PAM

Summary

PAM (peptidylglycine alpha-amidating monooxygenase, HGNC:8596) is a protein-coding gene on chromosome 5q21.1, encoding Peptidyl-glycine alpha-amidating monooxygenase (P19021). Bifunctional enzyme that catalyzes amidation of the C-terminus of proteins.

This gene encodes a multifunctional protein. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme includes two domains with distinct catalytic activities, a peptidylglycine alpha-hydroxylating monooxygenase (PHM) domain and a peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. These catalytic domains work sequentially to catalyze the conversion of neuroendocrine peptides to active alpha-amidated products. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 5066 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 113 total
• Druggable target: yes
• MANE Select transcript: NM_001177306

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8596
Approved symbol	PAM
Name	peptidylglycine alpha-amidating monooxygenase
Location	5q21.1
Locus type	gene with protein product
Status	Approved
Aliases	PAL, PHM, PAM-1
Ensembl gene	ENSG00000145730
Ensembl biotype	protein_coding
OMIM	170270
Entrez	5066

Gene structure

Transcript identifiers

Ensembl transcripts: 110 — 100 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000304400, ENST00000345721, ENST00000346918, ENST00000348126, ENST00000379799, ENST00000438793, ENST00000455264, ENST00000504456, ENST00000504691, ENST00000505372, ENST00000505654, ENST00000506006, ENST00000506127, ENST00000506260, ENST00000508060, ENST00000509523, ENST00000509636, ENST00000509832, ENST00000510006, ENST00000510208, ENST00000511429, ENST00000511477, ENST00000511839, ENST00000512073, ENST00000513648, ENST00000682024, ENST00000682407, ENST00000682882, ENST00000682972, ENST00000684043, ENST00000684379, ENST00000684529, ENST00000890191, ENST00000890192, ENST00000890193, ENST00000890194, ENST00000890195, ENST00000890196, ENST00000890197, ENST00000890198, ENST00000890199, ENST00000890200, ENST00000890201, ENST00000890202, ENST00000890203, ENST00000890204, ENST00000890205, ENST00000890206, ENST00000890207, ENST00000890208, ENST00000890209, ENST00000890210, ENST00000890211, ENST00000890212, ENST00000890213, ENST00000890214, ENST00000890215, ENST00000890216, ENST00000890217, ENST00000890218, ENST00000890219, ENST00000890220, ENST00000890221, ENST00000890222, ENST00000939731, ENST00000939732, ENST00000939734, ENST00000939736, ENST00000939739, ENST00000939740, ENST00000939741, ENST00000939742, ENST00000957482, ENST00000957483, ENST00000957484, ENST00000957485, ENST00000957486, ENST00000957487, ENST00000957488, ENST00000957489, ENST00000957490, ENST00000957491, ENST00000957492, ENST00000957493, ENST00000957494, ENST00000957495, ENST00000957496, ENST00000957497, ENST00000957498, ENST00000957499, ENST00000957500, ENST00000957501, ENST00000957502, ENST00000957503, ENST00000957504, ENST00000957505, ENST00000957506, ENST00000957507, ENST00000957508, ENST00000957509, ENST00000957510, ENST00000957511, ENST00000957512, ENST00000957513, ENST00000957514, ENST00000957515, ENST00000957516, ENST00000957517, ENST00000957518, ENST00000957519

RefSeq mRNA: 19 — MANE Select: NM_001177306 NM_000919, NM_001177306, NM_001319943, NM_001364582, NM_001364583, NM_001364584, NM_001364585, NM_001364586, NM_001364587, NM_001364588, NM_001364589, NM_001364590, NM_001364591, NM_001364592, NM_001364593, NM_001364594, NM_138766, NM_138821, NM_138822

CCDS: CCDS4092, CCDS4093, CCDS4094, CCDS43348, CCDS54885, CCDS93753, CCDS93754, CCDS93755, CCDS93756, CCDS93757

Canonical transcript exons

ENST00000438793 — 26 exons

Exon	Start	End
ENSE00001957372	103028887	103029716
ENSE00003459027	102949902	102949978
ENSE00003461968	102990272	102990401
ENSE00003470536	102924957	102925042
ENSE00003474257	103003033	103003149
ENSE00003495205	103028185	103028238
ENSE00003505311	103017334	103017433
ENSE00003512809	103025131	103025334
ENSE00003549530	102949537	102949617
ENSE00003552953	103019790	103019843
ENSE00003554562	102959875	102960059
ENSE00003557513	103005154	103005226
ENSE00003563882	102913934	102914021
ENSE00003564668	102950717	102950820
ENSE00003573210	102946837	102946885
ENSE00003578298	102926585	102926668
ENSE00003582428	102974116	102974436
ENSE00003596818	102865823	102866284
ENSE00003609741	103006801	103007011
ENSE00003623893	102901356	102901413
ENSE00003624006	103009751	103009866
ENSE00003633981	103007457	103007657
ENSE00003634022	102867273	102867393
ENSE00003653909	102961158	102961229
ENSE00003678493	102948378	102948445
ENSE00003920269	102755305	102755348

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.7303 / max 2250.7789, expressed in 1767 samples.

FANTOM5 promoters (26 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57807	40.3293	1757
57830	10.7537	1318
57827	5.3529	982
57831	3.7186	967
57826	3.5171	879
57805	1.2074	800
57806	1.0653	711
57818	1.0508	182
57823	1.0014	592
57825	0.8933	439

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	99.89	gold quality
heart right ventricle	UBERON:0002080	99.86	gold quality
cardiac atrium	UBERON:0002081	99.86	gold quality
right atrium auricular region	UBERON:0006631	99.85	gold quality
corpus epididymis	UBERON:0004359	99.83	gold quality
myocardium	UBERON:0002349	99.80	gold quality
parotid gland	UBERON:0001831	99.75	gold quality
type B pancreatic cell	CL:0000169	99.70	gold quality
vena cava	UBERON:0004087	99.65	gold quality
islet of Langerhans	UBERON:0000006	99.64	gold quality
descending thoracic aorta	UBERON:0002345	99.60	gold quality
renal glomerulus	UBERON:0000074	99.59	gold quality
metanephric glomerulus	UBERON:0004736	99.58	gold quality
heart	UBERON:0000948	99.54	gold quality
thoracic aorta	UBERON:0001515	99.52	gold quality
blood vessel layer	UBERON:0004797	99.52	gold quality
tibia	UBERON:0000979	99.51	gold quality
ascending aorta	UBERON:0001496	99.51	gold quality
synovial joint	UBERON:0002217	99.50	gold quality
cardiac ventricle	UBERON:0002082	99.46	gold quality
visceral pleura	UBERON:0002401	99.46	gold quality
left ventricle myocardium	UBERON:0006566	99.46	gold quality
heart left ventricle	UBERON:0002084	99.45	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.45	gold quality
skin of hip	UBERON:0001554	99.44	gold quality
right coronary artery	UBERON:0001625	99.40	gold quality
seminal vesicle	UBERON:0000998	99.39	gold quality
palpebral conjunctiva	UBERON:0001812	99.36	gold quality
middle temporal gyrus	UBERON:0002771	99.32	gold quality
aorta	UBERON:0000947	99.31	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	2569.86
E-HCAD-35	yes	1447.03
E-HCAD-25	yes	1055.86
E-MTAB-10287	yes	47.29
E-MTAB-5061	yes	17.51
E-GEOD-125970	yes	9.44
E-GEOD-83139	yes	4.75
E-ENAD-17	no	623.84
E-CURD-114	no	17.96
E-GEOD-81608	no	7.90
E-ENAD-27	no	3.34
E-HCAD-31	no	2.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

144 targeting PAM, 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-4262	100.00	73.26	3931
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798

Literature-anchored findings (GeneRIF, showing 19)

• nuclear retention of PAM mRNA is lost upon expressing the La proteins that lack a conserved nuclear retention element, suggesting a direct association between PAM mRNA and La protein in vivo (PMID:16107699)
• Data indicate that catalytic inactivation of PHM caused by pH changes is accompanied by structural change between two states of the protein involving strong Cu-S interaction that does not involve M314. (PMID:22080626)
• Detail the production of the catalytic core of human peptidylglycine alpha-hydroxylating monooxygenase (hPHMcc) in Escherichia coli possessing a N-terminal fusion to thioredoxin (Trx). (PMID:22554821)
• Two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of type 2 diabetes (OR = 1.23, P = 3.9 x 10(-10) and OR = 1.47, P = 1.7 x 10(-5), respectively) (PMID:24464100)
• Oxygen Sensitivity of the Peptidylglycine alpha-Amidating Monooxygenase (PAM) in Neuroendocrine Cells (PMID:26296884)
• PAM expression is increased in the secretory pathway of differentiated neurons. (PMID:26879543)
• Data suggest that His108 and a substrate molecule are involved in the reductive pathway while His172 and Tyr79 are important in the catalytic pathway in the copper-centered electron transfer catalyzed by peptidylglycine monooxygenase. (PMID:26982589)
• The ancient ability of PAM to localize to ciliary membranes, which release bioactive ectosomes, may be related to its ability to accumulate in intralumenal vesicles and exosomes (PMID:28377049)
• PAM single nucleotide polymorphism rs13175330 is associated with hypertension and insulin resistance in a Korean population. (PMID:29162152)
• PAM polyubiquitinates NMNAT2 and regulates NMNAT2 protein stability and degradation by the proteasome. (PMID:29997255)
• A role for PAM in beta-cell function. (PMID:30054598)
• The T2D risk-associated rs35658696 (p.Asp563Gly) allele of PAM confers decreased PAM expression in human islets. (PMID:30054598)
• The T2D risk-associated rs35658696 (p.Asp563Gly) allele of PAM confers reduced amidating activity. (PMID:30054598)
• siRNA-mediated knockdown of PAM in EndoC-BetaH1 cells caused reductions in insulin secretion and content. These effects were also observed in primary islets from human donors heterozygous for the T2D risk-associated rs35658696 variant. (PMID:30054598)
• PAM haploinsufficiency does not accelerate the development of diet- and human IAPP-induced diabetes in mice. (PMID:31984442)
• Mitochondrial Oxidative Stress Induces Rapid Intermembrane Space/Matrix Translocation of Apurinic/Apyrimidinic Endonuclease 1 Protein through TIM23 Complex. (PMID:33197464)
• PAM variants were associated with type 2 diabetes mellitus risk in the Chinese population. (PMID:35394266)
• Peptidylglycine alpha-amidating monooxygenase and adrenomedullin measurement in patients with hepatic cirrhosis. (PMID:37812053)
• PAM variants in patients with thyrotrophinomas, cyclical Cushing’s disease and prolactinomas. (PMID:38075079)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pam	ENSDARG00000100170
mus_musculus	Pam	ENSMUSG00000026335
rattus_norvegicus	Pam	ENSRNOG00000033280
drosophila_melanogaster	Pal2	FBGN0262728
drosophila_melanogaster	Pal1	FBGN0283510
caenorhabditis_elegans	pgal-1	WBGENE00017671

Protein

Protein identifiers

Peptidyl-glycine alpha-amidating monooxygenase — P19021 (reviewed: P19021)

All UniProt accessions (19): A0A804HI59, A0A804HIQ0, A0A804HJJ2, A0A804HK31, A0A804HKM7, A0A804HKV8, A0A804HLE0, A0A804HLJ2, A0A8C8KD64, P19021, D6R961, D6RAQ2, D6RCD5, D6RDU2, D6RF09, D6RG20, F8W8D9, H0Y9I4, H7BYD9

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme that catalyzes amidation of the C-terminus of proteins. Alpha-amidation is present at the C-terminus of many endocrine hormones and neuropeptides and is required for their activity. C-terminal amidation also takes place in response to protein fragmentation triggered by oxidative stress, promoting degradation of amidated protein fragments by the proteasome. Alpha-amidation involves two sequential reactions, both of which are catalyzed by separate catalytic domains of the enzyme. The first step, catalyzed by peptidyl alpha-hydroxylating monooxygenase (PHM) domain, is the copper-, ascorbate-, and O2- dependent stereospecific hydroxylation (with S stereochemistry) at the alpha-carbon (C-alpha) of the C-terminal glycine of the peptidylglycine substrate. The second step, catalyzed by the peptidylglycine amidoglycolate lyase (PAL) domain, is the zinc-dependent cleavage of the N-C-alpha bond, producing the alpha-amidated peptide and glyoxylate. Similarly, catalyzes the two-step conversion of an N-fatty acylglycine to a primary fatty acid amide and glyoxylate.

Subunit / interactions. Monomer. Interacts with RASSF9.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle membrane Membrane Membrane Secreted Secreted.

Activity regulation. PAM activity is inhibited by EDTA, phenylglyoxal and diethyl pyrocarbonate. PAL activity is stimulated by cadmium and inhibited by mercury.

Cofactor. Binds one Zn(2+) ion per subunit. Binds 2 Cu(2+) ions per subunit.

Miscellaneous. Soluble. Soluble.

Similarity. In the C-terminal section; belongs to the peptidyl-alpha-hydroxyglycine alpha-amidating lyase family. In the N-terminal section; belongs to the copper type II ascorbate-dependent monooxygenase family.

Isoforms (6)

UniProt ID	Names	Canonical?
P19021-1	1	yes
P19021-2	2
P19021-3	3
P19021-4	4
P19021-5	5
P19021-6	6

RefSeq proteins (19): NP_000910, NP_001170777, NP_001306872, NP_001351511, NP_001351512, NP_001351513, NP_001351514, NP_001351515, NP_001351516, NP_001351517, NP_001351518, NP_001351519, NP_001351520, NP_001351521, NP_001351522, NP_001351523, NP_620121, NP_620176, NP_620177 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000323	Cu2_ascorb_mOase_N	Domain
IPR000720	PHM/PAL	Family
IPR001258	NHL_repeat	Repeat
IPR008977	PHM/PNGase_F_dom_sf	Homologous_superfamily
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR014783	Cu2_ascorb_mOase_CS-2	Conserved_site
IPR014784	Cu2_ascorb_mOase-like_C	Homologous_superfamily
IPR020611	Cu2_ascorb_mOase_CS-1	Conserved_site
IPR024548	Cu2_monoox_C	Domain
IPR036939	Cu2_ascorb_mOase_N_sf	Homologous_superfamily

Pfam: PF01082, PF01436, PF03712

Enzyme classification (BRENDA):

• EC 1.14.17.3 — peptidylglycine monooxygenase (BRENDA: 16 organisms, 234 substrates, 143 inhibitors, 170 Km, 30 kcat entries)
• EC 4.3.2.5 — peptidylamidoglycolate lyase (BRENDA: 28 organisms, 21 substrates, 22 inhibitors, 30 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
NALPHA-ACETYL-TYR-VAL-ALPHA-HYDROXYGLYCINE	0.0102–0.33	10
O2	0.1–658.1	9
DANSYL-D-TYR-VAL-GLY	0.0009–0.8	6
N-ACETYL-TYR-VAL-GLY	0.0012–0.0098	6
N-ACETYLGLYCINE	9.3–18	5
TRINITROPHENYL-D-TYR-L-VAL-ALPHA-HYDROXY-GLY	0.014–0.033	5
D-TYR-PRO-GLY-GLY	0.033–0.289	4
D-TYR-VAL-GLY	0.007–0.22	4
DANSYL-L-TYR-L-VAL-GLY	0.0033–0.0194	4
PEPTIDYLGLYCINE	0.009–0.018	4
N-DANSYL-L-TYR-L-PHE-GLY	3.5–4.5	3
N-DECANOYLGLYCINE	0.1–0.2	3
ALPHA-N-ACETYL-TYR-VAL-ALPHA-HYDROXYGLYCINE	0.013–0.238	3
ACETYL-L-TYR-L-PHE-GLY	0.0003–1.39	2
DABSYL-GLY-PHE-GLY	0.022–0.143	2

Catalyzed reactions (Rhea), 12 shown:

• a [peptide]-C-terminal (2S)-2-hydroxyglycine = a [peptide]-C-terminal amide + glyoxylate (RHEA:20924)
• a [peptide]-C-terminal glycine + 2 L-ascorbate + O2 = a [peptide]-C-terminal (2S)-2-hydroxyglycine + 2 monodehydro-L-ascorbate radical + H2O (RHEA:21452)
• N-dodecanoylglycine + 2 L-ascorbate + O2 = N-dodecanoyl-(2S)-hydroxyglycine + 2 monodehydro-L-ascorbate radical + H2O (RHEA:58540)
• N-tetradecanoylglycine + 2 L-ascorbate + O2 = N-tetradecanoyl-(2S)-hydroxyglycine + 2 monodehydro-L-ascorbate radical + H2O (RHEA:58544)
• N-(9Z,12Z,15Z)-octadecatrienoylglycine + 2 L-ascorbate + O2 = N-(9Z,12Z,15Z)-octadecatrienoyl-(2S)-hydroxyglycine + 2 monodehydro-L-ascorbate radical + H2O (RHEA:58548)
• N-(9Z-octadecenoyl)glycine + 2 L-ascorbate + O2 = N-(9Z-octadecenoyl)-(2S)-hydroxyglycine + 2 monodehydro-L-ascorbate radical + H2O (RHEA:58600)
• N-decanoylglycine + 2 L-ascorbate + O2 = N-decanoyl-(2S)-hydroxyglycine + 2 monodehydro-L-ascorbate radical + H2O (RHEA:58608)
• N-octanoylglycine + 2 L-ascorbate + O2 = N-octanoyl-(2S)-hydroxyglycine + 2 monodehydro-L-ascorbate radical + H2O (RHEA:58612)
• N-octanoyl-(2S)-hydroxyglycine = octanamide + glyoxylate (RHEA:58616)
• N-decanoyl-(2S)-hydroxyglycine = decanamide + glyoxylate (RHEA:58620)
• N-dodecanoyl-(2S)-hydroxyglycine = dodecanamide + glyoxylate (RHEA:58624)
• N-tetradecanoyl-(2S)-hydroxyglycine = tetradecamide + glyoxylate (RHEA:58632)

UniProt features (58 total): binding site 15, modified residue 8, disulfide bond 7, repeat 5, splice variant 5, region of interest 4, sequence conflict 4, compositionally biased region 2, topological domain 2, signal peptide 1, propeptide 1, chain 1, glycosylation site 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19021-F1	71.54	0.44

Functional residue map

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

Ligand- & substrate-binding residues (15): 102; 103; 167; 237; 239; 309; 517; 530; 582; 584; 651; 687 …

Post-translational modifications (8): 918, 929, 942, 943, 946, 957, 893, 875

Disulfide bonds (7): 42–181, 76–121, 109–126, 222–329, 288–310, 631–652, 699–710

Glycosylation sites (1): 762

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 322 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_93, ZHAN_LATE_DIFFERENTIATION_GENES_UP, GOBP_RESPONSE_TO_ZINC_ION, GGTGTGT_MIR329, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOCC_SECRETORY_GRANULE, GCANCTGNY_MYOD_Q6, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, CAGCTG_AP4_Q5, GOBP_RESPONSE_TO_METAL_ION, SHAFFER_IRF4_TARGETS_IN_PLASMA_CELL_VS_MATURE_B_LYMPHOCYTE

GO Biological Process (7): peptide amidation (GO:0001519), response to zinc ion (GO:0010043), cellular response to oxidative stress (GO:0034599), fatty acid primary amide biosynthetic process (GO:0062112), peptide metabolic process (GO:0006518), lipid metabolic process (GO:0006629), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (13): peptidylglycine monooxygenase activity (GO:0004504), peptidylamidoglycolate lyase activity (GO:0004598), copper ion binding (GO:0005507), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), L-ascorbic acid binding (GO:0031418), catalytic activity (GO:0003824), monooxygenase activity (GO:0004497), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced ascorbate as one donor, and incorporation of one atom of oxygen (GO:0016715), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (6): extracellular region (GO:0005576), membrane (GO:0016020), transport vesicle membrane (GO:0030658), secretory granule membrane (GO:0030667), extracellular exosome (GO:0070062), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transition metal ion binding	2
catalytic activity	2
cellular anatomical structure	2
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
peptide modification	1
response to metal ion	1
response to oxidative stress	1
cellular response to chemical stress	1
fatty acid primary amide metabolic process	1
fatty acid derivative biosynthetic process	1
metabolic process	1
primary metabolic process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced ascorbate as one donor, and incorporation of one atom of oxygen	1
amidine-lyase activity	1
catalytic activity, acting on a protein	1
metal ion binding	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
molecular_function	1
oxidoreductase activity	1
binding	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
cation binding	1
transport vesicle	1
secretory granule	1
extracellular vesicle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

586 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAM	KALRN	O60229	967
PAM	CYB561	P49447	869
PAM	TOR2A	Q5JU69	826
PAM	RASSF9	O75901	820
PAM	CPE	P16870	687
PAM	PCSK1	P29120	652
PAM	ATP7A	Q04656	554
PAM	DAPK1	P53355	551
PAM	MCF2	P10911	510
PAM	TOR1A	O14656	495
PAM	F11R	Q9Y624	488
PAM	TYR	P14679	475
PAM	ATOX1	O00244	468
PAM	PCSK2	P16519	464
PAM	PDCD6IP	Q8WUM4	459

IntAct

59 interactions, top by confidence:

A	B	Type	Score
SERPINA6	COCH	psi-mi:“MI:0914”(association)	0.530
GAA	B3GAT3	psi-mi:“MI:0914”(association)	0.530
RALB	DBT	psi-mi:“MI:0914”(association)	0.530
UBR2	PAM	psi-mi:“MI:0914”(association)	0.530
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
TAZ	MANBA	psi-mi:“MI:0914”(association)	0.350
TMEM25	FUZ	psi-mi:“MI:0914”(association)	0.350
PTCH1	PLXNB2	psi-mi:“MI:0914”(association)	0.350
	HSPA12A	psi-mi:“MI:0914”(association)	0.350
B3GNT2	NDUFA10	psi-mi:“MI:0914”(association)	0.350
UBR2	GFAP	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
KLRC1	METTL15	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
TAFAZZIN	MANBA	psi-mi:“MI:0914”(association)	0.350
C1QTNF7	AGRN	psi-mi:“MI:0914”(association)	0.350
TMEM25	NME4	psi-mi:“MI:0914”(association)	0.350
ADPGK	TOR1B	psi-mi:“MI:0914”(association)	0.350
TRAV20	MAP2K7	psi-mi:“MI:0914”(association)	0.350
GAA	ENTPD6	psi-mi:“MI:0914”(association)	0.350
TAFA2	ERN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (75): PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Two-hybrid), PAM (PCA), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS), PAM (Affinity Capture-MS)

ESM2 similar proteins: A0A0A2JQ23, A0A0A7LRQ7, A0A1B2CTB9, A0A345BJP1, A0A3G1DJE8, A2Y6Z7, A6QS12, A6RBY1, C4QZ06, C4R7X9, C4R7Z8, C7YS44, D0MVS1, D4AR77, F2QQ67, F2QZ45, F2QZ65, I1BVT3, O59759, P08478, P10731, P10743, P12807, P12890, P14925, P19021, P27825, P34389, P46555, P47014, P56826, P80960, P83388, P97467, Q09109, Q09174, Q17043, Q19127, Q25264, Q53WK1

Diamond homologs: O01404, P08478, P10731, P12890, P14925, P19021, P83388, P97467, Q95XM2, P91268, Q9V5E1, Q9W1L5, Q8CCH2, Q5JS37, Q5R9V0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
UHMK1	unknown	PAM	phosphorylation
PAM	“up-regulates activity”	Oxytocin	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Metabolism of carbohydrates and carbohydrate derivatives	6	14.7×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	4
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

6412 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:102901373:C:G	C76W	0.999
5:102925006:T:A	W136R	0.999
5:102925006:T:C	W136R	0.999
5:102925008:G:C	W136C	0.999
5:102925008:G:T	W136C	0.999
5:102948392:C:A	A197D	0.999
5:102959897:T:A	C310S	0.999
5:102959898:G:C	C310S	0.999
5:102901372:G:A	C76Y	0.998
5:102913982:T:C	L106P	0.998
5:102913990:T:C	C109R	0.998
5:102913991:G:A	C109Y	0.998
5:102913992:C:G	C109W	0.998
5:102924962:G:A	C121Y	0.998
5:102924976:T:A	C126S	0.998
5:102924976:T:C	C126R	0.998
5:102924977:G:A	C126Y	0.998
5:102924977:G:C	C126S	0.998
5:102924978:T:G	C126W	0.998
5:102926594:T:C	F151S	0.998
5:102926633:T:C	L164P	0.998
5:102926641:C:G	H167D	0.998
5:102948404:T:C	L201P	0.998
5:102950720:T:C	F269L	0.998
5:102950722:C:A	F269L	0.998
5:102950722:C:G	F269L	0.998
5:102950777:T:A	C288S	0.998
5:102950777:T:C	C288R	0.998
5:102950778:G:C	C288S	0.998
5:102950779:T:G	C288W	0.998

dbSNP variants (sampled 300 via entrez): RS1000024077 (5:102896461 T>C), RS1000029222 (5:102881493 G>A), RS1000043308 (5:102972698 G>A), RS1000045865 (5:102880555 G>C), RS1000054525 (5:102897159 T>G), RS1000085532 (5:103024393 A>G), RS1000089328 (5:102849724 A>C), RS1000098214 (5:102831767 A>T), RS1000105015 (5:102896855 T>G), RS1000105931 (5:102867613 C>A), RS1000107200 (5:102979358 T>C), RS1000122529 (5:102882234 C>T), RS1000132033 (5:102786471 C>T), RS1000143413 (5:102758927 T>A), RS1000180215 (5:102999279 G>A,T)

Disease associations

OMIM: gene MIM:170270 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST003129_2	Primary biliary cholangitis	1.000000e-08
GCST005168_6	Systolic blood pressure	7.000000e-06
GCST005169_1	Diastolic blood pressure	6.000000e-07
GCST005413_19	Type 2 diabetes	4.000000e-07
GCST006585_1605	Blood protein levels	1.000000e-68
GCST006867_44	Type 2 diabetes	1.000000e-17
GCST006868_4	Type 2 diabetes	4.000000e-14
GCST006950_10	Feeling worry	2.000000e-10
GCST007045_28	PR interval	1.000000e-10
GCST007516_8	Type 2 diabetes (adjusted for BMI)	7.000000e-15
GCST007517_11	Type 2 diabetes	6.000000e-12
GCST007518_14	Type 2 diabetes (adjusted for BMI)	4.000000e-13
GCST007559_21	Sleep duration (short sleep)	2.000000e-08
GCST007923_40	Medication use (drugs used in diabetes)	2.000000e-15
GCST008110_1	Insulinogenic index	2.000000e-08
GCST008991_3	Early cardiac repolarization	1.000000e-06
GCST009325_34	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-09
GCST009379_42	Type 2 diabetes	2.000000e-24
GCST009379_43	Type 2 diabetes	1.000000e-30
GCST010002_34	Refractive error	2.000000e-10
GCST010105_168	Nicotine dependence symptom count	9.000000e-06
GCST010321_137	PR interval	2.000000e-29
GCST010796_2105	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-11
GCST010796_2106	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_2107	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-11
GCST010796_2108	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-10
GCST010796_2109	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-12
GCST011494_19	Daytime nap	3.000000e-14
GCST012228_108	Waist-hip index	9.000000e-09
GCST90000025_1	Appendicular lean mass	6.000000e-16

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0009589	worry measurement
EFO:0004462	PR interval
EFO:0009924	Drugs used in diabetes use measurement
EFO:0009961	Insulinogenic index measurement
EFO:0004885	early cardiac repolarization measurement
EFO:0009262	nicotine dependence symptom count
EFO:0004327	electrocardiography
EFO:0007828	daytime rest measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2544 (SINGLE PROTEIN)

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

ChEMBL bioactivities

14 potent at pChembl≥5 of 25 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	Ki	0.1	nM	CHEMBL127222
9.72	Ki	0.19	nM	CHEMBL335660
7.40	IC50	40	nM	CHEMBL3221589
7.30	IC50	50	nM	CHEMBL3221589
7.22	IC50	60	nM	CHEMBL3221585
7.02	Ki	96	nM	CHEMBL2269608
6.92	IC50	120	nM	CHEMBL3221589
5.70	IC50	2000	nM	CHEMBL2207130
5.70	IC50	2000	nM	CHEMBL3217795
5.52	IC50	3000	nM	CHEMBL2207128
5.30	IC50	5000	nM	CHEMBL2207127
5.22	IC50	6000	nM	CHEMBL2207129
5.22	IC50	6000	nM	CHEMBL2207127
5.05	IC50	9000	nM	CHEMBL2207128

PubChem BioAssay actives

5 with measured affinity, of 68 total; 4 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
2-[(2S)-2-[[(2S)-2-[[(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-[(2S)-butan-2-yl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]pyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]oxyacetic acid	717278: Competitive inhibition of PAM in human DMS53 cells using as(R)-Tyr-(S)-Val-Gly as substrate after 2 hrs by HPLC analysis	ic50	2.0000	uM
2-[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]-3-phenylpropanoyl]oxyacetic acid	717278: Competitive inhibition of PAM in human DMS53 cells using as(R)-Tyr-(S)-Val-Gly as substrate after 2 hrs by HPLC analysis	ic50	3.0000	uM
2-[(2S)-2-acetamido-3-phenylpropanoyl]oxyacetic acid	717278: Competitive inhibition of PAM in human DMS53 cells using as(R)-Tyr-(S)-Val-Gly as substrate after 2 hrs by HPLC analysis	ic50	5.0000	uM
2-[(2S)-2-[[(2S)-2-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]oxyacetic acid	717278: Competitive inhibition of PAM in human DMS53 cells using as(R)-Tyr-(S)-Val-Gly as substrate after 2 hrs by HPLC analysis	ic50	6.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Cadmium Chloride	increases expression, decreases expression, increases abundance	3
sodium arsenite	affects cotreatment, increases abundance, decreases expression	2
Air Pollutants	increases oxidation, decreases expression, affects cotreatment, increases abundance	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Oxygen	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
beta-lapachone	decreases expression	1
arsenite	affects expression	1
nickel sulfate	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
chloropicrin	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
NSC 689534	increases expression	1
Irinotecan	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Ethanol	affects cotreatment, increases expression	1
Allergens	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2211742	Binding	Binding affinity to secreted PAM in human DMS53 cell culture medium after 2 hrs by HPLC analysis	Prohormone-substrate peptide sequence recognition by peptidylglycine α-amidating monooxygenase and its reflection in increased glycolate inhibitor potency. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YB09	EndoC-betaH1 PAM-KO	Transformed cell line	Female

Clinical trials (associated diseases)

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