MACROD1

Summary

MACROD1 (mono-ADP ribosylhydrolase 1, HGNC:29598) is a protein-coding gene on chromosome 11q13.1, encoding ADP-ribose glycohydrolase MACROD1 (Q9BQ69). Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety.

Enables ADP-ribosylglutamate hydrolase activity and deacetylase activity. Involved in DNA damage response; peptidyl-glutamate ADP-deribosylation; and purine nucleoside metabolic process. Located in nucleoplasm.

Source: NCBI Gene 28992 — RefSeq curated summary.

At a glance

• GWAS associations: 65
• Clinical variants (ClinVar): 99 total
• Druggable target: yes
• MANE Select transcript: NM_014067

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29598
Approved symbol	MACROD1
Name	mono-ADP ribosylhydrolase 1
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	LRP16
Ensembl gene	ENSG00000133315
Ensembl biotype	protein_coding
OMIM	610400
Entrez	28992

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000255681, ENST00000538595, ENST00000541041, ENST00000542105, ENST00000542359, ENST00000543422, ENST00000545464, ENST00000675777, ENST00000909124, ENST00000909125, ENST00000909126, ENST00000909127, ENST00000909128, ENST00000909129, ENST00000909130, ENST00000909131, ENST00000941620, ENST00000941621

RefSeq mRNA: 2 — MANE Select: NM_014067 NM_001411019, NM_014067

CCDS: CCDS8056, CCDS91496

Canonical transcript exons

ENST00000255681 — 11 exons

Exon	Start	End
ENSE00001116801	63999331	63999404
ENSE00002299420	64165697	64166113
ENSE00002314785	63998558	63998687
ENSE00003467407	64152292	64152393
ENSE00003497031	64000227	64000343
ENSE00003523739	64151239	64151355
ENSE00003613000	63998955	63999036
ENSE00003624385	63999530	63999560
ENSE00003644221	63998838	63998872
ENSE00003676684	64015252	64015281
ENSE00003680126	63999642	63999763

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 99.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.3988 / max 248.6401, expressed in 1720 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120348	9.9419	1678
120345	4.5756	1097
120347	3.3857	1274
120344	0.7682	273
120346	0.5966	282
120343	0.1309	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.24	gold quality
apex of heart	UBERON:0002098	98.68	gold quality
gastrocnemius	UBERON:0001388	98.47	gold quality
muscle of leg	UBERON:0001383	97.77	gold quality
muscle organ	UBERON:0001630	97.60	gold quality
vastus lateralis	UBERON:0001379	97.48	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.45	gold quality
quadriceps femoris	UBERON:0001377	97.19	gold quality
skeletal muscle tissue	UBERON:0001134	97.03	gold quality
biceps brachii	UBERON:0001507	96.54	gold quality
triceps brachii	UBERON:0001509	96.39	gold quality
heart left ventricle	UBERON:0002084	96.34	gold quality
cardiac ventricle	UBERON:0002082	96.06	gold quality
diaphragm	UBERON:0001103	96.01	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.00	gold quality
right lobe of thyroid gland	UBERON:0001119	94.79	gold quality
left lobe of thyroid gland	UBERON:0001120	94.75	gold quality
body of pancreas	UBERON:0001150	94.73	gold quality
gluteal muscle	UBERON:0002000	94.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.24	gold quality
thyroid gland	UBERON:0002046	93.79	gold quality
deltoid	UBERON:0001476	93.57	gold quality
right atrium auricular region	UBERON:0006631	93.48	gold quality
right lobe of liver	UBERON:0001114	93.37	gold quality
heart	UBERON:0000948	93.25	gold quality
muscle tissue	UBERON:0002385	93.16	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.14	gold quality
skin of abdomen	UBERON:0001416	92.81	gold quality
adult mammalian kidney	UBERON:0000082	92.78	gold quality
cerebellar hemisphere	UBERON:0002245	92.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ESR1, RARA, SP1, SPI1

miRNA regulators (miRDB)

3 targeting MACROD1, 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-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3153	99.55	67.59	2337

Literature-anchored findings (GeneRIF, showing 20)

• ERalpha and Sp1 play a role in activation of the promoter (PMID:15691879)
• LRP16 overexpression is closely correlated to the positive rates of estrogen receptor and progesterone receptor, Ki-67 level, tumor diameter, and axillary lymph node metastasis of breast cancer. (PMID:16831279)
• identified a novel RUNX1 fusion partner, LRP16 on 11q13 involving t(11;21)(q13;q22) (PMID:17532767)
• A role for estrogenically regulated LRP16 as an ERalpha coactivator, providing a positive feedback regulatory loop for ERalpha signal transduction. (PMID:17914104)
• the single macro domain in LRP16 can serve as the androgen receptor coactivator (PMID:19022849)
• The unliganded ERalpha upregulated LRP16 expression and enhanced LRP16 promoter activity in SKOV3 cells; however, this induction was blocked by estrogen stimulation. (PMID:19403568)
• lrp16 is a leukemic oncogene and closely relates to genesis and progression of leukemia. (PMID:19698216)
• LRP16 may have a role in invasion, metastasis and prognosis of gastric cancer (PMID:19824120)
• LRP16 gene overexpression shows a promotive effect on proliferation of K562 cells. (PMID:19840441)
• LRP16 may play an important role in leukemia progression by promoting cell proliferation, regulating cell cycle, and antagonizing radiation-induced DNA damage. (PMID:19958623)
• K18 attenuates estrogen receptor alpha-mediated signaling by sequestering LRP16 in cytoplasm. (PMID:20035625)
• LRP16 expression is related to the degree of differentiation, invasiveness, metastasis and prognosis of colorectal carcinoma. (PMID:20355243)
• Findings not only indicate that LRP16 is a crucial regulator for NF-kappaB activation inside the nucleus, but also suggest that LRP16 may be an important contributor to the aberrant activation of NF-kappaB in tumors. (PMID:21483817)
• LRP16, through its constitutive interactions with PARP1 and IKKgamma, functions to facilitate the lesion-specific recruitment of PARP1 and IKKgamma and, ultimately, the concomitant recruitment of PIASy to IKKgamma in response to DNA damage. (PMID:25735744)
• The results indicate that abnormal LRP16 expression is noted in neuroendocrine lung tumors and the expression can give insight into the pathogenesis of the disease. (PMID:26261536)
• Here, the authors report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKKbeta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappaB) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. (PMID:28820388)
• We demonstrated that LRP16 positively regulates the Wnt signaling pathway in hepatocellular carcinoma (HCC), which elucidates an important mechanism of HCC cell growth, metastasis, and prognosis. (PMID:29748698)
• These findings revealed the functions of LRP16 in promoting the inflammatory response through activating the Rac1-MAPK1/ERK pathway in human adipocytes. (PMID:30562745)
• Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome. (PMID:32427867)
• Molecular basis for the MacroD1-mediated hydrolysis of ADP-ribosylation. (PMID:32683309)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	macrod1	ENSDARG00000029609
mus_musculus	Macrod1	ENSMUSG00000036278
rattus_norvegicus	Macrod1	ENSRNOG00000021174

Paralogs (2): MACROD2 (ENSG00000172264), GDAP2 (ENSG00000196505)

Protein

Protein identifiers

ADP-ribose glycohydrolase MACROD1 — Q9BQ69 (reviewed: Q9BQ69)

Alternative names: MACRO domain-containing protein 1, O-acetyl-ADP-ribose deacetylase MACROD1, Protein LRP16, [Protein ADP-ribosylaspartate] hydrolase MACROD1, [Protein ADP-ribosylglutamate] hydrolase MACROD1

All UniProt accessions (2): A0A6Q8PH91, Q9BQ69

UniProt curated annotations — full annotation on UniProt →

Function. Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety. Inactive towards proteins bearing poly-ADP-ribose. Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins. Plays a role in estrogen signaling. Binds to androgen receptor (AR) and amplifies the transactivation function of AR in response to androgen. May play an important role in carcinogenesis and/or progression of hormone-dependent cancers by feed-forward mechanism that activates ESR1 transactivation. Could be an ESR1 coactivator, providing a positive feedback regulatory loop for ESR1 signal transduction. Could be involved in invasive growth by down-regulating CDH1 in endometrial cancer cells. Enhances ESR1-mediated transcription activity.

Subunit / interactions. Interacts with ESR1; Interacts in a manner that is estrogen independent but is enhanced by estrogen. Interacts (via macro domain) with AR.

Subcellular location. Nucleus.

Disease relevance. A chromosomal aberration involving MACROD1 is found in acute leukemia. Translocation t(11;21)(q13;q22) that forms a RUNX1-MACROD1 fusion protein.

Activity regulation. Subject to competitive inhibition by the product ADP-ribose.

Induction. Overexpressed by estrogens in breast cancer MCF-7 cells, probably via an activation of nuclear receptors for steroids (ESR1 but not ESR2). Significantly increased by estrogens in ESR1-positive Ishikawa endometrial cancer cells. Up-regulated in 17-beta-estradiol-responsive BG-1 ovarian cancer cells but down-regulated in estrogen-resistant SKOV3 ovarian cancer cells. Induced by androgen.

Miscellaneous. Overexpression may promote MCF-7 cells proliferation. There is an approximate one-third increase of the invasive capacity of MACROD1-overexpressing cells. The expression of CDH1 is repressed by MACROD1. Further analysis demonstrates that MACROD1 inhibits CDH1 transactivation in a dose-dependent manner. Inhibition is abolished by estrogen deprivation, indicating that the down-regulation of CDH1 transcription by MACROD1 requires ESR1 mediation. Binding of ESR1 to the CDH1 promoter is antagonized by MACROD1, suggesting that MACROD1 could interfere with ESR1-mediated transcription. Knockdown of MACROD1 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as UXT and NCOA1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. MACROD1 knockdown does not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells.

Similarity. Belongs to the MacroD-type family. MacroD1/2-like subfamily.

RefSeq proteins (2): NP_001397948, NP_054786* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002589	Macro_dom	Domain
IPR043472	Macro_dom-like	Homologous_superfamily

Pfam: PF01661

Enzyme classification (BRENDA):

• EC 3.1.1.106 — O-acetyl-ADP-ribose deacetylase (BRENDA: 7 organisms, 24 substrates, 11 inhibitors, 10 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2’’-O-ACETYL-ADP-D-RIBOSE	0.37–2.74	5
O-ACETYL-ADP-D-RIBOSE	0.107–2	4
3’’-O-ACETYL-ADP-D-RIBOSE	0.0043	1

Catalyzed reactions (Rhea), 5 shown:

• 4-O-(ADP-D-ribosyl)-L-aspartyl-[protein] + H2O = L-aspartyl-[protein] + ADP-D-ribose + H(+) (RHEA:54428)
• 2’’-O-acetyl-ADP-D-ribose + H2O = ADP-D-ribose + acetate + H(+) (RHEA:57060)
• 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = L-glutamyl-[protein] + ADP-D-ribose + H(+) (RHEA:58248)
• 3’’-O-acetyl-ADP-D-ribose + H2O = ADP-D-ribose + acetate + H(+) (RHEA:59244)
• alpha-NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:68792)

UniProt features (40 total): helix 13, mutagenesis site 8, strand 6, binding site 5, modified residue 4, chain 1, domain 1, cross-link 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2X47	X-RAY DIFFRACTION	1.7
6LH4	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQ69-F1	83.29	0.70

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): 100 (breakpoint for translocation to form runx1-macrod1)

Ligand- & substrate-binding residues (5): 159–161; 172–174; 179–184; 267–273; 306

Post-translational modifications (5): 129, 163, 138, 96, 103

Mutagenesis-validated functional residues (8):

Position	Phenotype
160	reduced enzyme activity.
167	reduced enzyme activity.
171	reduced enzyme activity. no significant effect on affinity for substrate.
174	slightly reduced adp-ribosyl hydrolase activity; when associated with a-184. reduces o-acetyl-adp-ribose deacetylase act
184	slightly reduced adp-ribosyl hydrolase activity; when associated with a-174. reduces o-acetyl-adp-ribose deacetylase act
188	reduced enzyme activity.
268	no significant effect on enzyme activity.
270	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 130 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, RNGTGGGC_UNKNOWN, MYOGENIN_Q6, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, chr11q13, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, BLALOCK_ALZHEIMERS_DISEASE_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_DNA_DAMAGE_RESPONSE, TGGNNNNNNKCCAR_UNKNOWN

GO Biological Process (4): DNA damage response (GO:0006974), purine nucleoside metabolic process (GO:0042278), protein de-ADP-ribosylation (GO:0051725), peptidyl-glutamate ADP-deribosylation (GO:0140291)

GO Molecular Function (6): hydrolase activity, acting on glycosyl bonds (GO:0016798), deacetylase activity (GO:0019213), O-acetyl-ADP-ribose deacetylase activity (GO:0061463), ADP-ribosylglutamate-[protein] hydrolase activity (GO:0140293), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
cellular response to stress	1
nucleoside metabolic process	1
purine-containing compound metabolic process	1
protein modification process	1
protein de-ADP-ribosylation	1
hydrolase activity	1
deacylase activity	1
deacetylase activity	1
carboxylic ester hydrolase activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MACROD1	OARD1	Q9Y530	847
MACROD1	ADPRS	Q9NX46	834
MACROD1	PARG	Q86W56	821
MACROD1	NUDT16	Q96DE0	690
MACROD1	PARP10	Q53GL7	661
MACROD1	ESR1	P03372	645
MACROD1	UXT	Q9UBK9	593
MACROD1	ART5	Q96L15	575
MACROD1	PARP3	Q9Y6F1	561
MACROD1	TRPT1	Q86TN4	546
MACROD1	PARP6	Q2NL67	543
MACROD1	PARP2	Q9UGN5	533
MACROD1	PARP16	Q8N5Y8	526
MACROD1	HPF1	Q9NWY4	521
MACROD1	PARP12	Q9H0J9	512

IntAct

46 interactions, top by confidence:

A	B	Type	Score
EXOC3	EXOC5	psi-mi:“MI:0914”(association)	0.790
KRT31	HGS	psi-mi:“MI:0914”(association)	0.780
MACROD1	ESR1	psi-mi:“MI:0915”(physical association)	0.690
ESR1	MACROD1	psi-mi:“MI:0915”(physical association)	0.690
MACROD1	KRT18	psi-mi:“MI:0915”(physical association)	0.650
MACROD1	KRT18	psi-mi:“MI:0914”(association)	0.650
KRT18	MACROD1	psi-mi:“MI:0915”(physical association)	0.650
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
MACROD1	PARP1	psi-mi:“MI:0914”(association)	0.620
MACROD1	PARP1	psi-mi:“MI:0915”(physical association)	0.620
RELA	MACROD1	psi-mi:“MI:0915”(physical association)	0.600
MACROD1	RELA	psi-mi:“MI:0914”(association)	0.600
RELA	MACROD1	psi-mi:“MI:0403”(colocalization)	0.600
KPNA1	MACROD1	psi-mi:“MI:0915”(physical association)	0.560
LRRC15	TCAF2	psi-mi:“MI:0914”(association)	0.560
EPHA2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
NFKBIA	MACROD1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (85): MACROD1 (Affinity Capture-Western), MACROD1 (Affinity Capture-Western), IKBKG (Affinity Capture-Western), PARP1 (Affinity Capture-Western), XRCC6 (Affinity Capture-MS), XRCC5 (Affinity Capture-MS), PARP1 (Affinity Capture-MS), IKBKG (Affinity Capture-MS), IKBKB (Affinity Capture-MS), ERC1 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), HNRNPU (Affinity Capture-MS), CSTF3 (Affinity Capture-MS), YBX1 (Affinity Capture-MS), DHX9 (Affinity Capture-MS)

ESM2 similar proteins: A0A250YGJ5, A0A2K5TU92, A9SDL4, B2RZ55, B8ARK7, D3ZU57, D4ACP5, E1BRE2, E2RDZ6, F7EZ75, O94762, P23249, P38935, P40694, P52824, P59941, Q0P595, Q14147, Q1HG60, Q25337, Q2KHU5, Q3ZBQ0, Q4R834, Q5R6G3, Q5RBF1, Q5RJQ4, Q60560, Q68FX9, Q6DHI5, Q7XWV4, Q80SX8, Q8BKJ9, Q8IXJ6, Q8K2C6, Q8N6T7, Q8N8A6, Q8R104, Q8R216, Q8VDQ8, Q922B1

Diamond homologs: A0A166ACJ5, A0A559KX76, A1Z1Q3, A4W960, A7MG20, A7T167, A8AI35, B4T2X8, B5F961, B5RBF3, B5XXK9, B7LT90, C9Y0V8, D2TT52, D3RKJ0, D5CE05, E1PL40, E1SDF1, O28751, O59182, P0A8D6, P0A8D7, P0A8D8, P0DC28, P0DC29, P0DN70, P67341, P67342, P67343, P67344, Q0T5Z6, Q292F9, Q2KHU5, Q2KIX2, Q32E73, Q3UYG8, Q44020, Q4J9D2, Q5CZL1, Q5HIW9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3979 predictions. Top by Δscore:

Variant	Effect	Δscore
11:63998954:CCCA:C	donor_gain	1.0000
11:63999326:CTCA:C	donor_loss	1.0000
11:63999328:CACC:C	donor_loss	1.0000
11:63999329:A:AC	donor_gain	1.0000
11:63999329:AC:A	donor_gain	1.0000
11:63999330:C:CC	donor_gain	1.0000
11:63999330:CC:C	donor_gain	1.0000
11:63999400:GTAGC:G	acceptor_gain	1.0000
11:63999401:TAGC:T	acceptor_gain	1.0000
11:63999402:AGC:A	acceptor_gain	1.0000
11:63999403:GC:G	acceptor_gain	1.0000
11:63999403:GCC:G	acceptor_loss	1.0000
11:63999404:CC:C	acceptor_gain	1.0000
11:63999404:CCTG:C	acceptor_loss	1.0000
11:63999405:C:CC	acceptor_gain	1.0000
11:63999405:CTGAG:C	acceptor_loss	1.0000
11:63999411:C:CT	acceptor_gain	1.0000
11:63999635:C:A	donor_gain	1.0000
11:63999641:CCA:C	donor_gain	1.0000
11:63999760:ACGT:A	acceptor_gain	1.0000
11:63999761:CGT:C	acceptor_gain	1.0000
11:63999761:CGTC:C	acceptor_gain	1.0000
11:63999763:TC:T	acceptor_loss	1.0000
11:63999764:C:CA	acceptor_loss	1.0000
11:63999764:C:CC	acceptor_gain	1.0000
11:64000225:A:AC	donor_gain	1.0000
11:64000226:C:CC	donor_gain	1.0000
11:64000226:CA:C	donor_gain	1.0000
11:64000344:C:CC	acceptor_gain	1.0000
11:64151231:CCACT:C	donor_loss	1.0000

AlphaMissense

2078 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:63999760:A:T	V223D	0.999
11:63999029:C:G	R300P	0.998
11:64000319:G:T	A191D	0.998
11:64000331:A:T	I187N	0.998
11:63999010:G:C	F306L	0.997
11:63999010:G:T	F306L	0.997
11:63999012:A:G	F306L	0.997
11:63999690:G:C	C246W	0.997
11:64000232:G:T	A220D	0.997
11:64000320:C:G	A191P	0.997
11:64000331:A:C	I187S	0.997
11:64151250:A:T	I169N	0.997
11:64151253:G:T	A168D	0.997
11:63999531:A:C	F272L	0.996
11:63999531:A:T	F272L	0.996
11:63999533:A:G	F272L	0.996
11:63999559:G:T	A263E	0.996
11:63999678:A:C	S250R	0.996
11:63999678:A:T	S250R	0.996
11:63999680:T:G	S250R	0.996
11:63999691:C:T	C246Y	0.996
11:64000238:A:G	L218P	0.996
11:64000329:G:C	H188D	0.996
11:64000331:A:G	I187T	0.996
11:64151243:G:C	N171K	0.996
11:64151243:G:T	N171K	0.996
11:64151254:C:G	A168P	0.996
11:64152310:A:G	W128R	0.996
11:64152310:A:T	W128R	0.996
11:63999359:C:G	R288P	0.995

dbSNP variants (sampled 300 via entrez): RS1000004213 (11:64088296 C>T), RS1000005142 (11:64126970 G>A), RS1000042637 (11:64076537 G>A,C), RS1000049485 (11:64145557 G>C), RS1000055061 (11:64007712 C>T), RS1000058880 (11:64120804 GGA>G), RS1000064259 (11:64121094 G>A), RS1000075501 (11:64046752 A>G,T), RS1000087954 (11:64099027 G>A), RS1000091320 (11:64137039 G>A), RS1000111039 (11:64075171 C>A,T), RS1000113862 (11:64083623 G>A), RS1000124498 (11:64060193 C>A,T), RS1000150954 (11:64032817 G>A), RS1000166700 (11:64057719 T>C,G)

Disease associations

OMIM: gene MIM:610400 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): peripheral neuropathy (MONDO:0005244)

Orphanet (0):

HPO phenotypes

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

GWAS associations

65 associations (top):

Study	Trait	p-value
GCST002782_96	Waist-to-hip ratio adjusted for body mass index	3.000000e-11
GCST002782_97	Waist-to-hip ratio adjusted for body mass index	4.000000e-08
GCST002782_98	Waist-to-hip ratio adjusted for body mass index	6.000000e-10
GCST002782_99	Waist-to-hip ratio adjusted for body mass index	8.000000e-07
GCST002783_340	Body mass index	6.000000e-06
GCST004067_13	Hip circumference adjusted for BMI	7.000000e-06
GCST004067_208	Hip circumference adjusted for BMI	4.000000e-08
GCST004505_77	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	3.000000e-06
GCST004505_78	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	1.000000e-06
GCST004628_45	Immature fraction of reticulocytes	9.000000e-10
GCST008074_133	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-09
GCST008074_78	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-08
GCST008075_122	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-12
GCST008075_55	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-12
GCST008083_133	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-07
GCST008083_17	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-09
GCST008084_187	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-16
GCST008084_6	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-16
GCST008087_3	Triglyceride levels in current drinkers	3.000000e-06
GCST008087_99	Triglyceride levels in current drinkers	2.000000e-07
GCST008103_34	Bipolar disorder	6.000000e-08
GCST008862_10	Triacylglycerol 56:6 levels	8.000000e-07
GCST008971_91	Urate levels	1.000000e-06
GCST008972_139	Urate levels	4.000000e-41
GCST010136_47	Fruit consumption	9.000000e-10
GCST010512_10	Serum uric acid levels	7.000000e-22
GCST011334_8	Body mass index and triglycerides (pairwise)	1.000000e-10
GCST011336_7	Body mass index and HDL-C (pairwise)	8.000000e-11
GCST011345_16	Triglyceride levels	1.000000e-08
GCST011348_28	High density lipoprotein cholesterol levels	3.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004340	body mass index
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0007986	reticulocyte count
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004531	urate measurement
EFO:0008111	diet measurement
EFO:0004761	uric acid measurement
EFO:0010701	mean reticulocyte volume
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295934 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.05	Kd	900	nM	CHEMBL4226903

PubChem BioAssay actives

1 with measured affinity, of 22 total; 1 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
[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2S,3R,4S,5S)-3,4,5-trihydroxyoxolan-2-yl]methyl hydrogen phosphate	1390098: Binding affinity to human MDO1 by ITC	kd	0.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	4
Aflatoxin B1	affects expression, affects methylation, decreases expression	3
bisphenol A	decreases methylation, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
sodium arsenate	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, affects methylation	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Carbamazepine	affects expression	1
Citrulline	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methapyrilene	affects methylation	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4221661	Binding	Binding affinity to human MDO1 by ITC	Adenosine analogs bearing phosphate isosteres as human MDO1 ligands. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.