)-5-amino-5-oxo-1-pyrazin-2-ylpent-1-yn-3-yl]-2-[1-(4-chlorophenyl)cyclopropanecarbonyl]-1,3-dihydroisoindole-1-carboxamide	2007007: Inhibition of human 8His tagged AEP using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as fluorogenic substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0002	uM
(2S)-N-[(3S)-5-amino-5-oxo-1-pyrimidin-4-ylpent-1-yn-3-yl]-1-[1-(5-chlorothiophen-2-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2007007: Inhibition of human 8His tagged AEP using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as fluorogenic substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0002	uM
(2S)-N-[(3S)-5-amino-5-oxo-1-pyrimidin-4-ylpent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2007007: Inhibition of human 8His tagged AEP using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as fluorogenic substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0002	uM
(2S)-N-[(3S)-5-amino-1-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxopent-1-yn-3-yl]-1-[1-(5-chlorothiophen-2-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2007007: Inhibition of human 8His tagged AEP using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as fluorogenic substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0002	uM
ethyl (E)-4-[(2-amino-2-oxoethyl)-[[(2S)-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carbonyl]amino]amino]-4-oxobut-2-enoate	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0002	uM
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-2,2-dimethyl-3-[4-(2-methylindazol-5-yl)phenyl]sulfonylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0003	uM
2-[(2-chloroacetyl)-[[(2S)-1-[4-(4-methoxyphenyl)phenyl]sulfonylpyrrolidine-2-carbonyl]amino]amino]acetamide	2015449: Inhibition of human 8His-tagged AEP (V18 to Y433 residues) using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as substrate incubated for 30 mins followed by substrate addition by fluorescence based microplate reader analysis	ic50	0.0003	uM
(2S)-N-[(3S)-5-amino-1-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxopent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0003	uM
(2S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-1-[1-(1-benzyl-5-chloropyrazol-4-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0004	uM
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-3-[2-(1,3-benzothiazol-6-yl)phenyl]sulfonyl-2,2-dimethylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0005	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[1-[4-[(2,4-difluorophenyl)methoxy]phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0005	uM
(2S)-N-[(3S)-5-amino-5-oxo-1-pyrimidin-2-ylpent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0006	uM
(2S)-N-[(3S)-5-amino-5-oxo-1-[6-(trifluoromethyl)-2-pyridinyl]pent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0008	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[1-(4-phenoxyphenyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0008	uM
(1R,2S,5S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-6,6-dimethyl-3-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0009	uM
[4-(3-ethoxyphenyl)phenyl]methyl (2S)-2-[[(1S)-3-amino-1-cyano-3-oxopropyl]carbamoyl]pyrrolidine-1-carboxylate	1142243: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC fluorogenic substrate	ic50	0.0009	uM
2-[[[(2S)-1-[1-(4-ethynylphenyl)cyclopropanecarbonyl]pyrrolidine-2-carbonyl]amino]-(2-fluoroacetyl)amino]acetamide	2015449: Inhibition of human 8His-tagged AEP (V18 to Y433 residues) using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as substrate incubated for 30 mins followed by substrate addition by fluorescence based microplate reader analysis	ic50	0.0010	uM
2-[(2-fluoroacetyl)-[[(2S)-1-[4-(4-methoxyphenyl)phenyl]sulfonylpyrrolidine-2-carbonyl]amino]amino]acetamide	2015449: Inhibition of human 8His-tagged AEP (V18 to Y433 residues) using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as substrate incubated for 30 mins followed by substrate addition by fluorescence based microplate reader analysis	ic50	0.0010	uM
2-[(2-fluoroacetyl)-[[(2S)-1-[1-(4-prop-2-ynoxyphenyl)cyclopropanecarbonyl]pyrrolidine-2-carbonyl]amino]amino]acetamide	2015449: Inhibition of human 8His-tagged AEP (V18 to Y433 residues) using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as substrate incubated for 30 mins followed by substrate addition by fluorescence based microplate reader analysis	ic50	0.0010	uM
2-[[[(2S)-1-[1-(4-chlorophenyl)cyclobutanecarbonyl]pyrrolidine-2-carbonyl]amino]-(2-fluoroacetyl)amino]acetamide	2015449: Inhibition of human 8His-tagged AEP (V18 to Y433 residues) using Z-Ala-Ala-Asn-Rhl 10-(D-Pro) as substrate incubated for 30 mins followed by substrate addition by fluorescence based microplate reader analysis	ic50	0.0010	uM
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-3-[4-(3-fluorophenyl)phenyl]sulfonyl-2,2-dimethylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0013	uM
(2S)-N-[(3S)-5-amino-5-oxo-1-pyrazin-2-ylpent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0013	uM
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-3-[4-(6-tert-butyl-3-pyridinyl)phenyl]sulfonyl-2,2-dimethylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0014	uM
(2S)-N-[(3S)-5-amino-1-(1,3-oxazol-2-yl)-5-oxopent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0014	uM
(1S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-2-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]-1,3-dihydroisoindole-1-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0017	uM
2-[(2-fluoroacetyl)-[[(2S)-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carbonyl]amino]amino]acetamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0018	uM
(2S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-1-[3-methoxy-1-[4-(trifluoromethoxy)phenyl]cyclobutanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0018	uM
(2S)-N-[(3S)-5-amino-5-oxo-1-pyridazin-3-ylpent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0018	uM
(2S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-1-[1-[4-[(2,2-difluorocyclobutyl)methoxy]phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0022	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[1-(4-phenylphenyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0028	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025368: Inhibition of AEP (unknown origin) expressed in HEK293-A cells using fluorogenic substrate assessed as fluorescence emission intensity preincubated for 2 hrs followed by incubated with substrate for 5 hrs by cellular assay	ic50	0.0028	uM
(2S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-1-[3-fluoro-1-[4-(trifluoromethoxy)phenyl]cyclobutanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0030	uM
[4-(3-methoxyphenyl)phenyl]methyl (2S)-2-[[(1S)-3-amino-1-cyano-3-oxopropyl]carbamoyl]pyrrolidine-1-carboxylate	1142243: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC fluorogenic substrate	ic50	0.0032	uM
(2S,4R)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-4-methyl-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0034	uM
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-2,2-dimethyl-3-[4-(1-methylindazol-5-yl)phenyl]sulfonylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0036	uM
(2S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-1-[1-(5-chlorothiophen-2-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0039	uM
(2S)-N-[(3S)-5-amino-5-oxopent-1-yn-3-yl]-1-[1-[4-(cyclopropylmethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0042	uM
(2S)-N-[(3S)-5-amino-1-(6-methoxy-2-pyridinyl)-5-oxopent-1-yn-3-yl]-1-[1-[4-(trifluoromethoxy)phenyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0043	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[4-(4-propan-2-ylphenyl)phenyl]sulfonylpyrrolidine-2-carboxamide	1265055: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-MCA substrate measured every 2 mins for 60 mins by microplate reader analysis	ic50	0.0050	uM
[4-(4-fluorophenyl)phenyl]methyl (2S)-2-[[(1S)-3-amino-1-cyano-3-oxopropyl]carbamoyl]pyrrolidine-1-carboxylate	1142243: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC fluorogenic substrate	ic50	0.0050	uM
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-3-[4-(4-fluorophenyl)phenyl]sulfonyl-2,2-dimethylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0055	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[3-chloro-4-(4-chlorophenyl)phenyl]sulfonylpyrrolidine-2-carboxamide	1265055: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-MCA substrate measured every 2 mins for 60 mins by microplate reader analysis	ic50	0.0060	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[4-(4-methoxyphenyl)phenyl]sulfonylpyrrolidine-2-carboxamide	1265055: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-MCA substrate measured every 2 mins for 60 mins by microplate reader analysis	ic50	0.0060	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-(1-phenylcyclobutanecarbonyl)pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0064	uM
(2S)-N-[(1S)-3-amino-1-cyano-3-oxopropyl]-1-[1-(4-chlorophenyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2025364: Inhibition of recombinant AEP (unknown origin) using Z0AAn-Rh110 as peptide substrate measured for 15 to 30 mins by fluorescence assay	ic50	0.0064	uM
N-[(1S)-3-amino-1-cyano-3-oxopropyl]-3-[4-(4-chlorophenyl)phenyl]sulfonyl-2,2-dimethylpropanamide	1544468: Inhibition of recombinant human legumain using Z-Ala-Ala-Asn-AMC as substrate measured for every 2 mins for 60 mins by fluorescence-based microplate reader analysis	ic50	0.0071	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
bisphenol A	decreases expression, increases expression, increases methylation	3
Acetaminophen	increases expression, affects expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
cobaltous chloride	increases expression	2
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression, increases expression	2
bisphenol S	decreases methylation, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Rotenone	decreases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
terbufos	increases methylation	1
sodium bichromate	decreases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
deguelin	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
incobotulinumtoxinA	increases expression	1
(+)-JQ1 compound	increases expression	1

ChEMBL screening assays

43 unique, capped per target: 43 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1228605	Binding	Binding affinity to human purified legumain assessed as protein labeling	Activity-based probes that target diverse cysteine protease families. — Nat Chem Biol

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D2BK	Abcam HCT 116 LGMN KO	Cancer cell line	Male
CVCL_D2NL	Abcam THP-1 LGMN KO	Cancer cell line	Male

Clinical trials (associated diseases)

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