PNP

Summary

PNP (purine nucleoside phosphorylase, HGNC:7892) is a protein-coding gene on chromosome 14q11.2, encoding Purine nucleoside phosphorylase (P00491). Catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.

This gene encodes an enzyme which reversibly catalyzes the phosphorolysis of purine nucleosides. The enzyme is trimeric, containing three identical subunits. Mutations which result in nucleoside phosphorylase deficiency result in defective T-cell (cell-mediated) immunity but can also affect B-cell immunity and antibody responses. Neurologic disorders may also be apparent in patients with immune defects. A known polymorphism at aa position 51 that does not affect enzyme activity has been described. A pseudogene has been identified on chromosome 2.

Source: NCBI Gene 4860 — RefSeq curated summary.

At a glance

• Gene–disease (curated): purine nucleoside phosphorylase deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 310 total — 20 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 60
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000270

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7892
Approved symbol	PNP
Name	purine nucleoside phosphorylase
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	PUNP
Ensembl gene	ENSG00000198805
Ensembl biotype	protein_coding
OMIM	164050
Entrez	4860

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 5 retained_intron

ENST00000361505, ENST00000553418, ENST00000553591, ENST00000554056, ENST00000554065, ENST00000556293, ENST00000556754, ENST00000557229, ENST00000697613, ENST00000697614, ENST00000697615

RefSeq mRNA: 1 — MANE Select: NM_000270 NM_000270

CCDS: CCDS9552

Canonical transcript exons

ENST00000361505 — 6 exons

Exon	Start	End
ENSE00001096522	20474773	20474948
ENSE00001328906	20476384	20477089
ENSE00003477198	20474472	20474575
ENSE00003569245	20472308	20472477
ENSE00003662644	20475062	20475252
ENSE00003971186	20469406	20469535

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 100.6039 / max 1915.6351, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138437	100.5737	1824
138438	0.0302	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	98.86	gold quality
mucosa of transverse colon	UBERON:0004991	97.15	gold quality
monocyte	CL:0000576	96.55	gold quality
gall bladder	UBERON:0002110	96.53	gold quality
bone marrow	UBERON:0002371	96.47	gold quality
esophagus mucosa	UBERON:0002469	96.33	gold quality
rectum	UBERON:0001052	96.32	gold quality
adult mammalian kidney	UBERON:0000082	96.29	gold quality
mononuclear cell	CL:0000842	96.25	gold quality
leukocyte	CL:0000738	96.19	gold quality
trabecular bone tissue	UBERON:0002483	95.69	gold quality
bone marrow cell	CL:0002092	95.22	gold quality
lower esophagus mucosa	UBERON:0035834	95.20	gold quality
granulocyte	CL:0000094	95.16	gold quality
islet of Langerhans	UBERON:0000006	94.96	gold quality
duodenum	UBERON:0002114	94.72	gold quality
right lobe of liver	UBERON:0001114	94.44	gold quality
omental fat pad	UBERON:0010414	94.25	gold quality
peritoneum	UBERON:0002358	94.14	gold quality
metanephros cortex	UBERON:0010533	94.07	gold quality
nephron tubule	UBERON:0001231	94.06	gold quality
body of stomach	UBERON:0001161	93.63	gold quality
placenta	UBERON:0001987	93.47	gold quality
jejunal mucosa	UBERON:0000399	93.34	gold quality
kidney	UBERON:0002113	93.31	gold quality
esophagus squamous epithelium	UBERON:0006920	93.29	gold quality
upper lobe of left lung	UBERON:0008952	93.02	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.84	gold quality
ileal mucosa	UBERON:0000331	92.76	gold quality
transverse colon	UBERON:0001157	92.64	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	1147.30
E-MTAB-6701	yes	124.55
E-HCAD-13	yes	20.57
E-MTAB-9221	yes	15.13
E-MTAB-9067	yes	13.04
E-GEOD-135922	yes	12.55
E-HCAD-9	yes	5.69
E-MTAB-9801	yes	3.91
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 34)

• The optimum pH for PNP from human erythrocytes with xanthosine and xanthine is in the range 5-6, whereas those with guanosine, guanine, inosine & hypoxanthine are in the range 7-8. Possible PNP binding modes of Xan and Xao by mammalian PNPs are proposed. (PMID:12180982)
• Crystal structure of human purine nucleoside phosphorylase. (PMID:12914785)
• These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism. (PMID:12928150)
• investigation of the quaternary structure of recombinant human purine nucleoside phosphorylase (PMID:13679062)
• crystal structures in complex with inosine and 2’,3’-dideoxyinosine, refined to 2.8A resolution using synchrotron radiation. The structures provide explanation for ligand binding, refine the purine-binding site and can be used for future inhibitor design. (PMID:14706628)
• several recurring mutations were found in PNP in patients with purine nucleoside phosphorylase deficiency by DNA sequence analysis (PMID:15571269)
• crystal structure of human PNP in complex with hypoxanthine, refined to 2.6A resoluti (PMID:15582582)
• findings suggest that the G51S PNP polymorphism is associated with a faster rate of cognitive decline in Alzheimer’s disease patients, highlighting the important role of purine metabolism in the progression of this neurodegenerative disorder (PMID:17221831)
• Role of ionization of the phosphate cosubstrate on phosphorolysis by purine nucleoside phosphorylase (PMID:17639373)
• Altered thermodynamics from remote mutations altering human toward bovine purine nucleoside phosphorylase. (PMID:18281956)
• New interactions caused by the mutations increase the catalytic efficiency of the enzyme for formation of a late transition state with increased participation of the phosphate nucleophile. (PMID:18281957)
• Structural studies on NP are reported with a view towards a new specific scoring function. (PMID:18790691)
• Protein dynamics on the femtosecond to picosecond timescale are linked to enzymatic function. (PMID:18946041)
• Comparative analysis of the model of BfPNP and the structure of HsPNP allowed identification of structural features responsible for differences in the computationally determined ligand affinities (PMID:19172318)
• Results describe a tryptophan-free mutant of purine nucleoside phosphorylase and its dynamic activity. (PMID:19191546)
• Altered enthalpy-entropy compensation in picomolar transition state analogues of human purine nucleoside phosphorylase (PMID:19425594)
• Results show that some regions, responsible for entrance and exit of substrate, present a conformational variability, which is dissected by dynamics simulation analysis. (PMID:19932753)
• PNP operating at maximum catalytic potential permits more rapid peptide amide deuterium exchange and greater conformational flexibility of water-peptide bond exchange rate than in either of the complexes with transition state analogues. (PMID:20108972)
• investigation of catalytic mechanisms involved in catalysis by PNP: transition states in arsenolysis and phosphorolysis (PMID:21348499)
• This study for the first time describes elevated levels of alpha synuclein in pancreatic adenocarcinoma as well as highlights the potential of evaluating NP protein expression. (PMID:21448452)
• Biochemical and genetic data on a cohort of seven patients from six families identified as PNPase deficient, is reported. (PMID:22132981)
• Complete lack of PNP triggers accumulation of deoxyguanosine, thereby disrupting B-cell development, the consequence of which is more profound with time, as was found in the older sister. (PMID:22578971)
• Human small intestine is a key site for ribavirin phosphorolysis and that PNP is primarily involved in the metabolism. (PMID:24107682)
• insufficient data to evaluated impact of genetic polymorphisms on disease susceptibility (PMID:24792412)
• Study of genetic heterogeneity in systemic lupus erythematosus, the top associations in European ancestry were protein kinase, cyclic GMP-dependent, type I (PRKG1) rs7897633 (P(Meta) = 2.75 x 10(-8)) and purine nucleoside phosphorylase (PNP) rs1049564 (P(Meta) = 1.24 x 10(-7)). (PMID:25338677)
• the binding mechanism of a transition state analogue (DADMe-immucillin-H) to the purine nucleoside phosphorylase (PNP) enzyme, is reported. (PMID:25625196)
• Data show that [15N, 2H]His8-purine nucleoside phosphorylase (PNP) had reduced catalytic site chemistry larger than proportional to the enzymatic mass difference. (PMID:26305965)
• Data (including data from empirical valence bond/molecular dynamic simulations) suggest that PNP substrate specificity for inosine and guanosine is a direct result of electrostatic preorganization energy along the reaction coordinate. (PMID:26985580)
• Data show that the mutations in purine nucleoside phosphorylase (PNP) alters the enthalpy-entropy balance with little effect on the catalytic rates. (PMID:27976868)
• The PNP rs1049564 T allele is a loss-of-function variant that induces S-phase block and IFN pathway activation in lymphocytes. The S-phase block could be rescued in our in vitro experiments, suggesting the potential for personalized treatment. (PMID:28859258)
• The study suggests that mass-constrained femtosecond motions at the catalytic site of PNP can improve transition state barrier crossing by more frequent sampling of essential catalytic site contacts. (PMID:29915028)
• A Case with Purine Nucleoside Phosphorylase Deficiency Suffering from Late-Onset Systemic Lupus Erythematosus and Lymphoma. (PMID:32514656)
• Connecting Conformational Motions to Rapid Dynamics in Human Purine Nucleoside Phosphorylase. (PMID:36538016)
• Purine Nucleoside Phosphorylase Deficiency in Two Unrelated Patients with Autoimmune Hemolytic Anemia and Eosinophilia: Two Novel Mutations. (PMID:38431953)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	pnp5a	ENSDARG00000078619
danio_rerio	pnp5b	ENSDARG00000099802
mus_musculus	Pnp2	ENSMUSG00000068417
mus_musculus	Pnp	ENSMUSG00000115338
rattus_norvegicus	Pnp	ENSRNOG00000009982
drosophila_melanogaster	CG18128	FBGN0034898
drosophila_melanogaster	CG16758	FBGN0035348
caenorhabditis_elegans		WBGENE00019298

Paralogs (1): MTAP (ENSG00000099810)

Protein

Protein identifiers

Purine nucleoside phosphorylase — P00491 (reviewed: P00491)

Alternative names: Inosine phosphorylase, Inosine-guanosine phosphorylase

All UniProt accessions (6): A0A8V8TL37, P00491, G3V2H3, G3V393, G3V5M2, V9HWH6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. Preferentially acts on 6-oxopurine nucleosides including inosine and guanosine.

Subunit / interactions. Homotrimer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in red blood cells; overexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.

Disease relevance. Purine nucleoside phosphorylase deficiency (PNPD) [MIM:613179] A disorder that interrupts both the catabolism of inosine into hypoxanthine and guanosine into guanine, and leads to the accumulation of guanosine, inosine, and their deoxified by-products. The main clinical presentation is recurrent infections due to severe T-cell immunodeficiency. Some patients also have neurologic impairment. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by 5’-deaza-1’-aza-2c-deoxy-1’-(9-methylene)-Immucilin-G (DADMe-ImmG).

Pathway. Purine metabolism; purine nucleoside salvage.

Similarity. Belongs to the PNP/MTAP phosphorylase family.

RefSeq proteins (1): NP_000261* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000845	Nucleoside_phosphorylase_d	Domain
IPR011268	Purine_phosphorylase	Family
IPR011270	Pur_Nuc_Pase_Ino/Guo-sp	Family
IPR018099	Purine_phosphorylase-2_CS	Conserved_site
IPR035994	Nucleoside_phosphorylase_sf	Homologous_superfamily

Pfam: PF01048

Enzyme classification (BRENDA):

• EC 2.4.2.1 — purine-nucleoside phosphorylase (BRENDA: 89 organisms, 421 substrates, 535 inhibitors, 497 Km, 259 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
INOSINE	—	145
PHOSPHATE	0.013–91	61
GUANOSINE	0.0041–59.7	54
HYPOXANTHINE	0.0033–45.6	23
2’,3’-DIDEOXYINOSINE	0.391–14.9	17
7-METHYLGUANOSINE	0.0147–39.3	16
ADENOSINE	0.0061–6.1	16
GUANINE	0.006–35.9	15
DEOXYGUANOSINE	0.02–0.35	10
XANTHOSINE	0.051–1.6	10
2’-DEOXYINOSINE	0.043–2.06	9
DEOXYINOSINE	0.027–0.67	9
5’-METHYLTHIOINOSINE	0.0088–0.06	8
ALPHA-D-RIBOSE 1-PHOSPHATE	0.04–0.228	7
2’-DEOXYGUANOSINE	0.015–1.9	6

Catalyzed reactions (Rhea), 4 shown:

• guanosine + phosphate = alpha-D-ribose 1-phosphate + guanine (RHEA:13233)
• inosine + phosphate = alpha-D-ribose 1-phosphate + hypoxanthine (RHEA:27646)
• 2’-deoxyguanosine + phosphate = 2-deoxy-alpha-D-ribose 1-phosphate + guanine (RHEA:27738)
• 2’-deoxyinosine + phosphate = 2-deoxy-alpha-D-ribose 1-phosphate + hypoxanthine (RHEA:27750)

UniProt features (55 total): strand 14, helix 12, binding site 10, sequence variant 6, mutagenesis site 5, turn 4, modified residue 2, chain 1, site 1

Structure

Experimental structures (PDB)

41 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4EAR	X-RAY DIFFRACTION	1.7
7ZSL	X-RAY DIFFRACTION	1.8
7ZSO	X-RAY DIFFRACTION	1.95
3BGS	X-RAY DIFFRACTION	2.1
1RSZ	X-RAY DIFFRACTION	2.2
4GKA	X-RAY DIFFRACTION	2.2
5UGF	X-RAY DIFFRACTION	2.2
2A0W	X-RAY DIFFRACTION	2.28
2A0X	X-RAY DIFFRACTION	2.28
2A0Y	X-RAY DIFFRACTION	2.28
7ZSP	X-RAY DIFFRACTION	2.29
1M73	X-RAY DIFFRACTION	2.3
1RT9	X-RAY DIFFRACTION	2.3
3GB9	X-RAY DIFFRACTION	2.3
3PHB	X-RAY DIFFRACTION	2.3
4EB8	X-RAY DIFFRACTION	2.3
5ETJ	X-RAY DIFFRACTION	2.3
7ZSN	X-RAY DIFFRACTION	2.36
3K8O	X-RAY DIFFRACTION	2.4
1RR6	X-RAY DIFFRACTION	2.5
3K8Q	X-RAY DIFFRACTION	2.5
2ON6	X-RAY DIFFRACTION	2.5
3GGS	X-RAY DIFFRACTION	2.52
2OC9	X-RAY DIFFRACTION	2.59
2OC4	X-RAY DIFFRACTION	2.59
1PF7	X-RAY DIFFRACTION	2.6
4ECE	X-RAY DIFFRACTION	2.6
7ZSM	X-RAY DIFFRACTION	2.65
1V2H	X-RAY DIFFRACTION	2.7
3D1V	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00491-F1	94.13	0.83

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): 243 (important for substrate specificity)

Ligand- & substrate-binding residues (10): 33; 257; 64; 84–86; 88; 116; 201; 219; 220; 243

Post-translational modifications (2): 1, 251

Mutagenesis-validated functional residues (5):

Position	Phenotype
64	reduces catalytic activity towards inosine.
201	severe loss of catalytic activity.
243	reduces catalytic activity.
243	reduces catalytic activity towards inosine, hypoxanthine, guanosine and guanine. increases catalytic activity towards ad
257	reduces catalytic activity towards inosine.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-74217	Purine salvage
R-HSA-74259	Purine catabolism
R-HSA-9735763	Defective PNP disrupts phosphorolysis of (deoxy)guanosine and (deoxy)inosine
R-HSA-9755088	Ribavirin ADME

MSigDB gene sets: 588 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_52, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_INNATE_IMMUNE_SYSTEM, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, PAL_PRMT5_TARGETS_UP, GOCC_SECRETORY_GRANULE, MODULE_151, ENK_UV_RESPONSE_KERATINOCYTE_UP, ATACCTC_MIR202, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP

GO Biological Process (18): allantoin metabolic process (GO:0000255), nucleobase-containing compound metabolic process (GO:0006139), inosine catabolic process (GO:0006148), deoxyinosine catabolic process (GO:0006149), deoxyadenosine catabolic process (GO:0006157), purine ribonucleoside salvage (GO:0006166), IMP catabolic process (GO:0006204), nicotinamide riboside catabolic process (GO:0006738), immune response (GO:0006955), nucleotide biosynthetic process (GO:0009165), response to xenobiotic stimulus (GO:0009410), positive regulation of interleukin-2 production (GO:0032743), urate biosynthetic process (GO:0034418), positive regulation of T cell proliferation (GO:0042102), purine-containing compound salvage (GO:0043101), dAMP catabolic process (GO:0046059), positive regulation of alpha-beta T cell differentiation (GO:0046638), nucleoside metabolic process (GO:0009116)

GO Molecular Function (11): nucleoside binding (GO:0001882), purine nucleobase binding (GO:0002060), purine-nucleoside phosphorylase activity (GO:0004731), phosphate ion binding (GO:0042301), identical protein binding (GO:0042802), guanosine phosphorylase activity (GO:0047975), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), pentosyltransferase activity (GO:0016763)

GO Cellular Component (6): extracellular region (GO:0005576), cytoplasm (GO:0005737), cytosol (GO:0005829), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Innate Immune System	1
Nucleotide salvage	1
Nucleotide catabolism	1
Nucleotide catabolism defects	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
2’-deoxyribonucleoside catabolic process	2
purine deoxyribonucleoside catabolic process	2
purine-containing compound biosynthetic process	2
metabolic process	1
primary metabolic process	1
inosine metabolic process	1
purine ribonucleoside catabolic process	1
deoxyinosine metabolic process	1
deoxyadenosine metabolic process	1
purine-containing compound salvage	1
nucleoside salvage	1
purine ribonucleoside biosynthetic process	1
purine ribonucleotide catabolic process	1
purine ribonucleoside monophosphate catabolic process	1
IMP metabolic process	1
nicotinamide riboside metabolic process	1
pyridine nucleoside catabolic process	1
immune system process	1
response to stimulus	1
nucleotide metabolic process	1
nucleoside phosphate biosynthetic process	1
response to chemical	1
positive regulation of cytokine production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
small molecule biosynthetic process	1
urate metabolic process	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of T cell activation	1
metabolic compound salvage	1
purine deoxyribonucleotide catabolic process	1
purine deoxyribonucleoside monophosphate catabolic process	1
dAMP metabolic process	1
positive regulation of T cell differentiation	1
alpha-beta T cell differentiation	1
positive regulation of alpha-beta T cell activation	1
regulation of alpha-beta T cell differentiation	1

Protein interactions and networks

STRING

1744 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNP	ADA	P00813	980
PNP	XDH	P47989	931
PNP	UPP2	O95045	925
PNP	UPP1	Q16831	878
PNP	APRT	P07741	809
PNP	GDA	Q9Y2T3	789
PNP	ADK	P55263	770
PNP	AMPD3	Q01432	747
PNP	AMPD2	Q01433	739
PNP	PGM2L1	Q6PCE3	729
PNP	AMPD1	P23109	717
PNP	ADSL	P30566	716
PNP	HPRT1	P00492	704
PNP	PGM2	Q96G03	682
PNP	CS	O75390	680

IntAct

94 interactions, top by confidence:

A	B	Type	Score
PNP	PNP	psi-mi:“MI:0407”(direct interaction)	0.810
PNP	PNP	psi-mi:“MI:0915”(physical association)	0.810
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
CAMK2A	PNP	psi-mi:“MI:0915”(physical association)	0.560
DYNC1I1	PNP	psi-mi:“MI:0915”(physical association)	0.560
FYN	PNP	psi-mi:“MI:0915”(physical association)	0.560
GFAP	PNP	psi-mi:“MI:0915”(physical association)	0.560
PRKACA	PNP	psi-mi:“MI:0915”(physical association)	0.560
RAC1	PNP	psi-mi:“MI:0915”(physical association)	0.560
PNP	SORL1	psi-mi:“MI:0915”(physical association)	0.560
TGIF1	PNP	psi-mi:“MI:0915”(physical association)	0.560
KAT5	PNP	psi-mi:“MI:0915”(physical association)	0.560
PNP	PINK1	psi-mi:“MI:0915”(physical association)	0.560
APP	PNP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (105): PNP (Two-hybrid), PNP (Affinity Capture-RNA), PNP (Affinity Capture-RNA), PNP (Affinity Capture-RNA), PNP (Affinity Capture-MS), PNP (Affinity Capture-MS), PNP (Co-fractionation), PNP (Co-fractionation), TRAPPC4 (Co-fractionation), PNP (Two-hybrid), PNP (Affinity Capture-MS), PNP (Affinity Capture-MS), PNP (Affinity Capture-MS), PNP (Affinity Capture-MS), PNP (Affinity Capture-MS)

ESM2 similar proteins: A0A411KUP9, A1CA18, A2R9B9, A4Q998, A4SCI7, B9FK36, J9VTK7, O13702, O42938, O61199, O74378, O93937, O93988, O94200, O94337, P00491, P07382, P15937, P16126, P16393, P16862, P17709, P21342, P23492, P45563, P49365, P51820, P53585, P55859, P59680, P85973, Q03216, Q05788, Q07938, Q09580, Q2M197, Q38970, Q41140, Q5XI78, Q60597

Diamond homologs: A0QR54, A0RVQ7, A1RXU2, A2BIU4, A7EAA1, A7SN31, A8P7Y3, A8XGS6, A9A3N5, A9WAL0, B1L719, B5YKP5, B8E181, C0NRX4, C4YQD9, C7YLQ3, C8VP37, D5GFR0, E3K7C1, E3K7C3, E3XFR6, F6RQL9, F6V515, F6X2V8, O06401, O27633, O28486, O57865, O66839, P00491, P0DJF8, P0DJF9, P23139, Q05788, Q07938, Q09438, Q09816, Q0U796, Q13126, Q16MW6

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
PNP	“down-regulates quantity”	“alpha-D-ribose 1-phosphate(2-)”	“chemical modification”
PNP	“down-regulates quantity”	guanine	“chemical modification”
PNP	“up-regulates quantity”	guanosine	“chemical modification”
PNP	“down-regulates quantity”	“2-deoxy-D-ribofuranose 1-phosphate(2-)”	“chemical modification”
PNP	“up-regulates quantity”	2’-deoxyguanosine	“chemical modification”
PNP	“down-regulates quantity”	hypoxanthine	“chemical modification”
PNP	“up-regulates quantity”	inosine	“chemical modification”
PNP	“up-regulates quantity”	2’-deoxyinosine	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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.

GO biological processes:

GO term	Partners	Fold	FDR
response to ischemia	5	19.4×	3e-03
negative regulation of gene expression	8	8.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	11
Uncertain significance	120
Likely benign	105
Benign	29

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071551	NM_000270.4(PNP):c.171_172delinsTT (p.Arg58Ter)	Pathogenic
1074418	NM_000270.4(PNP):c.547dup (p.Glu183fs)	Pathogenic
1076064	NM_000270.4(PNP):c.244C>T (p.Gln82Ter)	Pathogenic
1344922	NM_000270.4(PNP):c.199C>T (p.Arg67Ter)	Pathogenic
13988	NM_000270.4(PNP):c.265G>A (p.Glu89Lys)	Pathogenic
13994	NM_000270.4(PNP):c.731del (p.Lys244fs)	Pathogenic
13995	NM_000270.4(PNP):c.70C>T (p.Arg24Ter)	Pathogenic
13996	NM_000270.4(PNP):c.172C>T (p.Arg58Ter)	Pathogenic
13997	NM_000270.4(PNP):c.285+1G>A	Pathogenic
1458553	NM_000270.4(PNP):c.700C>T (p.Arg234Ter)	Pathogenic
2163413	NM_000270.4(PNP):c.406dup (p.Ile136fs)	Pathogenic
2736067	NM_000270.4(PNP):c.569G>T (p.Gly190Val)	Pathogenic
2844130	NM_000270.4(PNP):c.632_644dup (p.Asp215fs)	Pathogenic
3023072	NM_000270.4(PNP):c.513del (p.Arg171fs)	Pathogenic
4710887	NM_000270.4(PNP):c.694G>T (p.Gly232Ter)	Pathogenic
4712212	NM_000270.4(PNP):c.397del (p.Arg133fs)	Pathogenic
4717066	NM_000270.4(PNP):c.519_522dup (p.Leu175fs)	Pathogenic
4731735	NM_000270.4(PNP):c.472del (p.Arg158fs)	Pathogenic
4731810	NM_000270.4(PNP):c.281G>A (p.Trp94Ter)	Pathogenic
845655	NM_000270.4(PNP):c.751del (p.Ser251fs)	Pathogenic
13989	NM_000270.4(PNP):c.520G>C (p.Ala174Pro)	Likely pathogenic
2137547	NM_000270.4(PNP):c.387_389del (p.Ile129del)	Likely pathogenic
2178845	NM_000270.4(PNP):c.182-2A>G	Likely pathogenic
2443221	NM_000270.4(PNP):c.331del (p.Leu111fs)	Likely pathogenic
2862345	NM_000270.4(PNP):c.11+2T>A	Likely pathogenic
3064932	NM_000270.4(PNP):c.83C>T (p.Ala28Val)	Likely pathogenic
3340502	NM_000270.4(PNP):c.41_44dup (p.Glu15fs)	Likely pathogenic
3576484	NM_000270.4(PNP):c.150_151delinsAA (p.Tyr50_Gly51delinsTer)	Likely pathogenic
4077435	NM_000270.4(PNP):c.349G>A (p.Ala117Thr)	Likely pathogenic
636526	NM_000270.4(PNP):c.547G>T (p.Glu183Ter)	Likely pathogenic

SpliceAI

573 predictions. Top by Δscore:

Variant	Effect	Δscore
14:20469534:GG:G	donor_gain	1.0000
14:20469535:GG:G	donor_gain	1.0000
14:20469536:G:GG	donor_gain	1.0000
14:20469537:T:G	donor_loss	1.0000
14:20472302:CCCCA:C	acceptor_loss	1.0000
14:20472303:CCCA:C	acceptor_loss	1.0000
14:20472304:CCA:C	acceptor_loss	1.0000
14:20472305:CAGAT:C	acceptor_loss	1.0000
14:20472306:A:AG	acceptor_gain	1.0000
14:20472307:G:GA	acceptor_gain	1.0000
14:20472307:G:T	acceptor_loss	1.0000
14:20472307:GAT:G	acceptor_gain	1.0000
14:20472307:GATAC:G	acceptor_gain	1.0000
14:20472403:G:GT	donor_gain	1.0000
14:20472469:G:GT	donor_gain	1.0000
14:20472476:AG:A	donor_loss	1.0000
14:20472477:GGTA:G	donor_loss	1.0000
14:20472478:G:A	donor_loss	1.0000
14:20474470:A:AG	acceptor_gain	1.0000
14:20474470:A:AT	acceptor_loss	1.0000
14:20474471:G:GT	acceptor_gain	1.0000
14:20474471:GT:G	acceptor_gain	1.0000
14:20474471:GTGC:G	acceptor_gain	1.0000
14:20474471:GTGCC:G	acceptor_gain	1.0000
14:20474754:C:A	acceptor_gain	1.0000
14:20474754:C:CA	acceptor_loss	1.0000
14:20474755:G:A	acceptor_gain	1.0000
14:20474759:T:A	acceptor_loss	1.0000
14:20474759:T:TA	acceptor_gain	1.0000
14:20474763:T:TA	acceptor_gain	1.0000

AlphaMissense

1903 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:20476389:A:C	S220R	0.998
14:20476391:T:A	S220R	0.998
14:20476391:T:G	S220R	0.998
14:20474546:C:G	H86D	0.995
14:20475075:T:C	F159L	0.995
14:20475077:C:A	F159L	0.995
14:20475077:C:G	F159L	0.995
14:20476388:G:A	M219I	0.995
14:20476388:G:C	M219I	0.995
14:20476388:G:T	M219I	0.995
14:20476390:G:T	S220I	0.993
14:20475205:C:T	T202I	0.992
14:20476387:T:C	M219T	0.992
14:20474541:G:T	R84M	0.991
14:20474888:A:T	D134V	0.991
14:20476456:C:T	T242I	0.991
14:20474502:G:A	G71E	0.990
14:20474556:A:T	E89V	0.989
14:20472379:C:A	A28E	0.988
14:20474832:T:A	N115K	0.988
14:20474832:T:G	N115K	0.988
14:20474836:G:C	A117P	0.988
14:20475198:T:C	F200L	0.988
14:20475200:T:A	F200L	0.988
14:20475200:T:G	F200L	0.988
14:20475246:G:C	A216P	0.988
14:20474541:G:C	R84T	0.987
14:20474548:C:A	H86Q	0.987
14:20474548:C:G	H86Q	0.987
14:20474828:C:T	T114I	0.987

dbSNP variants (sampled 300 via entrez): RS1000240099 (14:20475513 G>A), RS1000837774 (14:20469466 G>C,T), RS1000846561 (14:20476829 T>C), RS1000877435 (14:20476463 G>A), RS1001356590 (14:20470736 A>T), RS1001583915 (14:20474638 T>C), RS1001626446 (14:20468924 T>C), RS1002640234 (14:20473164 C>G), RS1002682611 (14:20473635 G>A), RS1002740241 (14:20467890 G>A), RS1002771594 (14:20467662 T>C), RS1003365489 (14:20473360 C>G), RS1003719252 (14:20474777 C>T), RS1003743962 (14:20468986 A>C,G), RS1004081318 (14:20475981 G>T)

Disease associations

OMIM: gene MIM:164050 | disease phenotypes: MIM:613179

GenCC curated gene-disease

Disease	Classification	Inheritance
purine nucleoside phosphorylase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
purine nucleoside phosphorylase deficiency	Definitive	AR

Mondo (2): purine nucleoside phosphorylase deficiency (MONDO:0013171), severe combined immunodeficiency (MONDO:0015974)

Orphanet (2): Purine nucleoside phosphorylase deficiency (Orphanet:760), Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000246	Sinusitis
HP:0000388	Otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000707	Abnormality of the nervous system
HP:0000708	Atypical behavior
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001297	Stroke
HP:0001337	Tremor
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001904	Autoimmune neutropenia
HP:0001973	Autoimmune thrombocytopenia
HP:0002090	Pneumonia
HP:0002194	Delayed gross motor development
HP:0002205	Recurrent respiratory infections
HP:0002273	Tetraparesis
HP:0002313	Spastic paraparesis

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C562587	Purine Nucleoside Phosphorylase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4338 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 723,257 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1619	CLADRIBINE	4	91,402
CHEMBL184	ACYCLOVIR	4	97,488
CHEMBL218291	FORODESINE	4	1,563
CHEMBL550755	FORODESINE HYDROCHLORIDE	4	65
CHEMBL219568	GUANINE	3	487,645
CHEMBL1236524	GALIDESIVIR	2	1,435
CHEMBL269864	ULODESINE	2	141
CHEMBL311300	PELDESINE	2	16,044
CHEMBL31882	DEZAGUANINE	2	27,474

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 2.4.2.1 Purine-nucleoside phosphorylase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
forodesine	Inhibition	10.14	pKi

Binding affinities (BindingDB)

34 measured of 40 human assays (46 total across all organisms); most potent 34 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
7-({[(1R,2S)-2,3-DIHYDROXY-1-(HYDROXYMETHYL)PROPYL]AMINO}METHYL)-3,5-DIHYDRO-4H-PYRROLO[3,2-D]PYRIMIDIN-4-ONE	KD	0.0086 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
Immucillins, 13	KD	0.156 nM
7-{(1S)-1-[(1,3-Dihydroxypropan-2-yl)amino]-2-hydroxyethyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	0.21 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
Immucillins, 11	KD	0.383 nM
7-{[(1,3-Dihydroxypropan-2-yl)(2-hydroxyethyl)amino]methyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	0.469 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
Immucillins, 10	KD	0.62 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[(2R/S,3S/R)-3,4-Dihydroxy-2-(hydroxymethyl)butyl]amino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	0.78 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[(2S,3R)-1,3,4-Trihydroxybutan-2-yl]amino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	1 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-{[(2-Hydroxyethyl)amino]methyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	1.1 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 12	KD	3 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({3-Hydroxy-2-(hydroxymethyl)propylamino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	3.7 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[(2S)-2,3-Dihydroxypropyl]amino}methyl)-3,5-dihydro-4Hpyrrolo[3,2-d]pyrimidin-4-one	KD	4.2 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[(2R,3R)-1,3,4-Trihydroxybutan-2-yl]amino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	4.3 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[(2S,3S)-1,3,4-Trihydroxybutan-2-yl]amino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	5.2 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 28	KD	5.6 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[3-Hydroxy-2-(hydroxymethyl)propyl]amino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	14.1 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[(2R)-2,3-Dihydroxypropyl]amino}methyl)-3,5-dihydro-4Hpyrrolo[3,2-d]pyrimidin-4-one	KD	14.9 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 24	KD	15 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-[[benzyl-[(3S)-3,4-dihydroxy-2-(methylsulfanylmethyl)butyl]amino]methyl]-1,2,3,4a,5,6,7,7a-octahydropyrrolo[3,2-d]pyrimidin-4-one	KD	22 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-{[(4-Hydroxybutyl)amino]methyl}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	25 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({[(2S,3R)-2,3,4-Trihydroxybutyl]amino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	31 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 19	KD	51 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
Immucillins, 14	KD	53 nM
US8853224, 26	KD	71 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 25	KD	74 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 20.5	KD	84 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({(2R)-2,3-Dihydroxypropylamino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	96 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 27	KD	142 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 23	KD	159 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({(2S)-2,3-Dihydroxypropylamino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	165 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-({(2R/S)-2,4-Dihydroxybutylamino}methyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one	KD	227 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
7-[[benzyl-[(2R)-2,3-dihydroxypropyl]amino]methyl]-1,2,3,4a,5,6,7,7a-octahydropyrrolo[3,2-d]pyrimidin-4-one	KD	300 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 20.8	KD	789 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases
US8853224, 22	KD	900 nM	US-8853224: Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases

ChEMBL bioactivities

496 potent at pChembl≥5 of 531 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.97	Ki	0.0107	nM	ULODESINE
10.96	Ki	0.011	nM	ULODESINE
10.80	Ki	0.016	nM	ULODESINE
10.71	Ki	0.0196	nM	CHEMBL514795
10.54	Ki	0.029	nM	CHEMBL473922
10.52	IC50	0.03	nM	CHEMBL349855
10.49	Ki	0.032	nM	CHEMBL498940
10.38	Ki	0.042	nM	CHEMBL473922
10.25	Ki	0.056	nM	FORODESINE
10.25	Kd	0.056	nM	FORODESINE
10.24	Ki	0.0579	nM	FORODESINE
10.24	Kd	0.058	nM	CHEMBL1213652
10.24	IC50	0.057	nM	CHEMBL349024
10.22	IC50	0.06	nM	FORODESINE
10.18	Ki	0.066	nM	CHEMBL498940
10.18	Ki	0.066	nM	CHEMBL443968
10.17	IC50	0.067	nM	CHEMBL159271
10.15	Ki	0.07	nM	CHEMBL514795
10.14	Ki	0.072	nM	FORODESINE
10.07	IC50	0.085	nM	CHEMBL422712
10.07	IC50	0.085	nM	CHEMBL159747
10.02	Ki	0.096	nM	CHEMBL41949
10.00	Ki	0.1	nM	CHEMBL514795
9.98	Ki	0.104	nM	CHEMBL2311112
9.96	Ki	0.11	nM	CHEMBL505564
9.96	Ki	0.11	nM	CHEMBL514795
9.93	Ki	0.117	nM	CHEMBL443968
9.80	Ki	0.16	nM	CHEMBL475750
9.80	IC50	0.16	nM	CHEMBL351228
9.79	Ki	0.163	nM	CHEMBL435085
9.74	Ki	0.18	nM	CHEMBL2311112
9.68	Kd	0.21	nM	CHEMBL522757
9.68	Ki	0.21	nM	CHEMBL522757
9.66	Ki	0.22	nM	CHEMBL114781
9.64	Ki	0.229	nM	CHEMBL407776
9.60	Ki	0.25	nM	CHEMBL115146
9.60	IC50	0.25	nM	CHEMBL351219
9.59	Ki	0.26	nM	CHEMBL269866
9.57	Ki	0.27	nM	ULODESINE
9.52	Ki	0.3	nM	CHEMBL514795
9.48	Ki	0.33	nM	CHEMBL498940
9.42	Ki	0.38	nM	CHEMBL454743
9.41	Ki	0.39	nM	CHEMBL542455
9.40	Ki	0.4	nM	CHEMBL489690
9.37	Ki	0.43	nM	CHEMBL508602
9.33	Kd	0.469	nM	CHEMBL508929
9.33	Ki	0.469	nM	CHEMBL508929
9.33	IC50	0.47	nM	CHEMBL350429
9.32	IC50	0.48	nM	FORODESINE HYDROCHLORIDE
9.30	Ki	0.5	nM	CHEMBL498940

PubChem BioAssay actives

489 with measured affinity, of 844 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
7-[[(3R,4S)-3-hydroxy-4-(methylsulfanylmethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	409914: Equilibrium binding affinity to wild type human PNP	ki	<0.0001	uM
2-amino-7-[[(3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1571179: Inhibition of recombinant human PNP expressed in Escherichia coli BL21 (DE3) using inosine as substrate preincubated for 5.5 hrs followed by substrate addition by xanthine oxidase coupled assay	ki	<0.0001	uM
2-amino-7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1571176: Inhibition of human PNP using inosine as substrate by xanthine oxidase coupled assay	ki	<0.0001	uM
7-[[(3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1571179: Inhibition of recombinant human PNP expressed in Escherichia coli BL21 (DE3) using inosine as substrate preincubated for 5.5 hrs followed by substrate addition by xanthine oxidase coupled assay	ki	<0.0001	uM
7-[[[(2R,3S)-1,3,4-trihydroxybutan-2-yl]amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	2108236: Binding affinity to human PNP assessed as inhibition constant by TR-FRET assay	ki	<0.0001	uM
7-[[(3R,4R)-3-hydroxy-4-[hydroxy(tritio)methyl]pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	495109: Binding affinity to human PNP	kd	<0.0001	uM
7-[(1,3-dihydroxypropan-2-ylamino)methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1571176: Inhibition of human PNP using inosine as substrate by xanthine oxidase coupled assay	ki	<0.0001	uM
2-amino-7-[(1,3-dihydroxypropan-2-ylamino)methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	2108236: Binding affinity to human PNP assessed as inhibition constant by TR-FRET assay	ki	<0.0001	uM
7-[[[(2R,3S)-3,4-dihydroxy-2-(hydroxymethyl)butyl]amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1571176: Inhibition of human PNP using inosine as substrate by xanthine oxidase coupled assay	ki	<0.0001	uM
7-[[(3S,4S)-3-fluoro-4-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	386683: Inhibition of human purine nucleoside phosphorylase by xanthine-oxidase coupled assay	ki	<0.0001	uM
7-[[(3R,4S)-3-hydroxy-4-(propylsulfanylmethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	409914: Equilibrium binding affinity to wild type human PNP	ki	<0.0001	uM
2-amino-7-[[(4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	164742: Dissociation constant against Human Purine Nucleoside Phosphorylase was reported	ki	<0.0001	uM
2-amino-7-[[[(2R,3S)-1,3,4-trihydroxybutan-2-yl]amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	2108236: Binding affinity to human PNP assessed as inhibition constant by TR-FRET assay	ki	<0.0001	uM
2-amino-6-(thiophen-2-ylmethyl)-3,7-dihydropyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	<0.0001	uM
7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1571176: Inhibition of human PNP using inosine as substrate by xanthine oxidase coupled assay	ki	0.0001	uM
3-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one	164744: Inhibitory activity of compound against human purine nucleoside phosphorylase (PNP)	ki	0.0001	uM
7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-[hydroxy(tritio)methyl]pyrrolidin-2-yl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	495109: Binding affinity to human PNP	kd	0.0001	uM
2-amino-6-benzyl-3,7-dihydropyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0001	uM
2-amino-6-(thiophen-3-ylmethyl)-3,7-dihydropyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0001	uM
2-amino-6-(furan-2-ylmethyl)-3,7-dihydropyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0001	uM
2-amino-8-(thiophen-3-ylmethylamino)-1,7-dihydropurin-6-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0001	uM
4-amino-5-[(3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-1H-pyrazole-3-carboxamide	164744: Inhibitory activity of compound against human purine nucleoside phosphorylase (PNP)	ki	0.0001	uM
7-[(1S)-1-(1,3-dihydroxypropan-2-ylamino)-2-hydroxyethyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0002	uM
7-[[3,3-bis(hydroxymethyl)azetidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1798156: PNP Inhibition Assay from Article 10.1021/jm701265n: “Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases.”	ki	0.0002	uM
2-amino-8-(thiophen-2-ylmethylamino)-1,7-dihydropurin-6-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0002	uM
2-amino-7-[(2R,4R,5R)-4-hydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	164928: Inhibition of human purine nucleoside phosphorylase; Initial rate.	ki	0.0002	uM
7-[[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1799859: Inhibtion Assay from Article 10.1021/bi9005896: “Altered enthalpy-entropy compensation in picomolar transition state analogues of human purine nucleoside phosphorylase.”	kd	0.0002	uM
7-[[2-(hydroxymethyl)azetidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	317479: Inhibition of human PNP	ki	0.0003	uM
2-amino-8-(furan-2-ylmethylamino)-1,7-dihydropurin-6-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0003	uM
7-[(2R,4R,5R)-4-hydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	164928: Inhibition of human purine nucleoside phosphorylase; Initial rate.	ki	0.0003	uM
7-[[(3S,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0004	uM
7-[[1,3-dihydroxypropan-2-yl(methyl)amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0004	uM
2-amino-7-[[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0004	uM
7-[(2S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-6-fluoro-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one;hydrochloride	164930: Equilibrium dissociation constant determined against human purine nucleoside phosphorylase (PNP) after slow-onset inhibition	ki	0.0004	uM
7-[(3-hydroxypyrrolidin-1-yl)methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1799859: Inhibtion Assay from Article 10.1021/bi9005896: “Altered enthalpy-entropy compensation in picomolar transition state analogues of human purine nucleoside phosphorylase.”	kd	0.0004	uM
7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one;hydrochloride	2142358: Inhibition of PNP (unknown origin)	ic50	0.0005	uM
7-[[1,3-dihydroxypropan-2-yl(2-hydroxyethyl)amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0005	uM
2-amino-8-(benzylamino)-1,7-dihydropurin-6-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0005	uM
7-[[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0006	uM
2-amino-6-(thiophen-3-ylmethylimino)-5,7-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0006	uM
7-[(3-hydroxypropylamino)methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0008	uM
7-[(1,3,4-trihydroxybutan-2-ylamino)methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0008	uM
2-amino-6-benzylimino-5,7-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0008	uM
2-amino-6-(furan-2-ylmethylimino)-5,7-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0008	uM
7-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1929576: Inhibition of human recombinant PNP	ic50	0.0009	uM
6-[[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	1929576: Inhibition of human recombinant PNP	ic50	0.0009	uM
2-amino-7-[[(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	272823: Inhibition of human PNP activity	ki	0.0010	uM
[5-(2-amino-4-oxo-3,5-dihydropyrrolo[3,2-d]pyrimidin-7-yl)-1,1-difluoropentyl]phosphonic acid	299577: Inhibition of human PNP in presence of 0.025 mM phosphate	ki	0.0010	uM
7-[[[(2S,3R)-1,3,4-trihydroxybutan-2-yl]amino]methyl]-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one	371442: Inhibition of human PNP by xanthine-oxidase coupled assay	ki	0.0010	uM
2-amino-6-(thiophen-2-ylmethylimino)-5,7-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one	156071: Inhibition of Purine nucleoside phosphorylase was evaluated against the enzyme from Human erythrocytic in 50 mM phosphate	ic50	0.0010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment	6
Arsenic	affects reaction, affects response to substance, affects abundance, affects metabolic processing, increases reduction (+4 more)	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression, affects expression	4
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	4
bisphenol A	decreases expression	3
Estradiol	increases expression, increases reaction, affects expression	3
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
arsenic acid	increases metabolic processing, increases chemical synthesis, increases reduction	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Arsenic Trioxide	decreases expression	2
Panobinostat	increases expression, affects cotreatment	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
arsenite	increases metabolic processing, increases chemical synthesis	1
afimoxifene	decreases reaction, increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
ferrous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

156 unique, capped per target: 139 binding, 16 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1023647	Binding	Inhibition of human purine nucleoside phosphorylase	Synthesis of analogs of forodesine HCl, a human purine nucleoside phosphorylase inhibitor-Part II. — Bioorg Med Chem Lett
CHEMBL3755834	ADMET	Prodrug activation assessed as recombinant human PNP-mediated compound cleavage at 100 uM by reverse phase HPLC analysis	6-Methylpurine derived sugar modified nucleosides: Synthesis and in vivo antitumor activity in D54 tumor expressing M64V-Escherichia coli purine nucleoside phosphorylase. — Eur J Med Chem
CHEMBL764862	Functional	Compound was evaluated for inhibition of PNP-catalyzed inosine phosphorylation in Cellulomonas sp	Synthesis and biological evaluation of 1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids possessing a N9-purinylmethyl functional group at the ring. a new class of inhibitors for purine nucleoside phosphorylases. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3E6	Abcam HEK293T PNP KO	Transformed cell line	Female
CVCL_TE77	HAP1 PNP (-) 1	Cancer cell line	Male
CVCL_TE78	HAP1 PNP (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID
NCT04246840	Not specified	COMPLETED	Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft