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GZMM

gene
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Also known as MET1LMET1

Summary

GZMM (granzyme M, HGNC:4712) is a protein-coding gene on chromosome 19p13.3, encoding Granzyme M (P51124). Cleaves peptide substrates after methionine, leucine, and norleucine.

Human natural killer (NK) cells and activated lymphocytes express and store a distinct subset of neutral serine proteases together with proteoglycans and other immune effector molecules in large cytoplasmic granules. These serine proteases are collectively termed granzymes and include 4 distinct gene products: granzyme A, granzyme B, granzyme H, and the protein encoded by this gene, granzyme M. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3004 — RefSeq curated summary.

At a glance

  • Clinical variants (ClinVar): 53 total
  • Druggable target: yes
  • MANE Select transcript: NM_005317

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:4712
Approved symbolGZMM
Namegranzyme M
Location19p13.3
Locus typegene with protein product
StatusApproved
AliasesMET1, LMET1
Ensembl geneENSG00000197540
Ensembl biotypeprotein_coding
OMIM600311
Entrez3004

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000264553, ENST00000592501

RefSeq mRNA: 2 — MANE Select: NM_005317 NM_001258351, NM_005317

CCDS: CCDS12031, CCDS74240

Canonical transcript exons

ENST00000264553 — 5 exons

ExonStartEnd
ENSE00001372154547280547436
ENSE00002900513544053544126
ENSE00003696014548922549185
ENSE00003699618548542548677
ENSE00003780386549630549922

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 97.83.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7803 / max 545.4441, expressed in 199 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter IDTPM avgSamples expressed
1726924.7803199

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
granulocyteCL:000009497.83gold quality
bloodUBERON:000017888.05gold quality
spleenUBERON:000210683.56gold quality
lymph nodeUBERON:000002979.97gold quality
vermiform appendixUBERON:000115476.77gold quality
mucosa of transverse colonUBERON:000499175.77gold quality
caecumUBERON:000115372.98gold quality
thymusUBERON:000237072.84silver quality
cerebellar hemisphereUBERON:000224572.50gold quality
right hemisphere of cerebellumUBERON:001489072.46gold quality
cerebellar cortexUBERON:000212972.21gold quality
bone marrowUBERON:000237171.12gold quality
cerebellumUBERON:000203770.48gold quality
leukocyteCL:000073870.36gold quality
small intestine Peyer’s patchUBERON:000345469.35gold quality
triceps brachiiUBERON:000150969.18gold quality
upper lobe of left lungUBERON:000895268.77gold quality
right lobe of liverUBERON:000111468.65gold quality
buccal mucosa cellCL:000233668.39gold quality
mononuclear cellCL:000084267.90gold quality
small intestineUBERON:000210867.67gold quality
monocyteCL:000057667.37gold quality
upper lobe of lungUBERON:000894867.07gold quality
right lungUBERON:000216767.00gold quality
bone marrow cellCL:000209266.76silver quality
gluteal muscleUBERON:000200066.75gold quality
type B pancreatic cellCL:000016966.40gold quality
right coronary arteryUBERON:000162565.92gold quality
mucosa of stomachUBERON:000119965.53gold quality
jejunal mucosaUBERON:000039965.30silver quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 16.

ExperimentMarker?Max mean expression
E-HCAD-4yes149.44
E-HCAD-1yes110.36
E-CURD-122yes64.84
E-MTAB-9467yes60.33
E-MTAB-10553yes50.15
E-MTAB-6701yes44.88
E-CURD-88yes40.32
E-HCAD-10yes37.78
E-MTAB-8410yes31.52
E-HCAD-8yes25.24
E-GEOD-135922yes23.78
E-CURD-46yes14.21
E-MTAB-10042yes12.55
E-CURD-112yes6.18
E-ANND-3yes5.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

1 targeting GZMM, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-331-3P98.7664.91793

Literature-anchored findings (GeneRIF, showing 20)

  • GM expression is a distinctive feature of the nasal NK/T-cell, gamma delta T-cell, and intestinal T-cell lymphomas, and suggest that these tumors develop from lymphocytes involved in innate immunity. (PMID:12506019)
  • granzyme M represents a third major and specialized perforin-dependent cell death pathway that plays a significant role in death mediated by NK cells (PMID:15028722)
  • proteinase inhibitor 9 was effectively hydrolyzed and inactivated by human granzyme M, raising the possibility that this orphan granzyme bypasses proteinase inhibitor 9 inhibition of granzyme B (PMID:15494398)
  • Granzyme (Gzm)M can directly degrade inhibitor of caspase-activated DNase (ICAD) to activate CAD, leading to DNA damage; GzmM cleaves DNA damage sensor enzyme poly(ADP-ribose) polymerase to prevent cellular DNA repair and force apoptosis. (PMID:16818775)
  • Granzyme M targets major components of the cytoskeleton that likely contribute to natural killer (NK) cell-induced cell death. (PMID:18523284)
  • NPM is essential for cell viability, these data suggest that targeting of NPM by granzyme M may contribute to tumor cell eradication by abolishing NPM function. (PMID:19103589)
  • Structure-based mutagenesis reveals that the amino-terminus and catalytic triad of GzmM are most essential for proteolytic function. (PMID:19542453)
  • These findings support not only a role for GrM in the innate but also in the adaptive immune response. (PMID:19896187)
  • Results describe the structural characterization of granzyme M by molecular modeling as well as by detailed comparison with other granzymes. (PMID:20107908)
  • survivin cleavage by Granzyme M triggers degradation of the survivin-X-linked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells (PMID:20406824)
  • Noncytotoxic inhibition of cytomegalovirus replication through NK cell protease granzyme M-mediated cleavage of viral phosphoprotein 71. (PMID:21059895)
  • Results indicate that cellular overexpression of SERPINB4 inhibits recombinant GrM-induced as well as NK cell-mediated cell death. (PMID:21857942)
  • GrM also exists extracellularly in plasma where it could play a physiological role in controlling blood coagulation by determining plasma FVIII levels via proteolytic processing of its carrier VWF. (PMID:21909423)
  • FADD cleavage by NK cell granzyme M enhances its self-association to facilitate procaspase-8 recruitment for auto-processing leading to caspase cascade. (PMID:21979465)
  • GrM is expressed in HCMV-specific CD8thorn T cells and cleaves host cell protein hnRNP K in the presence of RNA. (PMID:23099853)
  • Granzym M may be important in regulating HCMV latency and reactivation in SCT patients. (PMID:24316590)
  • We also report that TNFalpha induces the attachment of Met1-linked Ub chains directly to TNF receptor 1, which do not seem to be attached covalently to Lys63-linked or other types of ubiquitin chain. (PMID:27133719)
  • GzMM has a critical role during early stages of inflammation in ulcerative colitis; in its absence colonic inflammation is enhanced. (PMID:27441655)
  • Granzyme B and granzyme M cleave IE1 after Asp398 and Leu414, respectively, likely resulting in IE1 aberrant cellular localization. (PMID:32282833)
  • Cytotoxic Lymphocytes Target HIV-1 Gag Through Granzyme M-Mediated Cleavage. (PMID:33953729)

Cross-species orthologs

2 orthologs

OrganismSymbolGene ID
mus_musculusGzmmENSMUSG00000054206
rattus_norvegicusGzmmENSRNOG00000030530

Paralogs (14): PRSS33 (ENSG00000103355), PLAT (ENSG00000104368), PLG (ENSG00000122194), PLGLB2 (ENSG00000125551), PRSS37 (ENSG00000165076), PRSS27 (ENSG00000172382), KLK15 (ENSG00000174562), PLGLB1 (ENSG00000183281), PRSS57 (ENSG00000185198), TMPRSS12 (ENSG00000186452), OVCH1 (ENSG00000187950), PRSS48 (ENSG00000189099), KLK9 (ENSG00000213022), PRSS50 (ENSG00000283706)

Protein

Protein identifiers

Granzyme M — P51124 (reviewed: P51124)

Alternative names: Met-1 serine protease, Met-ase, Natural killer cell granular protease

All UniProt accessions (2): P51124, U3KQV5

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves peptide substrates after methionine, leucine, and norleucine. Physiological substrates include EZR, alpha-tubulins and the apoptosis inhibitor BIRC5/Survivin. Promotes caspase activation and subsequent apoptosis of target cells.

Subcellular location. Secreted. Cytoplasmic granule.

Tissue specificity. Highly and constitutively expressed in activated natural killer (NK) cells.

Similarity. Belongs to the peptidase S1 family. Granzyme subfamily.

RefSeq proteins (2): NP_001245280, NP_005308* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001254Trypsin_domDomain
IPR001314Peptidase_S1AFamily
IPR009003Peptidase_S1_PAHomologous_superfamily
IPR018114TRYPSIN_HISActive_site
IPR033116TRYPSIN_SERActive_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA):

  • EC 3.4.21.78 — granzyme A (BRENDA: 7 organisms, 52 substrates, 39 inhibitors, 11 Km, 14 kcat entries)
  • EC 3.4.21.B2 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

SubstrateKm (mM)Measurements
BENZYLOXYCARBONYL-ARG THIOBENZYL ESTER0.12–0.3152
BENZYLOXYCARBONYL-GLY-ARG THIOBENZYL ESTER0.105–0.162
BENZYLOXYCARBONYL-LYS THIOBENZYL ESTER0.13–0.192
BOC-ALA-ALA-ARG-SBZL0.8871
BOC-TRP-ARG-SBZL0.171
TERT-BUTYLOXYCARBONYL-ALA-ALA-ARG THIOBENZYL EST0.141
Z-ARG-SBZL0.1771
Z-LYS-SBZL0.7671
BENZYLOXYCARBONYL-LYS-THIOBENZYL ESTER—0

UniProt features (35 total): strand 14, helix 5, disulfide bond 4, turn 3, active site 3, signal peptide 1, propeptide 1, sequence variant 1, chain 1, domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDBMethodResolution (Å)
2ZGCX-RAY DIFFRACTION1.96
2ZGHX-RAY DIFFRACTION2.17
2ZGJX-RAY DIFFRACTION2.3
2ZKSX-RAY DIFFRACTION2.7

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P51124-F190.930.82

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): 66 (charge relay system); 111 (charge relay system); 207 (charge relay system)

Disulfide bonds (4): 176–192, 203–230, 51–67, 145–213

Glycosylation sites (1): 177

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-173736Alternative complement activation

MSigDB gene sets: 150 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GNF2_ZAP70, GOLDRATH_ANTIGEN_RESPONSE, GOBP_PROTEIN_MATURATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, MODULE_109, MODULE_99, GNF2_IL2RB, GOBP_ADAPTIVE_IMMUNE_RESPONSE, GOBP_IMMUNE_EFFECTOR_PROCESS, HU_GENOTOXIN_ACTION_DIRECT_VS_INDIRECT_4HR

GO Biological Process (7): T cell mediated cytotoxicity (GO:0001913), proteolysis (GO:0006508), apoptotic process (GO:0006915), killing of cells of another organism (GO:0031640), innate immune response (GO:0045087), protein maturation (GO:0051604), immune system process (GO:0002376)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), membrane (GO:0016020), extracellular region (GO:0005576), azurophil granule lumen (GO:0035578)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Initial triggering of complement1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
protein metabolic process2
peptidase activity2
cellular anatomical structure2
leukocyte mediated cytotoxicity1
T cell mediated immunity1
programmed cell death1
apoptotic signaling pathway1
execution phase of apoptosis1
cell killing1
disruption of cell in another organism1
immune response1
defense response to symbiont1
gene expression1
biological_process1
endopeptidase activity1
serine-type peptidase activity1
serine hydrolase activity1
binding1
hydrolase activity1
catalytic activity, acting on a protein1
catalytic activity1
vacuolar lumen1
secretory granule lumen1
azurophil granule1

Protein interactions and networks

STRING

1710 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
GZMMBACE1P56817874
GZMMOTULINQ96BN8754
GZMMRNF31Q96EP0583
GZMMSHARPINQ9H0F6567
GZMMTRIM13O60858519
GZMMCD5P06127509
GZMMLMNB2Q03252508
GZMMPRF1P14222505
GZMMMS4A1P08984497
GZMMDLDP09622494
GZMMTIMM8BQ9Y5J9490
GZMMZUP1Q96AP4479
GZMMDPP7Q9UHL4477
GZMMADCY10Q96PN6476
GZMMGZMHP20718474

IntAct

4 interactions, top by confidence:

ABTypeScore
GZMMZNF774psi-mi:“MI:0915”(physical association)0.560
ZNF774GZMMpsi-mi:“MI:0915”(physical association)0.000

BioGRID (9): GZMM (Two-hybrid), GZMM (Negative Genetic), GZMM (Negative Genetic), GZMM (Cross-Linking-MS (XL-MS)), DFFA (Biochemical Activity), PARP1 (Biochemical Activity), EZR (Biochemical Activity), TUBA1B (Biochemical Activity), NPM1 (Biochemical Activity)

ESM2 similar proteins: A1L453, A6NIE9, O43240, P07288, P15944, P20151, P20231, P33619, P49862, P51124, P51779, P83748, Q03238, Q14B24, Q15661, Q16651, Q2L4Q9, Q2UVH8, Q571E5, Q5K2P8, Q5K2P9, Q61096, Q6BEA2, Q6DT45, Q6IE59, Q6IE62, Q6UWY2, Q76B45, Q7JIG6, Q7RTY9, Q7Z5A4, Q80WM7, Q8K4I7, Q920S2, Q92876, Q9BQR3, Q9BZJ3, Q9ER04, Q9ES87, Q9ESD1

Diamond homologs: O18783, O35164, O35205, O46683, O60259, O88780, P00746, P00747, P00752, P00756, P00758, P00759, P00760, P00761, P00762, P00763, P00764, P00770, P03953, P04187, P07146, P07288, P08311, P08426, P08882, P08883, P09582, P09650, P10144, P11032, P11034, P12323, P12544, P12545, P15119, P15946, P15949, P18291, P19799, P20151

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance44
Likely benign2
Benign3

Top pathogenic / likely-pathogenic (0)

SpliceAI

798 predictions. Top by Δscore:

VariantEffectΔscore
19:544122:AGTAG:Adonor_loss1.0000
19:544123:GTAG:Gdonor_gain1.0000
19:547270:A:AGacceptor_gain1.0000
19:547274:T:TAacceptor_gain1.0000
19:547278:A:AGacceptor_gain1.0000
19:547278:A:Tacceptor_loss1.0000
19:547279:G:GGacceptor_gain1.0000
19:547279:GGC:Gacceptor_gain1.0000
19:547279:GGCA:Gacceptor_gain1.0000
19:548537:CCCA:Cacceptor_loss1.0000
19:548538:CCAG:Cacceptor_loss1.0000
19:548539:CAGG:Cacceptor_loss1.0000
19:548540:A:AGacceptor_gain1.0000
19:548540:A:Cacceptor_loss1.0000
19:548540:AG:Aacceptor_gain1.0000
19:548540:AGGAT:Aacceptor_gain1.0000
19:548541:G:GGacceptor_gain1.0000
19:548541:GG:Gacceptor_gain1.0000
19:548541:GGA:Gacceptor_gain1.0000
19:548541:GGAT:Gacceptor_gain1.0000
19:548541:GGATG:Gacceptor_gain1.0000
19:548675:CAG:Cdonor_loss1.0000
19:548677:GGTG:Gdonor_loss1.0000
19:548678:G:Cdonor_loss1.0000
19:548679:T:Adonor_loss1.0000
19:548687:G:Tdonor_gain1.0000
19:548914:A:AGacceptor_gain1.0000
19:548917:CGTA:Cacceptor_loss1.0000
19:548918:GTAG:Gacceptor_loss1.0000
19:548920:A:AGacceptor_gain1.0000

AlphaMissense

1627 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
19:549023:G:CW150C0.968
19:549023:G:TW150C0.968
19:549690:T:CF225L0.960
19:549692:C:AF225L0.960
19:549692:C:GF225L0.960
19:549114:T:CF181L0.948
19:549116:C:AF181L0.948
19:549116:C:GF181L0.948
19:549761:G:CW248C0.942
19:549761:G:TW248C0.942
19:547404:G:CW60C0.937
19:547404:G:TW60C0.937
19:548662:C:AD111E0.932
19:548662:C:GD111E0.932
19:549763:T:CI249T0.927
19:548626:C:AH99Q0.911
19:548626:C:GH99Q0.911
19:549119:G:CW182C0.905
19:549119:G:TW182C0.905
19:548658:A:TN110I0.900
19:548661:A:TD111V0.899
19:549021:T:AW150R0.895
19:549021:T:CW150R0.895
19:548673:T:AL115H0.888
19:548661:A:CD111A0.887
19:548600:T:CF91L0.881
19:548602:C:AF91L0.881
19:548602:C:GF91L0.881
19:549099:T:AC176S0.879
19:549100:G:CC176S0.879

dbSNP variants (sampled 300 via entrez): RS1000011741 (19:544473 G>C), RS1000510502 (19:544289 G>A), RS1000873739 (19:542200 G>A), RS1000918848 (19:544572 C>T), RS1001250362 (19:543849 A>G), RS1001276565 (19:549316 A>C), RS1001678892 (19:544494 G>A), RS1002626095 (19:549868 G>A,C,T), RS1002932247 (19:543175 G>A), RS1003267691 (19:542409 G>A,T), RS1003448149 (19:545788 T>C), RS1003525246 (19:546660 A>C), RS1003616124 (19:545295 G>A), RS1003730057 (19:542394 C>T), RS1003826328 (19:545903 A>G,T)

Disease associations

OMIM: gene MIM:600311 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523234 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

ChemicalActions (top 5)PubMed papers
aristolochic acid Iincreases expression1
GSK-J4decreases expression1
beta-lapachoneincreases expression1
di-n-butylphosphoric acidaffects expression1
licochalcone Bincreases expression1
jinfukangdecreases expression1
(+)-JQ1 compounddecreases expression1
Acetaminophenincreases expression1
Air Pollutantsincreases abundance, increases expression1
Cisplatindecreases expression1
Glucosedecreases expression1
Tobacco Smoke Pollutionincreases expression1
Urethanedecreases expression1
Valproic Acidincreases methylation1
Aflatoxin B1increases methylation1
Particulate Matterincreases abundance, increases expression1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4344616BindingInhibition of Granzyme M (unknown origin) expressed in Pichia pastoris using Ac-Lys-Val-Pro-Leu-ACC substrate by spectrofluorometry relative to controlDetection of Active Granzyme A in NK92 Cells with Fluorescent Activity-Based Probe. — J Med Chem

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.4
BioBTree
v2.0.2

Sources 78

This page pulls from 78 datasets indexed by BioBTree:

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