PGAM5

Summary

PGAM5 (PGAM family member 5, mitochondrial serine/threonine protein phosphatase, HGNC:28763) is a protein-coding gene on chromosome 12q24.33, encoding Serine/threonine-protein phosphatase PGAM5, mitochondrial (Q96HS1). Mitochondrial serine/threonine phosphatase that dephosphorylates various substrates and thus plays a role in different biological processes including cellular senescence or mitophagy.

Enables GTPase activator activity and protein serine/threonine phosphatase activity. Involved in necroptotic process. Located in mitochondrial inner membrane.

Source: NCBI Gene 192111 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 75 total
• Druggable target: yes
• MANE Select transcript: NM_001170543

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28763
Approved symbol	PGAM5
Name	PGAM family member 5, mitochondrial serine/threonine protein phosphatase
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	MGC5352, BXLBv68
Ensembl gene	ENSG00000247077
Ensembl biotype	protein_coding
OMIM	614939
Entrez	192111

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000317555, ENST00000454808, ENST00000498926, ENST00000543955, ENST00000704860, ENST00000931581, ENST00000955085

RefSeq mRNA: 3 — MANE Select: NM_001170543 NM_001170543, NM_001170544, NM_138575

CCDS: CCDS53845, CCDS91784, CCDS9280

Canonical transcript exons

ENST00000498926 — 6 exons

Exon	Start	End
ENSE00001218078	132717987	132718120
ENSE00003532738	132717439	132717564
ENSE00003651219	132717710	132717798
ENSE00003665278	132714858	132715036
ENSE00003992626	132720678	132722734
ENSE00003992627	132710842	132711067

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 90.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.0590 / max 176.1941, expressed in 1797 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128832	16.9788	1780
128831	4.9594	1542
128830	1.4596	893
128829	0.6613	422

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	90.23	gold quality
muscle of leg	UBERON:0001383	89.69	gold quality
mucosa of transverse colon	UBERON:0004991	87.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.07	gold quality
cortical plate	UBERON:0005343	86.27	gold quality
right adrenal gland	UBERON:0001233	86.05	gold quality
islet of Langerhans	UBERON:0000006	85.90	gold quality
right lobe of liver	UBERON:0001114	85.81	gold quality
buccal mucosa cell	CL:0002336	85.60	gold quality
vermiform appendix	UBERON:0001154	85.39	gold quality
left adrenal gland	UBERON:0001234	85.39	gold quality
right adrenal gland cortex	UBERON:0035827	85.23	gold quality
left adrenal gland cortex	UBERON:0035825	84.82	gold quality
prefrontal cortex	UBERON:0000451	84.80	gold quality
granulocyte	CL:0000094	84.20	gold quality
esophagus mucosa	UBERON:0002469	84.19	gold quality
apex of heart	UBERON:0002098	84.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.98	gold quality
lower esophagus mucosa	UBERON:0035834	83.81	gold quality
stromal cell of endometrium	CL:0002255	83.73	gold quality
body of pancreas	UBERON:0001150	83.63	gold quality
anterior cingulate cortex	UBERON:0009835	83.58	gold quality
adrenal gland	UBERON:0002369	83.57	gold quality
heart left ventricle	UBERON:0002084	83.49	gold quality
pancreas	UBERON:0001264	83.39	gold quality
right frontal lobe	UBERON:0002810	83.32	gold quality
body of stomach	UBERON:0001161	82.94	gold quality
esophagus	UBERON:0001043	82.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.81	gold quality
ganglionic eminence	UBERON:0004023	82.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.18

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TAL1

miRNA regulators (miRDB)

11 targeting PGAM5, 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-3617-3P	99.98	67.86	918
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-921	97.09	66.45	562
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-551A	93.83	70.97	38
HSA-MIR-551B-3P	93.83	70.97	38

Literature-anchored findings (GeneRIF, showing 34)

• The N terminus of the PGAM5 protein contains a conserved NXESGE motif that binds to the substrate binding pocket in the Kelch domain of Keap1. (PMID:17046835)
• Results suggest that this member of the PGAM family has crossed over from small molecules to protein substrates and been adapted to serve as a specialized activator of ASK1. (PMID:19590015)
• Experimental data indicate that the two splice variants of the mitochondrial protein phosphatase PGAM5 are at the convergent point of multiple necrosis pathways. (PMID:22265414)
• Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. (PMID:22915595)
• PGAM5 is proteolytically processed, accumulates in the cytosol during apoptosis, and sensitizes cells to death. (PMID:23201124)
• Dephosphorylation of FUNDC1 by PGAM5 induces mitophagy. (PMID:24746696)
• The BCL2L1-PGAM5-FUNDC1 axis is critical for receptor-mediated mitophagy. (PMID:25126723)
• Results indicate that a multiprotein complex including PGAM5, Bax and Drp1 proteins specifically formed during intrinsic apoptosis induction. (PMID:26356820)
• Results identify a crucial role for RIPK3-PGAM5-Drp1/NFAT signalling in NKT cell activation, and further suggest that RIPK3-PGAM5 signalling may mediate crosstalk between mitochondrial function and immune signalling. (PMID:26381214)
• PGAM5 regulates histidine phosphorylation to control TCR activation of CD4-positive T cells. (PMID:27453048)
• An intact complex of PGAM5-KEAP1-Nrf2 preserves mitochondrial motility by suppressing dominant-negative KEAP1 activity. (PMID:28839075)
• Damaged mitochondria may induce replenishment of the mitochondrial pool by cell-intrinsic activation of Wnt signaling via the Pgam5-beta-catenin axis. (PMID:29438981)
• results reveal that the Stx17-PGAM5 axis plays pivotal roles in mitochondrial division and PINK1/Parkin-mediated mitophagy. (PMID:30237312)
• suggests that PGAM5 senses mitochondrial dysfunction in the inner mitochondrial membrane and serves as a signalling intermediate that regulates the cellular response to mitochondrial stress upon its cleavage and release from mitochondria (PMID:30247576)
• Elevated PGAM5 expression in hepatocellular carcinoma is associated with a poor prognostic phenotype. Knocking down PGAM5 in hepatocellular carcinoma cells inhibited cell viability and enhanced chemosensitivity. (PMID:30250224)
• PGAM5 is expressed in pre-neoplastic tissue and non-small cell lung carcinoma, but not in normal epithelium. (PMID:30526542)
• have identified phosphoglycerate mutase family member 5 (PGAM5), a serine/threonine specific protein phosphatase, as a regulator of Lipin-1 activity. Activation of endogenous PGAM5, promoted dephosphorylation and nuclear accumulation of Lipin-1 (PMID:30642635)
• PGAM5-mediated mitophagy in turn leads to a self-perpetuating escalation of DeltaPsi depolarization. Loss of the mitophagy-based damage-enhancing loop under PGAM5-deficient conditions breaks this vicious cycle, leading to improved mitochondrial homeostasis. (PMID:31168659)
• Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate. (PMID:31367011)
• Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics. (PMID:32439975)
• Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway. (PMID:32777444)
• PGAM5: A crucial role in mitochondrial dynamics and programmed cell death. (PMID:33370650)
• Cleaved PGAM5 dephosphorylates nuclear serine/arginine-rich proteins during mitophagy. (PMID:33872670)
• The expression of IFN-beta is suppressed by the viral 3D polymerase via its impact on PGAM5 expression during enterovirus D68 infection. (PMID:34425164)
• Phosphoglycerate mutase family member 5 maintains oocyte quality via mitochondrial dynamic rearrangement during aging. (PMID:34995407)
• DHEA restores mitochondrial dynamics of cumulus cells by regulating PGAM5 expression in poor ovarian responders. (PMID:35361380)
• Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state. (PMID:35921890)
• PGAM5 interacts with Bcl-rambo and regulates apoptosis and mitophagy. (PMID:36075447)
• PGAM5 expression levels in heart failure and protection ROS-induced oxidative stress and ferroptosis by Keap1/Nrf2. (PMID:36780919)
• PGAM5 deacetylation mediated by SIRT2 facilitates lipid metabolism and liver cancer proliferation. (PMID:37580952)
• The Effect of PGAM5 on Regulating Mitochondrial Dysfunction in Ischemic Stroke. (PMID:38058078)
• ZBP1 promotes hepatocyte pyroptosis in acute liver injury by regulating the PGAM5/ROS pathway. (PMID:38331384)
• Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis. (PMID:38433252)
• Pgam5 aggravates hyperglycemia-induced myocardial dysfunction through disrupting Phb2-dependent mitochondrial dynamics. (PMID:38818468)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pgam5	ENSDARG00000035608
mus_musculus	Pgam5	ENSMUSG00000029500
rattus_norvegicus	Pgam5	ENSRNOG00000037443
drosophila_melanogaster	Pgam5	FBGN0023517
drosophila_melanogaster	Pgam5-2	FBGN0035004
caenorhabditis_elegans		WBGENE00019941

Protein

Protein identifiers

Serine/threonine-protein phosphatase PGAM5, mitochondrial — Q96HS1 (reviewed: Q96HS1)

Alternative names: Bcl-XL-binding protein v68, Phosphoglycerate mutase family member 5

All UniProt accessions (3): A0A994J4Y8, F5GXG4, Q96HS1

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial serine/threonine phosphatase that dephosphorylates various substrates and thus plays a role in different biological processes including cellular senescence or mitophagy. Modulates cellular senescence by regulating mitochondrial dynamics. Mechanistically, participates in mitochondrial fission through dephosphorylating DNM1L/DRP1. Additionally, dephosphorylates MFN2 in a stress-sensitive manner and consequently protects it from ubiquitination and degradation to promote mitochondrial network formation. Regulates mitophagy independent of PARKIN by interacting with and dephosphorylating FUNDC1, which interacts with LC3. Regulates anti-oxidative response by forming a tertiary complex with KEAP1 and NRF2. Regulates necroptosis by acting as a RIPK3 target and recruiting the RIPK1-RIPK3-MLKL necrosis ‘attack’ complex to mitochondria.

Subunit / interactions. Dimer. Forms a ternary complex with NFE2L2 and KEAP1. Interacts with BCL2L1 and MAP3K5. Upon TNF-induced necrosis, forms in complex with RIPK1, RIPK3 and MLKL; the formation of this complex leads to PGAM5 phosphorylation. Isoform 2, but not isoform 1, interacts with DNM1L; this interaction leads to DNM1L dephosphorylation and activation and eventually to mitochondria fragmentation.

Subcellular location. Mitochondrion outer membrane. Mitochondrion inner membrane.

Post-translational modifications. Both isoform 1 and isoform 2 are phosphorylated by the RIPK1/RIPK3 complex under necrotic conditions. This phosphorylation increases PGAM5 phosphatase activity. Proteolytically cleaved by PARL in response to loss of mitochondrial membrane potential.

Domain organisation. The N-terminal 35 amino acids, including the potential transmembrane alpha-helix, function as a non-cleaved mitochondrial targeting sequence that targets the protein to the cytosolic side of the outer mitochondrial membrane.

Similarity. Belongs to the phosphoglycerate mutase family. BPG-dependent PGAM subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96HS1-1	1, PGAM5-L	yes
Q96HS1-2	2, PGAM5-S

RefSeq proteins (3): NP_001164014, NP_001164015, NP_612642 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013078	His_Pase_superF_clade-1	Family
IPR029033	His_PPase_superfam	Homologous_superfamily
IPR051021	Mito_Ser/Thr_phosphatase	Family

Pfam: PF00300

Enzyme classification (BRENDA):

• EC 3.1.3.16 — protein-serine/threonine phosphatase (BRENDA: 92 organisms, 641 substrates, 468 inhibitors, 127 Km, 67 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.023–0.862	22
4-NITROPHENYL PHOSPHATE	0.0028–12.7	13
P-NITROPHENYL PHOSPHATE	3–200	11
RRAPTVA	0.058–1.954	4
PHOSPHOCASEIN	0.0001–0.002	3
PHOSPHOHISTONE	0.0023–0.0723	3
PHOSPHORYLATED MYOSIN LIGHT CHAIN PEPTIDE	0.01–0.11	3
PHOSPHOSERINE-MYELIN BASIC PROTEIN	0.0004–0.022	3
DLDVPIPGRFDRRVSVAAE	0.0006–0.0138	2
DLDVPIPGRFDRRVY(P)VAAE	0.0025–0.023	2
PHOSPHORYLASE A	0.004–0.021	2
RRA(PT)VA	0.0536–0.308	2
80S-RIBOSOME	0.0027	1
AAAPTVA	0.206	1
AGPALSPVPPV	0.357	1

Catalyzed reactions (Rhea), 2 shown:

• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (39 total): helix 10, strand 7, modified residue 5, mutagenesis site 4, topological domain 2, sequence conflict 2, turn 2, region of interest 2, chain 1, splice variant 1, transmembrane region 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3MXO	X-RAY DIFFRACTION	1.7
6CNI	X-RAY DIFFRACTION	1.7
8IN0	X-RAY DIFFRACTION	1.8
3O0T	X-RAY DIFFRACTION	1.9
6CNL	X-RAY DIFFRACTION	2.6
5MUF	X-RAY DIFFRACTION	3.1
7QAL	SOLUTION NMR
7QAM	SOLUTION NMR
7QAO	SOLUTION NMR
7QAP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HS1-F1	85.94	0.72

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 24–25 (cleavage; by parl)

Post-translational modifications (5): 116, 144, 191, 80, 87

Mutagenesis-validated functional residues (4):

Position	Phenotype
24	abolishes cleavage by parl.
79	loss of interaction with keap1; when associated with a-80.
80	loss of interaction with keap1; when associated with a-79.
105	loss of phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8934903	Receptor Mediated Mitophagy
R-HSA-9861718	Regulation of pyruvate metabolism

MSigDB gene sets: 96 (showing top): GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_MACROAUTOPHAGY, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_ORGANELLE_FISSION, GOBP_MITOCHONDRIAL_FISSION, GOBP_REGULATION_OF_MITOCHONDRIAL_FISSION, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, BASAKI_YBX1_TARGETS_UP, DOUGLAS_BMI1_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_TEMPERATURE_HOMEOSTASIS, REACTOME_PYRUVATE_METABOLISM

GO Biological Process (5): macroautophagy (GO:0016236), necroptotic process (GO:0070266), positive regulation of mitochondrial fission (GO:0090141), negative regulation of cold-induced thermogenesis (GO:0120163), programmed cell death (GO:0012501)

GO Molecular Function (3): protein serine/threonine phosphatase activity (GO:0004722), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Mitophagy	1
Pyruvate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrial membrane	2
autophagosome assembly	1
autophagy	1
programmed necrotic cell death	1
mitochondrial fission	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
negative regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
signal transduction	1
cell death	1
phosphoprotein phosphatase activity	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle outer membrane	1
organelle inner membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1312 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PGAM5	KEAP1	Q14145	993
PGAM5	BCL2L1	Q07817	963
PGAM5	RIPK1	Q13546	913
PGAM5	MLKL	Q8NB16	909
PGAM5	DNM1L	O00429	908
PGAM5	FUNDC1	Q8IVP5	815
PGAM5	PARL	Q9H300	770
PGAM5	A0A1W2PP11	A0A1W2PP11	748
PGAM5	PINK1	Q9BXM7	744
PGAM5	SOCS6	O14544	725
PGAM5	NME2	P22392	702
PGAM5	NFE2L2	Q16236	701
PGAM5	RIPK3	Q9Y572	666
PGAM5	PHB2	Q99623	666
PGAM5	BNIP3L	O60238	598

IntAct

162 interactions, top by confidence:

A	B	Type	Score
RIPK3	RIPK1	psi-mi:“MI:0914”(association)	0.970
STRN3	STRN	psi-mi:“MI:0914”(association)	0.880
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLX4	ERCC1	psi-mi:“MI:0914”(association)	0.640
RIPK3	MLKL	psi-mi:“MI:0914”(association)	0.640
TNS2	YWHAB	psi-mi:“MI:2364”(proximity)	0.570
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
NME1	NME2P1	psi-mi:“MI:0914”(association)	0.530
P/V	IRS4	psi-mi:“MI:0914”(association)	0.530
STRN	TCP1	psi-mi:“MI:0914”(association)	0.530
ESR1		psi-mi:“MI:0914”(association)	0.460
AIFM1	HAX1	psi-mi:“MI:0914”(association)	0.420
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
PGAM5	MAP3K5	psi-mi:“MI:0915”(physical association)	0.400
GTF2F2	PGAM5	psi-mi:“MI:0915”(physical association)	0.400
LRRC8E	PGAM5	psi-mi:“MI:0915”(physical association)	0.400
Top3a		psi-mi:“MI:0915”(physical association)	0.400
Mad2l2	CALU	psi-mi:“MI:0915”(physical association)	0.400
PGAM5	MAVS	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
Ttll12	TPM1	psi-mi:“MI:0914”(association)	0.350
Rbm8a	GOSR1	psi-mi:“MI:0914”(association)	0.350
Cd2ap		psi-mi:“MI:0914”(association)	0.350
MYH7B	SRRM1	psi-mi:“MI:0914”(association)	0.350

BioGRID (363): PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS), PGAM5 (Affinity Capture-MS)

ESM2 similar proteins: A1A4J8, A6H784, D3ZS74, D4A6D7, E9QBI7, O42899, O43819, O60341, O75880, P00258, P10109, P23833, P24483, P30048, P38072, Q05B51, Q0VCH8, Q12931, Q2KHU5, Q2NKY8, Q2TBI4, Q3ULF4, Q4VAE3, Q5EA41, Q5REY3, Q5RH02, Q5SUC9, Q69ZP3, Q6DKK2, Q6PI78, Q6ZQ88, Q7ZUC7, Q8BMS4, Q8JZQ2, Q8LAL0, Q8N490, Q8VCL2, Q920A7, Q95N00, Q96HS1

Diamond homologs: A9IXE7, B2VH13, B3MR30, B3P9N0, B4GXS1, B4I9J6, B4JMM7, B4L6S9, B4M7S0, B4NE96, B4PY69, B4R313, O46084, P36623, Q07UT3, Q09422, Q1QRT7, Q29HG0, Q3SW71, Q502L2, Q55129, Q562B5, Q5FWM4, Q61CA3, Q6GL33, Q8BX10, Q96HS1, A6UEW3, C3MBY8, Q92T25, A1UTM4, B0US27, B9J6R3, C0QV47, Q0I4D8, Q9CKU9, B4RZM6, B5Y7Q7, C5BJ25, Q54751

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PGAM5	“up-regulates activity”	FUNDC1	dephosphorylation
PGAM5	“up-regulates activity”	MAP3K5	dephosphorylation
KEAP1	“down-regulates quantity by destabilization”	PGAM5	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	PGAM5	polyubiquitination
PGAM5	“up-regulates activity”	ME1	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chaperonin-mediated protein folding	5	10.4×	7e-03
Signaling by ALK in cancer	5	9.4×	8e-03
Recycling pathway of L1	6	9.3×	4e-03
Protein folding	5	9.0×	9e-03
mRNA 3’-end processing	6	8.2×	6e-03
Transport of Mature mRNA derived from an Intron-Containing Transcript	7	7.4×	4e-03
Signaling by ALK fusions and activated point mutants	7	7.3×	4e-03
Cellular Senescence	7	6.7×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
centriole replication	5	21.8×	1e-03
peptidyl-tyrosine phosphorylation	5	12.5×	9e-03
mRNA transcription by RNA polymerase II	6	11.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	1
Benign	24

Top pathogenic / likely-pathogenic (0)

SpliceAI

921 predictions. Top by Δscore:

Variant	Effect	Δscore
12:132714850:A:AG	acceptor_gain	1.0000
12:132714851:A:G	acceptor_gain	1.0000
12:132714852:C:G	acceptor_gain	1.0000
12:132714853:A:AG	acceptor_gain	1.0000
12:132714853:ATCAG:A	acceptor_gain	1.0000
12:132714854:T:G	acceptor_gain	1.0000
12:132714854:TCAG:T	acceptor_loss	1.0000
12:132714856:A:AG	acceptor_gain	1.0000
12:132714856:A:T	acceptor_loss	1.0000
12:132714856:AG:A	acceptor_gain	1.0000
12:132714856:AGGC:A	acceptor_gain	1.0000
12:132714857:G:GC	acceptor_gain	1.0000
12:132714857:GG:G	acceptor_gain	1.0000
12:132714857:GGC:G	acceptor_gain	1.0000
12:132714857:GGCG:G	acceptor_gain	1.0000
12:132714857:GGCGA:G	acceptor_gain	1.0000
12:132715015:G:GT	donor_gain	1.0000
12:132715032:GCTGG:G	donor_gain	1.0000
12:132715035:GG:G	donor_gain	1.0000
12:132715036:GG:G	donor_gain	1.0000
12:132715037:G:GG	donor_gain	1.0000
12:132717434:TCCA:T	acceptor_loss	1.0000
12:132717435:CCA:C	acceptor_loss	1.0000
12:132717436:CA:C	acceptor_loss	1.0000
12:132717437:A:AC	acceptor_loss	1.0000
12:132717437:A:AG	acceptor_gain	1.0000
12:132717437:AGGTC:A	acceptor_gain	1.0000
12:132717438:G:A	acceptor_loss	1.0000
12:132717438:G:GG	acceptor_gain	1.0000
12:132717438:GGT:G	acceptor_gain	1.0000

AlphaMissense

1857 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:132711062:G:C	W62C	1.000
12:132711062:G:T	W62C	1.000
12:132714977:G:T	R104M	1.000
12:132717450:G:C	A128P	1.000
12:132717469:G:C	R134P	1.000
12:132717743:A:T	E177V	1.000
12:132717752:C:A	P180H	1.000
12:132718023:T:C	F208L	1.000
12:132718025:C:A	F208L	1.000
12:132718025:C:G	F208L	1.000
12:132718027:G:C	R209P	1.000
12:132718041:C:A	R214S	1.000
12:132718088:T:G	C229W	1.000
12:132718097:C:A	N232K	1.000
12:132718097:C:G	N232K	1.000
12:132720703:T:A	W249R	1.000
12:132720703:T:C	W249R	1.000
12:132720730:A:C	S258R	1.000
12:132720732:C:A	S258R	1.000
12:132720732:C:G	S258R	1.000
12:132720784:G:T	G276W	1.000
12:132711060:T:A	W62R	0.999
12:132711060:T:C	W62R	0.999
12:132711063:G:C	D63H	0.999
12:132714959:G:C	R98P	0.999
12:132714971:T:C	L102P	0.999
12:132714974:T:A	I103N	0.999
12:132714977:G:C	R104T	0.999
12:132714978:G:C	R104S	0.999
12:132714978:G:T	R104S	0.999

dbSNP variants (sampled 300 via entrez): RS1000002859 (12:132713379 C>G), RS1000031393 (12:132722699 T>C), RS1000167188 (12:132711287 C>A,T), RS1000520795 (12:132719639 G>A,C), RS1000823642 (12:132719749 C>T), RS1000826085 (12:132721095 G>A), RS1001054985 (12:132712379 G>A), RS1001404170 (12:132712661 G>A,C), RS1001544177 (12:132715298 C>T), RS1001737373 (12:132717041 T>C), RS1001767847 (12:132710457 C>G,T), RS1001799144 (12:132716411 A>C,T), RS1001820356 (12:132710238 C>T), RS1001835101 (12:132713158 T>C), RS1001994855 (12:132715134 C>T)

Disease associations

OMIM: gene MIM:614939 | 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
GCST90002390_181	Mean corpuscular hemoglobin	7.000000e-13
GCST90002396_544	Mean reticulocyte volume	2.000000e-10
GCST90002397_53	Mean spheric corpuscular volume	3.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4802013 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.10	Kd	801.6	nM	CHEMBL3752910
6.09	ED50	809.1	nM	CHEMBL3752910
5.14	Kd	7272	nM	CHEMBL5653589
5.13	ED50	7339	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148986: Binding affinity to human PGAM5 incubated for 45 mins by Kinobead based pull down assay	kd	0.8016	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148986: Binding affinity to human PGAM5 incubated for 45 mins by Kinobead based pull down assay	kd	7.2716	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression, increases methylation	3
bisphenol S	decreases methylation, increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Atrazine	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cannabidiol	decreases expression	1
Carbonyl Cyanide m-Chlorophenyl Hydrazone	increases expression, increases reaction	1
Clozapine	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Furaldehyde	affects cotreatment, increases expression, affects localization	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects expression, affects response to substance	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4775911	Binding	Binding affinity to PGAMS in PMA-differentiated human THP-1 cells incubated for 2 hrs by SDS-PAGE and LC-MS/MS analysis	Berberine Directly Targets the NEK7 Protein to Block the NEK7-NLRP3 Interaction and Exert Anti-inflammatory Activity. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2AI	Abcam HeLa PGAM5 KO	Cancer cell line	Female
CVCL_E2GN	HAP1 PGAM5 (-) 1	Cancer cell line	Male
CVCL_E2GP	HAP1 PGAM5 (-) 2	Cancer cell line	Male
CVCL_F1UB	HyCyte THP-1 KO-hPGAM5	Cancer cell line	Male

Clinical trials (associated diseases)

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