SIRT3

Summary

SIRT3 (sirtuin 3, HGNC:14931) is a protein-coding gene on chromosome 11p15.5, encoding NAD-dependent protein deacetylase sirtuin-3, mitochondrial (Q9NTG7). NAD-dependent protein deacetylase.

SIRT3 encodes a member of the sirtuin family of class III histone deacetylases, homologs to the yeast Sir2 protein. The encoded protein is found exclusively in mitochondria, where it can eliminate reactive oxygen species, inhibit apoptosis, and prevent the formation of cancer cells. SIRT3 has far-reaching effects on nuclear gene expression, cancer, cardiovascular disease, neuroprotection, aging, and metabolic control.

Source: NCBI Gene 23410 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 107 total
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012239

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14931
Approved symbol	SIRT3
Name	sirtuin 3
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	SIR2L3
Ensembl gene	ENSG00000142082
Ensembl biotype	protein_coding
OMIM	604481
Entrez	23410

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 27 protein_coding, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000382743, ENST00000524564, ENST00000525237, ENST00000525319, ENST00000525776, ENST00000526854, ENST00000528469, ENST00000528702, ENST00000529055, ENST00000529382, ENST00000529937, ENST00000530067, ENST00000531753, ENST00000532837, ENST00000532956, ENST00000534381, ENST00000852931, ENST00000852932, ENST00000852933, ENST00000852934, ENST00000852935, ENST00000852936, ENST00000852937, ENST00000852938, ENST00000852939, ENST00000852940, ENST00000852941, ENST00000852942, ENST00000852943, ENST00000934321, ENST00000934322, ENST00000934323, ENST00000934324, ENST00000941616, ENST00000941617

RefSeq mRNA: 16 — MANE Select: NM_012239 NM_001017524, NM_001370310, NM_001370312, NM_001370314, NM_001370315, NM_001370316, NM_001370317, NM_001370318, NM_001370319, NM_001370320, NM_001370321, NM_001370322, NM_001370323, NM_001370324, NM_001370325, NM_012239

CCDS: CCDS53590, CCDS7691, CCDS91392, CCDS91393, CCDS91394

Canonical transcript exons

ENST00000382743 — 7 exons

Exon	Start	End
ENSE00001493185	215030	216718
ENSE00001493204	236048	236342
ENSE00003482617	218832	219041
ENSE00003551044	233343	233534
ENSE00003582960	224078	224239
ENSE00003625134	230452	230552
ENSE00003787814	232983	233215

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 94.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.0378 / max 43.1173, expressed in 1752 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117723	6.1988	1735
206069	0.8390	310

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	94.02	gold quality
apex of heart	UBERON:0002098	93.95	gold quality
left testis	UBERON:0004533	93.88	gold quality
right testis	UBERON:0004534	93.59	gold quality
right uterine tube	UBERON:0001302	93.01	gold quality
right lobe of liver	UBERON:0001114	92.90	gold quality
nucleus accumbens	UBERON:0001882	92.84	gold quality
caudate nucleus	UBERON:0001873	92.66	gold quality
adenohypophysis	UBERON:0002196	92.38	gold quality
anterior cingulate cortex	UBERON:0009835	92.30	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.30	gold quality
cingulate cortex	UBERON:0003027	92.25	gold quality
pituitary gland	UBERON:0000007	92.09	gold quality
putamen	UBERON:0001874	91.86	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.50	gold quality
cerebellar hemisphere	UBERON:0002245	91.35	gold quality
testis	UBERON:0000473	91.27	gold quality
cerebellar cortex	UBERON:0002129	91.24	gold quality
metanephros cortex	UBERON:0010533	91.02	gold quality
heart left ventricle	UBERON:0002084	90.62	gold quality
right atrium auricular region	UBERON:0006631	90.46	gold quality
body of pancreas	UBERON:0001150	90.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.45	gold quality
left ovary	UBERON:0002119	90.35	gold quality
right lobe of thyroid gland	UBERON:0001119	90.26	gold quality
cardiac ventricle	UBERON:0002082	90.15	gold quality
right ovary	UBERON:0002118	90.12	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.10	gold quality
left lobe of thyroid gland	UBERON:0001120	89.99	gold quality
cerebellum	UBERON:0002037	89.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOXO3	Unknown

Upstream regulators (CollecTRI, top): ESRRA, FOXO3, PPARG, SIRT5

miRNA regulators (miRDB)

61 targeting SIRT3, 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-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-491-5P	99.13	65.98	1468

Literature-anchored findings (GeneRIF, showing 40)

• hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. hSIRT3 is proteolytically processed in the mitochondrial matrix to a 28-kD product. (PMID:12186850)
• the role of SIRT3 in mitochondria involves protein deacetylation (PMID:12374852)
• the underexpression of a human sirtuin gene seems to be detrimental for longevity as it occurs in model organisms. (PMID:15676284)
• The SIRT3 5’ flanking region encompasses the PSMD13 gene encoding the p40.5 regulator subunit of the 26S proteasome. (PMID:17059877)
• Using a highly specific antibody against the N terminus of SirT3, we found that SirT3 is transported from the nucleus to the mitochondria upon cellular stress. (PMID:17437997)
• Pro-apoptotic functioning of SIRT3 is selectively coupled with defined pathways regulating cell survival under basal conditions. (PMID:17957139)
• full-length mouse SIRT3 protein is a 37 kDa mitochondrial precursor protein contrary to the previously suggested 29 kDa protein (PMID:18215119)
• Results describe the substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. (PMID:18680753)
• These studies underscore an essential role of SIRT3 in the survival of cardiomyocytes in stress situations. (PMID:18710944)
• Data propose that SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway. (PMID:18781224)
• results show SIRT1 & SIRT3 are localized in different intracellular compartments, mainly nuclei & mitochondria; identified novel SIRT protein interacting partners which may be critically involved in anti-aging & metabolic regulatory activities of sirtuins (PMID:19343720)
• the acetylated peptide is the first substrate to bind to SIRT3, before NAD(+). (PMID:19535340)
• Results established that GATA2 and AP-1 Activator elements c-Jun/c-Fos act additively in modulating the SIRT3-VNTR enhancer function. (PMID:19714312)
• These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor. (PMID:20129246)
• SIRT3 (sirtuin3) reduces lipid accumulation via AMP-Activated Protein Kinase activation in human hepatic cells (PMID:20132432)
• Report the impact of SIRT3 SNPs on protein stability and cellular energy metabolism. (PMID:20198340)
• These studies identify a complex relationship between p53, SirT3, and chaperoning factor BAG-2 that may link the salvaging and quality assurance of the p53 protein for control of cellular fate independent of transcriptional activity. (PMID:20463968)
• Results indicate that Sirt3 functions as a downstream target gene of PGC-1alpha and mediates the PGC-1alpha effects on cellular ROS production and mitochondrial biogenesis. (PMID:20661474)
• SIRT3 substrates are involved in several metabolic pathways such as the urea cycle, ATP synthesis, and fatty acid oxidation. (PMID:20945913)
• SirT3 acts to suppress the growth of tumors, at least in part through its ability to suppress ROS and HIF-1alpha. (PMID:21358671)
• SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1alpha target genes. (PMID:21397863)
• Human rSIRT3 was treated with 4-Hydroxynonenal, an endogenous product of lipid peroxidation to identify modified residues using nLC-MS/MS. (PMID:21449565)
• Mitochondrial deacetylase SIRT3 binds to, deacetylates and activates SOD2 (PMID:21566644)
• Data show that Sirt1 and Sirt3 act on homologous substrates based on their evolutionary relationship. (PMID:21701047)
• Studies indicate that sirtuin 3 (Sirt3) as a genomically expressed, mitochondrial localized tumor suppressor. (PMID:22016654)
• Ethanol-induced eNOS activation in HAECs may be dependent on ALDH2 hyperacetylation by SIRT3 inactivation. (PMID:22155639)
• The expression of the SIRT3 gene was down-regulated in cybrids harboring mtDNA of the J haplogroup. (PMID:22326535)
• SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status (PMID:22416140)
• NAD(+)-dependent SIRT deacetylase has a role in regulating the expression of mitochondrial steroidogenic P450 (PMID:22585829)
• SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis.( (PMID:22589271)
• SIRT3 inhibits mitochondrial permeability transition and loss of membrane potential by preventing HKII binding to the mitochondria and increases carbonic anhydrase VB, thereby preventing intracellular acidification. (PMID:22595756)
• these data suggests that Sirt3 may play an important role in hepatocellular carcinoma development and progression. Sirt3 overexpression upregulated p53 protein level through downregulating Mdm2 and thereby slowing p53 degradation. (PMID:22609775)
• Receptor-interacting protein (RIP) and Sirtuin-3 (SIRT3) are on opposite sides of anoikis and tumorigenesis. (PMID:22674009)
• The present study demonstrates a sex-specific effect of genetic variants in UCP1 and SIRT3 on cIMT (PMID:22750084)
• nuclear full-length (FL) SIRT3 is subjected to rapid degradation under conditions of cellular stress, including oxidative stress and UV irradiation, whereas the mitochondrial processed form is unaffected (PMID:23045395)
• Sirt3 physically interacted with the OSCP and led to its subsequent deacetylation. (PMID:23046812)
• Studies indicate that SIRT1, SIRT3 and SIRT6 are induced by calorie restriction conditions and are considered anti-aging molecules. (PMID:23075334)
• These data suggest a role for SIRT3 in mechanisms sensing and tackling reactive oxygen species- and Alzheimer’s disease-mediated mitochondrial stress. (PMID:23139766)
• SIRT3 is decreased in HCC and is a novel unfavorable marker for prognosis of patients with this fatal disease. (PMID:23272146)
• Data suggest that SIRT3 expression is markedly decreased in islets isolated from type 2 diabetes patients (compared to islets from normal subjects); down-regulation of beta cell SIRT3 level seems key step in onset of beta cell dysfunction. (PMID:23397292)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sirt3	ENSDARG00000035819
mus_musculus	Sirt3	ENSMUSG00000025486
rattus_norvegicus	Sirt3	ENSRNOG00000013828

Paralogs (6): SIRT2 (ENSG00000068903), SIRT6 (ENSG00000077463), SIRT4 (ENSG00000089163), SIRT1 (ENSG00000096717), SIRT5 (ENSG00000124523), SIRT7 (ENSG00000187531)

Protein

Protein identifiers

NAD-dependent protein deacetylase sirtuin-3, mitochondrial — Q9NTG7 (reviewed: Q9NTG7)

Alternative names: NAD-dependent protein delactylase sirtuin-3, Regulatory protein SIR2 homolog 3, SIR2-like protein 3

All UniProt accessions (10): Q9NTG7, B7WNN4, E9PIT6, E9PJS6, E9PK80, E9PM52, E9PM75, E9PN58, E9PNA0, E9PR48

UniProt curated annotations — full annotation on UniProt →

Function. NAD-dependent protein deacetylase. Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues. Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA, MRPL12 and the ATP synthase subunit ATP5PO. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels. In response to metabolic stress, deacetylates transcription factor FOXO3 and recruits FOXO3 and mitochondrial RNA polymerase POLRMT to mtDNA to promote mtDNA transcription. Acts as a regulator of ceramide metabolism by mediating deacetylation of ceramide synthases CERS1, CERS2 and CERS6, thereby increasing their activity and promoting mitochondrial ceramide accumulation. Regulates hepatic lipogenesis. Uses NAD(+) substrate imported by SLC25A47, triggering downstream activation of PRKAA1/AMPK-alpha signaling cascade that ultimately downregulates sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance. In addition to protein deacetylase activity, also acts as a protein-lysine deacylase by recognizing other acyl groups, such as benzoyl and lactoyl, leading to protein debenzoylation and delactylation, respectively. Catalyzes debenzoylation of PPIF and ACLY. Mediates delactylation of CCNE2 and ‘Lys-16’ of histone H4 (H4K16la).

Subunit / interactions. Upon metabolic stress, forms a complex composed of FOXO3, SIRT3 and mitochondrial RNA polymerase POLRMT; the complex is recruited to mtDNA in a SIRT3-dependent manner. Also forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT. Interacts with NDUFA9, ACSS1, IDH2 and GDH. Interacts with PCCA.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Widely expressed.

Post-translational modifications. Processed by mitochondrial processing peptidase (MPP) to give a 28 kDa product. Such processing is probably essential for its enzymatic activity.

Cofactor. Binds 1 zinc ion per subunit.

Miscellaneous. Has some ability to deacetylate histones in vitro, but seeing its subcellular location, this is unlikely in vivo.

Similarity. Belongs to the sirtuin family. Class I subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NTG7-1	1	yes
Q9NTG7-2	2

RefSeq proteins (16): NP_001017524, NP_001357239, NP_001357241, NP_001357243, NP_001357244, NP_001357245, NP_001357246, NP_001357247, NP_001357248, NP_001357249, NP_001357250, NP_001357251, NP_001357252, NP_001357253, NP_001357254, NP_036371* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003000	Sirtuin	Family
IPR026590	Ssirtuin_cat_dom	Domain
IPR026591	Sirtuin_cat_small_dom_sf	Homologous_superfamily
IPR029035	DHS-like_NAD/FAD-binding_dom	Homologous_superfamily
IPR050134	NAD-dep_sirtuin_deacylases	Family

Pfam: PF02146

Enzyme classification (BRENDA):

• EC 2.3.1.24 — sphingosine N-acyltransferase (BRENDA: 14 organisms, 68 substrates, 31 inhibitors, 18 Km, 0 kcat entries)
• EC 2.3.1.286 — protein acetyllysine N-acetyltransferase (BRENDA: 13 organisms, 147 substrates, 140 inhibitors, 18 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
NAD+	0.0161–0.4535	4
SPHINGOSINE	0.0011–0.171	3
NICOTINAMIDE	0.037–0.16	3
PALMITOYL-COA	0.0124–0.141	2
SPHINGANINE	0.023–0.144	2
TETRACOSANOYL-COA	0.0546–0.0629	2
[HISTONE H3]-N6-ACETYL-L-LYSINE9	0.019–0.039	2
[HISTONE H3]-N6-MYRISTOYL-L-LYSINE9	0.0002–0.001	2
BEHENOYL-COA	0.299	1
HEXANOYL-COA	0.522	1
LAUROYL-COA	0.358	1
OLEOYL-COA	0.18	1
STEAROYL-COA	0.146	1
K382AZAKAC-CONTAINING P53 PEPTIDE	0.0109	1
K382KAC-CONTAINING P53 PEPTIDE	0.0718	1

Catalyzed reactions (Rhea), 3 shown:

• N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2’’-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein] (RHEA:43636)
• N(6)-[(S)-lactoyl]-L-lysyl-[protein] + NAD(+) + H2O = 2’’-O-(S)-lactoyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein] (RHEA:80287)
• N(6)-benzoyl-L-lysyl-[protein] + NAD(+) + H2O = 2’’-O-benzoyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein] (RHEA:83535)

UniProt features (58 total): helix 17, strand 12, binding site 8, mutagenesis site 7, turn 4, sequence variant 3, transit peptide 1, chain 1, modified residue 1, splice variant 1, domain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

44 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8ANC	X-RAY DIFFRACTION	1.11
4BN4	X-RAY DIFFRACTION	1.3
8V5U	X-RAY DIFFRACTION	1.48
9S27	X-RAY DIFFRACTION	1.6
8CCW	X-RAY DIFFRACTION	1.65
4JSR	X-RAY DIFFRACTION	1.7
8V2N	X-RAY DIFFRACTION	1.74
3GLR	X-RAY DIFFRACTION	1.8
5D7N	X-RAY DIFFRACTION	1.83
5Z94	X-RAY DIFFRACTION	1.9
4BVH	X-RAY DIFFRACTION	1.9
5BWN	X-RAY DIFFRACTION	1.94
5Z93	X-RAY DIFFRACTION	1.95
8CCZ	X-RAY DIFFRACTION	1.95
9CBT	X-RAY DIFFRACTION	1.95
4BV3	X-RAY DIFFRACTION	2
4BVB	X-RAY DIFFRACTION	2
4C78	X-RAY DIFFRACTION	2
4O8Z	X-RAY DIFFRACTION	2
8HLY	X-RAY DIFFRACTION	2
4BVE	X-RAY DIFFRACTION	2.05
3GLT	X-RAY DIFFRACTION	2.1
4C7B	X-RAY DIFFRACTION	2.1
4FZ3	X-RAY DIFFRACTION	2.1
4JT9	X-RAY DIFFRACTION	2.24
4JT8	X-RAY DIFFRACTION	2.26
4HD8	X-RAY DIFFRACTION	2.3
5BWO	X-RAY DIFFRACTION	2.38
8V15	X-RAY DIFFRACTION	2.4
4FVT	X-RAY DIFFRACTION	2.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NTG7-F1	76.27	0.60

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): 248 (proton acceptor)

Ligand- & substrate-binding residues (8): 283; 319–321; 344–346; 145–165; 228–231; 256; 259; 280

Post-translational modifications (1): 122

Mutagenesis-validated functional residues (7):

Position	Phenotype
7	suppresses targeting to mitochondrion; when associated with g-13 or q-13.
13	suppresses targeting to mitochondrion; when associated with g-7 or q-7.
17	reduces targeting to mitochondrion; when associated with g-21 or q-21.
21	reduces targeting to mitochondrion; when associated with g-17 or q-17.
99–100	abolishes processing by mpp (in vitro).
229	loss of function.
248	loss of protein deacetylase and delactylase.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9617629	Regulation of FOXO transcriptional activity by acetylation
R-HSA-9841251	Mitochondrial unfolded protein response (UPRmt)
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9614085	FOXO-mediated transcription

MSigDB gene sets: 240 (showing top): PID_HDAC_CLASSI_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, MODY_HIPPOCAMPUS_POSTNATAL, YANG_BREAST_CANCER_ESR1_LASER_UP, GOBP_POSITIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_INSULIN_SECRETION, GOBP_MACROMOLECULE_DEACYLATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_REGULATION_OF_OXIDOREDUCTASE_ACTIVITY, GOBP_HORMONE_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_CELL_CELL_SIGNALING

GO Biological Process (11): protein deacetylation (GO:0006476), aerobic respiration (GO:0009060), positive regulation of insulin secretion (GO:0032024), cellular response to stress (GO:0033554), peptidyl-lysine deacetylation (GO:0034983), negative regulation of ERK1 and ERK2 cascade (GO:0070373), positive regulation of superoxide dismutase activity (GO:1901671), positive regulation of catalase activity (GO:1902553), positive regulation of oxidative phosphorylation (GO:1903862), positive regulation of ceramide biosynthetic process (GO:2000304), negative regulation of reactive oxygen species metabolic process (GO:2000378)

GO Molecular Function (13): zinc ion binding (GO:0008270), histone deacetylase activity, NAD-dependent (GO:0017136), enzyme binding (GO:0019899), protein lysine deacetylase activity (GO:0033558), NAD-dependent protein lysine deacetylase activity (GO:0034979), sequence-specific DNA binding (GO:0043565), NAD+ binding (GO:0070403), NAD-dependent protein lysine delactylase activity (GO:0141208), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747), metal ion binding (GO:0046872), NAD binding (GO:0051287)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
FOXO-mediated transcription	2
Mitochondrial biogenesis	1
Cellular responses to stress	1
Citric acid cycle (TCA cycle)	1
Metabolism	1
Organelle biogenesis and maintenance	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Aerobic respiration and respiratory electron transport	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of oxidoreductase activity	2
NAD-dependent protein lysine deacetylase activity	2
intracellular membrane-bounded organelle	2
protein deacylation	1
cellular respiration	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
response to stress	1
cellular response to stimulus	1
protein deacetylation	1
peptidyl-lysine modification	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
superoxide dismutase activity	1
regulation of superoxide dismutase activity	1
catalase activity	1
regulation of oxidative phosphorylation	1
oxidative phosphorylation	1
positive regulation of cellular respiration	1
ceramide biosynthetic process	1
positive regulation of sphingolipid biosynthetic process	1
regulation of ceramide biosynthetic process	1
negative regulation of metabolic process	1
reactive oxygen species metabolic process	1
regulation of reactive oxygen species metabolic process	1
transition metal ion binding	1
histone deacetylase activity	1
protein binding	1
deacetylase activity	1
catalytic activity, acting on a protein	1
NAD-dependent protein lysine deacylase activity	1
DNA binding	1
anion binding	1
NAD binding	1
binding	1
catalytic activity	1
acyltransferase activity	1

Protein interactions and networks

STRING

3076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIRT3	NDUFA9	Q16795	960
SIRT3	FOXO3	O43524	930
SIRT3	PPARGC1A	Q9UBK2	920
SIRT3	ACSS1	Q9NUB1	920
SIRT3	ACADL	P28330	886
SIRT3	NMNAT2	Q9BZQ4	841
SIRT3	IDH2	P48735	825
SIRT3	F5H3C5	F5H3C5	823
SIRT3	SOD2	P04179	823
SIRT3	SIRT4	Q9Y6E7	809
SIRT3	TFAM	Q00059	798
SIRT3	TP53	P04637	749
SIRT3	XRCC6	P12956	719
SIRT3	NAMPT	P43490	713
SIRT3	UCP1	P25874	698

IntAct

76 interactions, top by confidence:

A	B	Type	Score
SKP2	CDK2	psi-mi:“MI:0914”(association)	0.900
ELP3	ELP1	psi-mi:“MI:0914”(association)	0.840
SDHA	SDHB	psi-mi:“MI:0914”(association)	0.820
SSBP3	LMX1B	psi-mi:“MI:0914”(association)	0.740
SIRT3	HSPD1	psi-mi:“MI:0914”(association)	0.730
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
SIRT4	IDE	psi-mi:“MI:0914”(association)	0.620
SKP2	SIRT3	psi-mi:“MI:0915”(physical association)	0.580
SIRT3	SKP2	psi-mi:“MI:0915”(physical association)	0.580
GRN	SIRT3	psi-mi:“MI:0915”(physical association)	0.560
SIRT3	OPA1	psi-mi:“MI:0915”(physical association)	0.540
SIRT3	OPA1	psi-mi:“MI:0407”(direct interaction)	0.540
MRPL42	GATC	psi-mi:“MI:0914”(association)	0.530
REG4	ATE1	psi-mi:“MI:0914”(association)	0.530
LSM14B	SEMG1	psi-mi:“MI:0914”(association)	0.530
MTG2	HSPD1	psi-mi:“MI:0914”(association)	0.530
ASS1	PC	psi-mi:“MI:0914”(association)	0.530
MRPS18C	MRPS14	psi-mi:“MI:0914”(association)	0.530
MARS2	CLUH	psi-mi:“MI:0914”(association)	0.530

BioGRID (148): SIRT3 (Affinity Capture-MS), SIRT3 (Affinity Capture-MS), SIRT3 (Affinity Capture-MS), DMC1 (Affinity Capture-MS), SIRT3 (Affinity Capture-MS), SIRT3 (Two-hybrid), MDM2 (Biochemical Activity), PDHA1 (Biochemical Activity), PDP1 (Biochemical Activity), SIRT3 (Affinity Capture-Western), PDHA1 (Affinity Capture-Western), PDP1 (Affinity Capture-Western), SIRT3 (Reconstituted Complex), SIRT3 (Affinity Capture-MS), SIRT3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9UVG7, A0A250YGJ5, A0A2K5TU92, A8NWP2, A9UVV1, B0X4N8, B2RZ55, E1BRE2, E2RDZ6, E9GD30, F4P804, F7DKV7, F7EZ75, O54747, P16081, P27967, P27968, P27969, P38681, P43100, P49102, P59941, Q0P595, Q0UI56, Q1JQC6, Q3ZBQ0, Q4PEJ3, Q5AW69, Q5HZN8, Q5R6G3, Q5RBF1, Q5RJQ4, Q68FX9, Q6DHI5, Q7ZVK3, Q8BKJ9, Q8IRR5, Q8IXJ6, Q8K2C6, Q8N6T7

Diamond homologs: A0A0G2JZ79, A8MBU4, B0RM75, B5YJW3, C1DBX3, C6A243, C8V3W5, E9GD30, O07595, O28597, O30124, O58669, O59923, O94640, P06700, P0CS88, P33294, P53685, P53686, P53687, Q21921, Q25337, Q4JBN2, Q4R834, Q4UZX0, Q54GV7, Q54LF0, Q54P49, Q54QE6, Q57V41, Q5A985, Q5AQ47, Q5AW69, Q5HM33, Q5KZE8, Q5L014, Q5RBF1, Q5RJQ4, Q5V4Q5, Q607X6

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
SIRT3	up-regulates	IDH2	deacetylation
SIRT5	“up-regulates quantity by expression”	SIRT3	“transcriptional regulation”
SIRT3	“down-regulates activity”	PDHA1	deacetylation
SIRT3	“up-regulates quantity by stabilization”	CYP11A1	deacetylation
CyclinB/CDK1	“up-regulates activity”	SIRT3	phosphorylation
CDK1	“up-regulates activity”	SIRT3	phosphorylation
FLT3	“down-regulates activity”	SIRT3	phosphorylation
SIRT3	“up-regulates activity”	SOD2	deacetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 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
Complex I biogenesis	7	22.7×	2e-06
Aerobic respiration and respiratory electron transport	11	19.1×	3e-09
Mitochondrial protein degradation	8	17.9×	1e-06
Respiratory electron transport	9	16.8×	4e-07
Mitochondrial ribosome-associated quality control	6	14.4×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
proton motive force-driven mitochondrial ATP synthesis	10	40.5×	3e-11
mitochondrial electron transport, NADH to ubiquinone	6	33.1×	5e-06
aerobic respiration	8	30.5×	6e-08
mitochondrial translation	5	13.4×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	83
Likely benign	7
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1508 predictions. Top by Δscore:

Variant	Effect	Δscore
11:218834:T:A	donor_gain	1.0000
11:224079:T:TA	donor_gain	1.0000
11:232977:GCTCA:G	donor_loss	1.0000
11:232978:CTCA:C	donor_loss	1.0000
11:232982:CCT:C	donor_gain	1.0000
11:232982:CCTCT:C	donor_gain	1.0000
11:233212:CGAT:C	acceptor_gain	1.0000
11:233216:C:CC	acceptor_gain	1.0000
11:216715:CAAG:C	acceptor_gain	0.9900
11:224054:C:CA	donor_gain	0.9900
11:224074:AAAC:A	donor_loss	0.9900
11:224075:AACC:A	donor_loss	0.9900
11:224076:AC:A	donor_loss	0.9900
11:224077:CC:C	donor_loss	0.9900
11:224236:CAGC:C	acceptor_gain	0.9900
11:224240:C:CC	acceptor_gain	0.9900
11:232970:A:AC	donor_gain	0.9900
11:232971:C:CC	donor_gain	0.9900
11:233211:GCGAT:G	acceptor_gain	0.9900
11:233212:CGATC:C	acceptor_gain	0.9900
11:233213:GAT:G	acceptor_gain	0.9900
11:233214:ATCT:A	acceptor_loss	0.9900
11:233215:TCT:T	acceptor_loss	0.9900
11:233216:C:A	acceptor_loss	0.9900
11:233217:T:A	acceptor_loss	0.9900
11:233498:C:T	acceptor_gain	0.9900
11:234746:A:AC	donor_gain	0.9900
11:216714:TCAAG:T	acceptor_gain	0.9800
11:216715:CAAGC:C	acceptor_gain	0.9800
11:216719:C:CC	acceptor_gain	0.9800

AlphaMissense

2572 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:224183:C:A	K288N	0.997
11:224183:C:G	K288N	0.997
11:233345:G:C	F157L	0.997
11:233345:G:T	F157L	0.997
11:233347:A:G	F157L	0.997
11:230513:C:T	G249E	0.996
11:233005:C:A	Q228H	0.996
11:233005:C:G	Q228H	0.996
11:233149:A:C	F180L	0.996
11:233149:A:T	F180L	0.996
11:233151:A:G	F180L	0.996
11:233369:G:C	S149R	0.996
11:233369:G:T	S149R	0.996
11:233371:T:G	S149R	0.996
11:224165:A:C	F294L	0.995
11:224165:A:T	F294L	0.995
11:224167:A:G	F294L	0.995
11:230491:G:C	C256W	0.995
11:230493:A:G	C256R	0.995
11:230513:C:A	G249V	0.995
11:233002:G:C	N229K	0.995
11:233002:G:T	N229K	0.995
11:233113:A:C	F192L	0.995
11:233113:A:T	F192L	0.995
11:233115:A:G	F192L	0.995
11:230492:C:T	C256Y	0.993
11:224185:T:C	K288E	0.992
11:224209:A:G	C280R	0.992
11:233343:C:G	R158T	0.992
11:233346:A:C	F157C	0.992

dbSNP variants (sampled 300 via entrez): RS1000072392 (11:214932 G>A,C), RS1000114269 (11:224914 G>A), RS1000363104 (11:220348 A>G), RS1000393950 (11:216268 T>C), RS1000433799 (11:221667 G>C), RS1000457614 (11:231508 A>G), RS1000487333 (11:231223 G>A), RS1000606867 (11:227888 C>T), RS1000756257 (11:236526 G>A), RS1000811385 (11:225289 G>A), RS1000932655 (11:217970 G>A), RS1000970460 (11:219031 A>G), RS1001174153 (11:215649 G>A), RS1001181308 (11:225671 A>G), RS1001202621 (11:238697 G>A,T)

Disease associations

OMIM: gene MIM:604481 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001027_3	Uterine fibroids	4.000000e-12
GCST002186_8	Platelet count	5.000000e-12
GCST002541_82	Menarche (age at onset)	4.000000e-08
GCST006462_34	Uterine fibroids	3.000000e-16
GCST010866_149	Coronary artery disease	3.000000e-11
GCST90002388_529	Lymphocyte count	8.000000e-15
GCST90002389_457	Lymphocyte percentage of white cells	1.000000e-09
GCST90002396_449	Mean reticulocyte volume	6.000000e-15
GCST90002397_555	Mean spheric corpuscular volume	3.000000e-28

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004703	age at menarche
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4461 (SINGLE PROTEIN), CHEMBL4742322 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 544,441 (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
CHEMBL113	CAFFEINE	4	200,591
CHEMBL1140	NIACINAMIDE	4	231,688
CHEMBL633	AMIODARONE	4	29,704
CHEMBL165	RESVERATROL	3	60,144
CHEMBL99	TRICHOSTATIN	1	22,314

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 3.5.1.- Histone deacetylases (HDACs)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 17 [PMID: 23570514]	Inhibition	8.49	pIC50
SIRT3 activator 5329973	Activation	7.58	pKd

Binding affinities (BindingDB)

3 measured of 4 human assays (4 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
phenyl N-[1-anilino-6-(heptanethioylamino)-1-oxohexan-2-yl]carbamate	IC50	310 nM	US-9359293: Methods of treatment using modulators of SIRT2
phenyl N-[1-anilino-6-(butanethioylamino)-1-oxohexan-2-yl]carbamate	IC50	2400 nM	US-9359293: Methods of treatment using modulators of SIRT2
phenyl N-[1-anilino-6-(ethanethioylamino)-1-oxohexan-2-yl]carbamate	IC50	30000 nM	US-9359293: Methods of treatment using modulators of SIRT2

ChEMBL bioactivities

240 potent at pChembl≥5 of 366 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.49	IC50	3.2	nM	CHEMBL2332041
8.40	IC50	4	nM	CHEMBL2332039
8.31	IC50	4.9	nM	CHEMBL2332037
8.30	IC50	5	nM	CHEMBL5614132
8.14	IC50	7.2	nM	CHEMBL2338810
8.12	IC50	7.6	nM	CHEMBL2332043
7.89	IC50	13	nM	CHEMBL2332042
7.64	IC50	23	nM	CHEMBL2332040
7.62	IC50	24	nM	CHEMBL2332038
7.55	IC50	28	nM	CHEMBL2338813
7.54	IC50	29	nM	CHEMBL2332044
7.52	IC50	30	nM	CHEMBL2338814
7.48	IC50	33	nM	CHEMBL2332055
7.41	IC50	39	nM	CHEMBL2332052
7.37	IC50	42.9	nM	CHEMBL3781397
7.37	IC50	43	nM	CHEMBL5612303
7.35	Ki	45	nM	CHEMBL3343652
7.34	IC50	46	nM	CHEMBL4438193
7.28	IC50	52.5	nM	CHEMBL3781226
7.26	IC50	55	nM	CHEMBL4446458
7.25	IC50	56	nM	CHEMBL2332045
7.24	IC50	57.2	nM	CHEMBL3781129
7.21	IC50	61	nM	CHEMBL2338812
7.17	IC50	67	nM	CHEMBL2338808
7.15	IC50	71	nM	CHEMBL3780552
7.11	IC50	77	nM	CHEMBL4447813
7.08	IC50	82.9	nM	CHEMBL3781485
7.04	IC50	92	nM	CHEMBL2338809
7.00	IC50	100	nM	CHEMBL5192844
6.99	IC50	102.6	nM	CHEMBL3780405
6.96	IC50	110	nM	CHEMBL2338816
6.96	IC50	110	nM	CHEMBL4457496
6.94	IC50	114	nM	CHEMBL5612571
6.92	IC50	120	nM	CHEMBL5201717
6.90	IC50	125	nM	CHEMBL5614219
6.89	IC50	130	nM	CHEMBL4438193
6.88	Ki	131	nM	CHEMBL3343652
6.82	IC50	150	nM	CHEMBL2338818
6.78	Ki	165	nM	CHEMBL3343652
6.77	EC50	170	nM	HONOKIOL
6.77	IC50	170	nM	CHEMBL5195052
6.77	IC50	170	nM	CHEMBL5182719
6.75	IC50	180	nM	CHEMBL4461872
6.72	IC50	190	nM	CHEMBL4446458
6.68	EC50	210	nM	CHEMBL4868328
6.68	IC50	210	nM	CHEMBL5192524
6.57	IC50	269.5	nM	CHEMBL3781645
6.55	IC50	280	nM	CHEMBL2332053
6.54	Kd	290	nM	HONOKIOL
6.52	IC50	300	nM	CHEMBL2332046

PubChem BioAssay actives

229 with measured affinity, of 1435 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
tert-butyl 5-[2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethylcarbamoyl]thiophene-2-carboxylate	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0032	uM
2-N-[2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl]-5-N-ethylthiophene-2,5-dicarboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0040	uM
3-N-[2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl]-1-N-ethylbenzene-1,3-dicarboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0049	uM
4-[4-[2-[[5-(ethylcarbamothioyl)thiophene-2-carbonyl]amino]ethyl]piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	2125801: Inhibition of recombinant human SIRT3 using Fluor de lys as substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0050	uM
4-[4-[2-(methanesulfonamido)ethyl]piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0072	uM
4-[4-[2-(thiophene-2-carbonylamino)ethyl]piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0076	uM
5-[2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethylcarbamoyl]thiophene-2-carboxylic acid	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0130	uM
2-N-[2-[4-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl]ethyl]-5-N-ethylthiophene-2,5-dicarboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0230	uM
3-N-[2-[4-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl]ethyl]-1-N-ethylbenzene-1,3-dicarboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0240	uM
4-[4-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0280	uM
tert-butyl N-[2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl]carbamate	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0290	uM
4-[4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0300	uM
4-[4-[2-(2,2-dimethylpropanoylamino)ethyl]piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0330	uM
4-[4-[2-(ethanethioylamino)ethyl]piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0390	uM
(2S,5S,8S,33S)-33-acetamido-2-(4-aminobutyl)-N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-5-[4-(ethanethioylamino)butyl]-3,6,14,17,24,27,34-heptaoxo-1,4,7,13,16,25,28-heptazacyclotetratriacontane-8-carboxamide	1286979: Inhibition of recombinant His6 tagged human SIRT3 using 0.105 mM H2N-HK-[N(epsilon)-acetyl-lysine]-LM-COOH as substrate measured after 10 mins HPLC analysis in presence of 3.5 mM beta-NAD+	ic50	0.0429	uM
4-[(1R,5S)-3-[[4-(trifluoromethyl)phenyl]carbamoyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]thieno[3,2-d]pyrimidine-6-carboxamide	2125801: Inhibition of recombinant human SIRT3 using Fluor de lys as substrate incubated for 30 mins by fluorescence based analysis	ic50	0.0430	uM
5-(5-benzamidonaphthalen-1-yl)oxypyridine-3-carboxamide	1167221: Competitive inhibition of catalytically active human SIRT3 (102 to 399 amino acids) expressed in Escherichia coli BL21 (DE3) cells using varying (Ac)RHKK(Ac)-AMC substrate by fluorescence assay based Morrison’s equation based enzyme kinetic analysis	ki	0.0450	uM
(2S)-2-[[(2S,3S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-N-[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-6-(tetradecanethioylamino)hexanamide	1509510: Inhibition of recombinant human SIRT3 (118 to 399 residues) defatty-acylase activity expressed in Escherichia coli using SFP3 as substrate measured at 5 mins interval for 60 mins in presence of NAD+ by fluorescence assay	ic50	0.0460	uM
(2S,5S,8S,31S)-31-acetamido-2-(4-aminobutyl)-N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-5-[4-(ethanethioylamino)butyl]-3,6,14,17,22,25,32-heptaoxo-1,4,7,13,16,23,26-heptazacyclodotriacontane-8-carboxamide	1286979: Inhibition of recombinant His6 tagged human SIRT3 using 0.105 mM H2N-HK-[N(epsilon)-acetyl-lysine]-LM-COOH as substrate measured after 10 mins HPLC analysis in presence of 3.5 mM beta-NAD+	ic50	0.0525	uM
(2S)-2-[[(2S,3S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-N-[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-6-[[2-[4-[(4-hydroxyphenyl)diazenyl]phenyl]acetyl]amino]hexanamide	1509510: Inhibition of recombinant human SIRT3 (118 to 399 residues) defatty-acylase activity expressed in Escherichia coli using SFP3 as substrate measured at 5 mins interval for 60 mins in presence of NAD+ by fluorescence assay	ic50	0.0550	uM
4-[4-(2-acetamidoethyl)piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0560	uM
(2S,5S,8S,27S)-27-acetamido-2-(4-aminobutyl)-N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-5-[4-(ethanethioylamino)butyl]-3,6,14,21,28-pentaoxo-1,4,7,13,22-pentazacyclooctacosane-8-carboxamide	1286979: Inhibition of recombinant His6 tagged human SIRT3 using 0.105 mM H2N-HK-[N(epsilon)-acetyl-lysine]-LM-COOH as substrate measured after 10 mins HPLC analysis in presence of 3.5 mM beta-NAD+	ic50	0.0572	uM
4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0610	uM
4-[4-[3-(2,2-dimethylpropanoylamino)propyl]piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0670	uM
(2S,5S,8S,25S)-25-acetamido-2-(4-aminobutyl)-N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-5-[4-(ethanethioylamino)butyl]-3,6,14,19,26-pentaoxo-1,4,7,13,20-pentazacyclohexacosane-8-carboxamide	1286979: Inhibition of recombinant His6 tagged human SIRT3 using 0.105 mM H2N-HK-[N(epsilon)-acetyl-lysine]-LM-COOH as substrate measured after 10 mins HPLC analysis in presence of 3.5 mM beta-NAD+	ic50	0.0710	uM
(2S)-2-[[(2S,3S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-N-[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-6-[[2-(4-phenyldiazenylphenyl)acetyl]amino]hexanamide	1509510: Inhibition of recombinant human SIRT3 (118 to 399 residues) defatty-acylase activity expressed in Escherichia coli using SFP3 as substrate measured at 5 mins interval for 60 mins in presence of NAD+ by fluorescence assay	ic50	0.0770	uM
(2S,5S,8S,23S)-23-acetamido-2-(4-aminobutyl)-N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-5-[4-(ethanethioylamino)butyl]-3,6,14,17,24-pentaoxo-1,4,7,13,18-pentazacyclotetracosane-8-carboxamide	1286979: Inhibition of recombinant His6 tagged human SIRT3 using 0.105 mM H2N-HK-[N(epsilon)-acetyl-lysine]-LM-COOH as substrate measured after 10 mins HPLC analysis in presence of 3.5 mM beta-NAD+	ic50	0.0829	uM
4-[4-[2-(2,2-dimethylpropanoylamino)ethyl]piperazin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.0920	uM
8-[(1,3-diethyl-2,6-dioxo-7H-purin-8-yl)disulfanyl]-1,3-diethyl-7H-purine-2,6-dione	1873024: Inhibition of human SIRT3 (118 to 399 aa) expressed in Escherichia coli BL21 cells	ic50	0.1000	uM
(2S,5S,8S,29S)-29-acetamido-2-(4-aminobutyl)-N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-5-[4-(ethanethioylamino)butyl]-3,6,14,17,20,23,30-heptaoxo-1,4,7,13,16,21,24-heptazacyclotriacontane-8-carboxamide	1286979: Inhibition of recombinant His6 tagged human SIRT3 using 0.105 mM H2N-HK-[N(epsilon)-acetyl-lysine]-LM-COOH as substrate measured after 10 mins HPLC analysis in presence of 3.5 mM beta-NAD+	ic50	0.1026	uM
(2S)-2-[[(2S,3S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-N-[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-6-[[2-[4-[[4-(dimethylamino)phenyl]diazenyl]phenyl]acetyl]amino]hexanamide	1509510: Inhibition of recombinant human SIRT3 (118 to 399 residues) defatty-acylase activity expressed in Escherichia coli using SFP3 as substrate measured at 5 mins interval for 60 mins in presence of NAD+ by fluorescence assay	ic50	0.1100	uM
7-[4-[2-(2,2-dimethylpropanoylamino)ethyl]piperidin-1-yl]thieno[3,2-b]pyridine-2-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.1100	uM
4-[(1R,5S)-3-[(4-chlorophenyl)carbamoyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]thieno[3,2-d]pyrimidine-6-carboxamide	2125801: Inhibition of recombinant human SIRT3 using Fluor de lys as substrate incubated for 30 mins by fluorescence based analysis	ic50	0.1140	uM
8-[(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)disulfanyl]-1,3-dipropyl-7H-purine-2,6-dione	1873024: Inhibition of human SIRT3 (118 to 399 aa) expressed in Escherichia coli BL21 cells	ic50	0.1200	uM
4-[(1R,5S)-3-[(3,4-dichlorophenyl)carbamoyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]thieno[3,2-d]pyrimidine-6-carboxamide	2125801: Inhibition of recombinant human SIRT3 using Fluor de lys as substrate incubated for 30 mins by fluorescence based analysis	ic50	0.1250	uM
4-[4-[2-(2,2-dimethylpropanoylamino)ethyl]piperidin-1-yl]-7-methylthieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.1500	uM
3-ethyl-8-[[3-ethyl-2,6-dioxo-1-(2-phenylethyl)-7H-purin-8-yl]disulfanyl]-1-(2-phenylethyl)-7H-purine-2,6-dione	1873024: Inhibition of human SIRT3 (118 to 399 aa) expressed in Escherichia coli BL21 cells	ic50	0.1700	uM
3-ethyl-8-[[3-ethyl-1-(oxan-4-ylmethyl)-2,6-dioxo-7H-purin-8-yl]disulfanyl]-1-(oxan-4-ylmethyl)-7H-purine-2,6-dione	1873024: Inhibition of human SIRT3 (118 to 399 aa) expressed in Escherichia coli BL21 cells	ic50	0.1700	uM
2-(4-hydroxy-3-prop-2-enylphenyl)-4-prop-2-enylphenol	1780359: Activation of recombinant human SIRT3 assessed as lysyl deacetylase activity using (Gln-Pro-Lys-Lys(Ac)) peptide substrate by fluorescent assay	ec50	0.1700	uM
(2S)-2-[[(2S,3S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-N-[(2S)-1-[[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-6-[[2-[4-[[4-(diethylamino)phenyl]diazenyl]phenyl]acetyl]amino]hexanamide	1509510: Inhibition of recombinant human SIRT3 (118 to 399 residues) defatty-acylase activity expressed in Escherichia coli using SFP3 as substrate measured at 5 mins interval for 60 mins in presence of NAD+ by fluorescence assay	ic50	0.1800	uM
(2-butyl-1-benzofuran-3-yl)-[3,5-diiodo-4-(3-pyrrolidin-1-ylpropoxy)phenyl]methanone	1780359: Activation of recombinant human SIRT3 assessed as lysyl deacetylase activity using (Gln-Pro-Lys-Lys(Ac)) peptide substrate by fluorescent assay	ec50	0.2100	uM
3-ethyl-8-[[3-ethyl-1-[2-(4-methoxyphenyl)ethyl]-2,6-dioxo-7H-purin-8-yl]disulfanyl]-1-[2-(4-methoxyphenyl)ethyl]-7H-purine-2,6-dione	1873024: Inhibition of human SIRT3 (118 to 399 aa) expressed in Escherichia coli BL21 cells	ic50	0.2100	uM
(2S)-2-[[(2S)-2-acetamido-3-(1H-imidazol-5-yl)propanoyl]amino]-6-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-(ethanethioylamino)-1-oxohexan-2-yl]hexanamide	1286979: Inhibition of recombinant His6 tagged human SIRT3 using 0.105 mM H2N-HK-[N(epsilon)-acetyl-lysine]-LM-COOH as substrate measured after 10 mins HPLC analysis in presence of 3.5 mM beta-NAD+	ic50	0.2695	uM
4-[4-[2-(ethanethioylamino)ethyl]piperazin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.2800	uM
4-[4-(2-aminoethyl)piperidin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.3000	uM
(2S)-2,6-diacetamido-N-[(2S)-1-[[(2S)-1-amino-1-oxo-4-phenylbutan-2-yl]amino]-6-(ethanethioylamino)-1-oxohexan-2-yl]hexanamide	1242835: Inhibition of human His6-tagged SIRT3 after 10 mins by HPLC analysis in presence of beta-NAD	ic50	0.3200	uM
4-[(1R,5S)-3-[(3-cyanophenyl)carbamoyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]thieno[3,2-d]pyrimidine-6-carboxamide	2125801: Inhibition of recombinant human SIRT3 using Fluor de lys as substrate incubated for 30 mins by fluorescence based analysis	ic50	0.3260	uM
(2S)-2,6-diacetamido-N-[(2S)-1-[[(2S)-3-acetamido-1-amino-1-oxopropan-2-yl]amino]-6-(ethanethioylamino)-1-oxohexan-2-yl]hexanamide	1242835: Inhibition of human His6-tagged SIRT3 after 10 mins by HPLC analysis in presence of beta-NAD	ic50	0.3600	uM
4-[4-[2-(methanesulfonamido)ethyl]piperazin-1-yl]thieno[3,2-d]pyrimidine-6-carboxamide	735748: Inhibition of human His-tagged SIRT3 (102 to 399) expressed in Escherichia coli BL21(DE3) assessed as inhibition of deacetylation of Ac-RHKKAcW-NH2 substrate preincubated for 20 mins measured after 30 mins by mass spectrophotometric analysis	ic50	0.3700	uM
3-ethyl-8-[[3-ethyl-1-(2-methylpropyl)-2,6-dioxo-7H-purin-8-yl]disulfanyl]-1-(2-methylpropyl)-7H-purine-2,6-dione	1873024: Inhibition of human SIRT3 (118 to 399 aa) expressed in Escherichia coli BL21 cells	ic50	0.4300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	increases acetylation, decreases acetylation, decreases reaction, decreases expression, increases activity (+4 more)	4
perfluorooctane sulfonic acid	increases expression, decreases expression	2
erastin	decreases reaction, increases expression	2
RSL3 compound	decreases reaction, increases expression	2
Acetylcysteine	decreases reaction, increases expression, decreases expression	2
Berberine	affects cotreatment, decreases expression, increases expression	2
Cisplatin	increases activity, increases reaction, decreases response to substance, decreases activity, decreases expression (+3 more)	2
Fluorides	increases abundance, increases expression, affects reaction, decreases acetylation, decreases activity (+3 more)	2
Glucose	increases expression, decreases expression, decreases reaction, increases acetylation	2
Niacinamide	affects cotreatment, decreases expression, decreases reaction	2
Sodium Fluoride	decreases expression, decreases reaction, affects reaction, decreases acetylation, increases abundance (+3 more)	2
GSK-J4	decreases expression	1
polyethylene glycol loxenatide	decreases expression, decreases reaction	1
polymarcine	decreases activity	1
diisononyl phthalate	decreases expression	1
trichostatin A	decreases expression, decreases reaction	1
hesperetin	affects binding	1
mancozeb	decreases activity	1
beta-lapachone	increases expression	1
sulforaphane	increases expression, decreases expression, increases reaction, increases phosphorylation	1
sodium arsenite	decreases expression	1
linalool	affects binding, decreases reaction, decreases expression	1
mangostin	decreases secretion, increases expression, affects reaction, decreases expression	1
butylbenzyl phthalate	decreases expression	1
4-hydroxy-2-nonenal	decreases activity, affects binding	1
oxophenylarsine	decreases expression, decreases reaction	1
propionic acid	increases expression	1
tris(chloroethyl)phosphate	decreases expression	1
hydroquinone	increases reaction, decreases degradation, increases expression, decreases expression, decreases reaction (+1 more)	1
baicalin	decreases expression, decreases reaction	1

ChEMBL screening assays

286 unique, capped per target: 277 binding, 6 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1044032	Binding	Inhibition of human recombinant SIRT3 after 60 mins by fluorimetric analysis	Identification of a cell-active non-peptide sirtuin inhibitor containing N-thioacetyl lysine. — Bioorg Med Chem Lett
CHEMBL4322655	ADMET	Inhibition of human sirtuin 3 at 25 uM relative to control	Structure-Reactivity Relationships on Substrates and Inhibitors of the Lysine Deacylase Sirtuin 2 from Schistosoma mansoni (SmSirt2). — J Med Chem
CHEMBL4839944	Functional	In vivo activation of SIRT3 in human MDA-MB-231 cells xenografted in BALB/c mouse assessed as decrease in acetylation of whole cell extract protein in tumor tissue at 25 to 100 mg/kg once daily measured up to 16 days by Western blot analysi	Structure-Guided Design of a Small-Molecule Activator of Sirtuin-3 that Modulates Autophagy in Triple Negative Breast Cancer. — J Med Chem

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A6D9	SEES3-1V human SIRT3, clone1	Embryonic stem cell	Male
CVCL_A6E0	SEES3-1V human SIRT3, clone2	Embryonic stem cell	Male
CVCL_A6E1	SEES3-1V human SIRT3, clone3	Embryonic stem cell	Male
CVCL_B8PE	Abcam HCT 116 SIRT3 KO	Cancer cell line	Male
CVCL_B9RS	Abcam A-549 SIRT3 KO	Cancer cell line	Male
CVCL_D9WL	Ubigene HT-29 SIRT3 KO	Cancer cell line	Female
CVCL_E0TE	Ubigene HeLaS3 SIRT3 KO	Cancer cell line	Female
CVCL_E1EP	Ubigene U-87 MG SIRT3 KO	Cancer cell line	Male
CVCL_TL30	HAP1 SIRT3 (-) 1	Cancer cell line	Male
CVCL_TL31	HAP1 SIRT3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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