SIRT6

Summary

SIRT6 (sirtuin 6, HGNC:14934) is a protein-coding gene on chromosome 19p13.3, encoding NAD-dependent protein deacylase sirtuin-6 (Q8N6T7). NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging.

This gene encodes a member of the sirtuin family of NAD-dependent enzymes that are implicated in cellular stress resistance, genomic stability, aging and energy homeostasis. The encoded protein is localized to the nucleus, exhibits ADP-ribosyl transferase and histone deacetylase activities, and plays a role in DNA repair, maintenance of telomeric chromatin, inflammation, lipid and glucose metabolism. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 51548 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 88 total — 1 likely-pathogenic
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_016539

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14934
Approved symbol	SIRT6
Name	sirtuin 6
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000077463
Ensembl biotype	protein_coding
OMIM	606211
Entrez	51548

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 8 protein_coding, 7 retained_intron, 2 nonsense_mediated_decay

ENST00000305232, ENST00000337491, ENST00000594279, ENST00000594341, ENST00000595670, ENST00000596119, ENST00000596298, ENST00000597896, ENST00000599365, ENST00000599394, ENST00000600540, ENST00000600938, ENST00000601069, ENST00000601488, ENST00000601571, ENST00000915977, ENST00000970129

RefSeq mRNA: 9 — MANE Select: NM_016539 NM_001193285, NM_001321058, NM_001321059, NM_001321060, NM_001321061, NM_001321062, NM_001321063, NM_001321064, NM_016539

CCDS: CCDS12122, CCDS54199, CCDS82275, CCDS82276

Canonical transcript exons

ENST00000337491 — 8 exons

Exon	Start	End
ENSE00001208778	4182474	4182563
ENSE00003464817	4175842	4175937
ENSE00003469162	4175028	4175151
ENSE00003548633	4179104	4179286
ENSE00003556122	4180782	4180909
ENSE00003594042	4174109	4174946
ENSE00003636504	4177079	4177138
ENSE00003685070	4175680	4175760

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 97.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.3637 / max 89.2489, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178418	10.0501	1804
178417	1.3136	972

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	97.24	gold quality
transverse colon	UBERON:0001157	93.02	gold quality
granulocyte	CL:0000094	92.17	gold quality
tendon of biceps brachii	UBERON:0008188	89.50	silver quality
small intestine Peyer’s patch	UBERON:0003454	89.10	gold quality
adenohypophysis	UBERON:0002196	89.02	gold quality
metanephros cortex	UBERON:0010533	88.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.33	gold quality
lower esophagus mucosa	UBERON:0035834	88.19	gold quality
body of pancreas	UBERON:0001150	88.01	gold quality
cerebellar hemisphere	UBERON:0002245	87.97	gold quality
apex of heart	UBERON:0002098	87.87	gold quality
pituitary gland	UBERON:0000007	87.82	gold quality
spleen	UBERON:0002106	87.76	gold quality
cerebellar cortex	UBERON:0002129	87.75	gold quality
left adrenal gland cortex	UBERON:0035825	87.71	gold quality
left adrenal gland	UBERON:0001234	87.65	gold quality
right adrenal gland	UBERON:0001233	87.44	gold quality
rectum	UBERON:0001052	87.39	gold quality
right lobe of thyroid gland	UBERON:0001119	86.91	gold quality
right adrenal gland cortex	UBERON:0035827	86.90	gold quality
body of stomach	UBERON:0001161	86.87	gold quality
small intestine	UBERON:0002108	86.71	gold quality
monocyte	CL:0000576	86.17	gold quality
colon	UBERON:0001155	86.12	gold quality
leukocyte	CL:0000738	86.01	gold quality
mononuclear cell	CL:0000842	85.99	gold quality
adrenal cortex	UBERON:0001235	85.97	gold quality
esophagus mucosa	UBERON:0002469	85.96	gold quality
skin of leg	UBERON:0001511	85.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.62

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
ISG15	Repression
TP53	Repression

Upstream regulators (CollecTRI, top): FOS, FOXO3, NRF1

miRNA regulators (miRDB)

18 targeting SIRT6, 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-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-483-3P	97.77	64.95	731
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-6747-5P	96.17	64.99	743

Literature-anchored findings (GeneRIF, showing 40)

• Levels of the mammalian sirtuin, SIRT6, increased upon nutrient deprivation in cultured cells, in mice after fasting, and in rats fed a calorie-restricted diet. (PMID:18242175)
• the first identification of a physiological enzymatic activity of SIRT6 (as histone H3 lysine 9 deacetylase), and linking chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome (PMID:18337721)
• suggests similarities in the molecular mechanisms by which SIRT6 and WRN may prevent premature aging-like phenotypes (PMID:18388907)
• Study identifies H3K56Ac as a novel substrate for SIRT6, a role for SIRT6 in modulating this chromatin mark at telomeric chromatin. H3K56Ac levels in human cells are differentially regulated at telomeres and globally in response to cell cycle arrest. (PMID:19625767)
• SIRT6 associates dynamically with chromatin in response to DNA damage, and stabilizes the DNA double-strand break (DSB) repair factor, DNA-dependent protein kinase (DNA-PK), at DSBs. (PMID:20157594)
• These findings suggest that accelerated epithelial senescence plays a role in idiopathic pulmonary fibrosis pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6. (PMID:21224216)
• This study suggested that altered SIRT1, 2 and 6 expression is state-dependent and might be associated with the pathogenesis and/or pathophysiology of mood disorders. (PMID:21349544)
• SIRT6 could act as an NAD(+) metabolite sensor (PMID:21362626)
• The 25% CR diet increased the expression of both SIRT1 and SIRT6 in the ovary. (PMID:21502801)
• results indicate that SIRT6 physically associates with PARP1 and mono-ADP-ribosylates PARP1 on lysine residue 521, stimulating PARP1 poly-ADP-ribosylase activity and enhancing DSB repair under oxidative stress (PMID:21680843)
• SIRT6 is important for maintaining telomeric chromatin structure that is required for silencing of nearby genes. (PMID:21847107)
• SIRT6 overexpression selectively kills cancer cells. (PMID:21900744)
• SIRT6 knockdown in HDFs influence the synthesis and degradation of collagen by hyperactive NF-kappaB signalling, which leads to a decrease in dermal collagen fibrils. SIRT6 may therefore play an important role in the process of skin anti-aging. (PMID:21981042)
• observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque (PMID:22087257)
• in TLR4-stimulated promonocytes SirT1 and SirT 6 support a switch from increased glycolysis to increased fatty acid oxidation as early inflammation converts to late inflammation. (PMID:22700961)
• Sirt6 was enriched in the nucleolus in the G 1 phase of the cell cycle, while S phase nucleoli were almost entirely free of Sirt6. (PMID:22743824)
• Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence. (PMID:22753495)
• We observed that overexpression of SIRT6 had little influence on NFkappaB-dependent genes, but overexpression of the catalytically inactive mutant affected gene expression in developmental pathways. (PMID:22792191)
• Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. (PMID:23041974)
• Studies indicate that SIRT1, SIRT3 and SIRT6 are induced by calorie restriction conditions and are considered anti-aging molecules. (PMID:23075334)
• NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses (PMID:23086953)
• Results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation, vascular remodelling, and angiogenesis. (PMID:23132960)
• SIRT6 plays a role in regulating the terminal effector pathways of human labor and delivery via the NFKB pathway. (PMID:23136298)
• SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence. (PMID:23201774)
• By using a combination of in vitro and in vivo studies, as well as data from several human cancer databases, study demonstrated that loss of SIRT6 leads to tumorigenesis, and its expression is selectively downregulated in several human cancers. (PMID:23217706)
• SIRT6 is upregulated in both paclitaxel-resistant and epirubicin-resistant MCF-7 cells. (PMID:23514751)
• Sirtuin-6-dependent genetic and epigenetic alterations are associated with poor clinical outcome in hepatocellular carcinoma patients. (PMID:23526469)
• the crystal structure of SIRT6 reveals a large hydrophobic pocket that can accommodate long-chain fatty acyl groups; SIRT6 is an enzyme that controls protein lysine fatty acylation (PMID:23552949)
• Data indicate that miR-766 regulates SIRT6 expression posttranscriptionally. (PMID:23653361)
• SIRT6 is a direct target of miR-34a in primary human keratinocytes and its down-modulation is sufficient to reproduce miR-34a pro-differentiation effects. (PMID:23860128)
• Endotoxin and tumor necrosis factor-alpha suppressed SIRT1, SIRT3, and SIRT6 expression in human monocytes (PMID:23928404)
• Tissue micro-array studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cycle, increased apoptosis, elevated DNA damage level and decrease in BCL2 gene expression. (PMID:23982738)
• CHIP noncanonically ubiquitinates SirT6 at K170, which stabilizes SirT6 and prevents SirT6 canonical ubiquitination by other ubiquitin ligases. (PMID:24043303)
• Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. (PMID:24052263)
• our study reveals putative means of regulation of SIRT6 functions via interactions and modifications, providing an important resource for future studies on the molecular mechanisms underlying sirtuin functions. (PMID:24163442)
• Extended analysis of the SIRT6 interaction with G3BP1, a master stress response factor, uncovers an unexpected role and mechanism of SIRT6 in regulating stress granule assembly and cellular stress resistance. (PMID:24169447)
• REVIEW: current information regarding the molecular and physiological relevance of SIRT6 in the context of epigenetics, metabolism and disease (PMID:24171769)
• Overexpression of Sirt6 in the HepG2 HCC cell line exhibited antitumor effects through the induction of apoptosis and the inhibition of the ERK1/2 signaling pathway. (PMID:24366394)
• SIRT6 expression decreased in COPD lung homogenates correlating with lung function tests. Overexpression induced autophagy. SIRT6 affects CSE-induced HBEC senescence via autophagy regulation attributed to attenuation of IGF-Akt-mTOR signaling. (PMID:24367027)
• SIRT6 impacts upon cellular homeostasis by regulating DNA repair, telomere maintenance, and glucose and lipid metabolism, thus affecting diseases such as diabetes, obesity, heart disease, and cancer. (Review) (PMID:24438746)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sirt6	ENSDARG00000102963
mus_musculus	Sirt6	ENSMUSG00000034748
rattus_norvegicus	Sirt6	ENSRNOG00000006393
drosophila_melanogaster	Sirt6	FBGN0037802
caenorhabditis_elegans	sir-2.4	WBGENE00004803

Paralogs (6): SIRT2 (ENSG00000068903), SIRT4 (ENSG00000089163), SIRT1 (ENSG00000096717), SIRT5 (ENSG00000124523), SIRT3 (ENSG00000142082), SIRT7 (ENSG00000187531)

Protein

Protein identifiers

NAD-dependent protein deacylase sirtuin-6 — Q8N6T7 (reviewed: Q8N6T7)

Alternative names: NAD-dependent protein deacetylase sirtuin-6, Protein mono-ADP-ribosyltransferase sirtuin-6, Regulatory protein SIR2 homolog 6, SIR2-like protein 6

All UniProt accessions (6): Q8N6T7, M0QXA0, M0QZ09, M0R0B2, M0R1F6, M0R1N9

UniProt curated annotations — full annotation on UniProt →

Function. NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging. Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context. Acts as a key histone deacetylase by catalyzing deacetylation of histone H3 at ‘Lys-9’, ‘Lys-18’ and ‘Lys-56’ (H3K9ac, H3K18ac and H3K56ac, respectively), suppressing target gene expression of several transcription factors, including NF-kappa-B. Acts as an inhibitor of transcription elongation by mediating deacetylation of H3K9ac and H3K56ac, preventing release of NELFE from chromatin and causing transcriptional pausing. Involved in DNA repair by promoting double-strand break (DSB) repair: acts as a DSB sensor by recognizing and binding DSB sites, leading to (1) recruitment of DNA repair proteins, such as SMARCA5/SNF2H, and (2) deacetylation of histone H3K9ac and H3K56ac. SIRT6 participation to DSB repair is probably involved in extension of life span. Also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53. Specifically deacetylates H3K18ac at pericentric heterochromatin, thereby maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence. Involved in telomere maintenance by catalyzing deacetylation of histone H3 in telomeric chromatin, regulating telomere position effect and telomere movement in response to DNA damage. Required for embryonic stem cell differentiation by mediating histone deacetylation of H3K9ac. Plays a major role in metabolism by regulating processes such as glycolysis, gluconeogenesis, insulin secretion and lipid metabolism. Inhibits glycolysis via histone deacetylase activity and by acting as a corepressor of the transcription factor HIF1A, thereby controlling the expression of multiple glycolytic genes. Has tumor suppressor activity by repressing glycolysis, thereby inhibiting the Warburg effect. Also regulates glycolysis and tumorigenesis by mediating deacetylation and nuclear export of non-histone proteins, such as isoform M2 of PKM (PKM2). Acts as a negative regulator of gluconeogenesis by mediating deacetylation of non-histone proteins, such as FOXO1 and KAT2A/GCN5. Promotes beta-oxidation of fatty acids during fasting by catalyzing deacetylation of NCOA2, inducing coactivation of PPARA. Acts as a regulator of lipid catabolism in brown adipocytes, both by catalyzing deacetylation of histones and non-histone proteins, such as FOXO1. Also acts as a regulator of circadian rhythms, both by regulating expression of clock-controlled genes involved in lipid and carbohydrate metabolism, and by catalyzing deacetylation of PER2. The defatty-acylase activity is specifically involved in regulation of protein secretion. Has high activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as RRAS2 and TNF, thereby regulating their secretion. Also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170. Mono-ADP-ribosyltransferase activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription.

Subunit / interactions. Homodimer; binds to nucleosomes and DNA ends as a homodimer. Interacts with RELA; interferes with RELA binding to target DNA. Interacts with SMARCA5; promoting recruitment of SMARCA5/SNF2H to double-strand breaks (DSBs) sites. Interacts with the mTORC2 complex; preventing the ability of SIRT6 to deacetylate FOXO1. Interacts with the CLOCK-BMAL1 complex; recruited by the CLOCK-BMAL1 complex to regulate expression of clock-controlled genes. Interacts with CSNK2A2; preventing CSNK2A2 localization to the nucleus. (Microbial infection) Interacts with Kaposi’s sarcoma-associated herpesvirus protein VIRF-1; this interaction prevents SIRT6 deubiquitination by USP10.

Subcellular location. Nucleus. Chromosome. Telomere. Endoplasmic reticulum.

Post-translational modifications. Acetylated at Lys-33. Deacetylation at Lys-33 by SIRT1 promotes homomultimerization and binding to double-strand breaks (DSBs) sites. Phosphorylation at Ser-10 by MAPK8/JNK1 in response to oxidative stress stimulates the mono-ADP-ribosyltransferase activity on PARP1, leading to PARP1 recruitment to double-strand breaks (DSBs). Monoubiquitinated at Lys-170 by STUB1/CHIP, preventing its degradation by the proteasome. Deubiquitinated by USP10, also preventing its degradation by the proteasome. Sumoylated, leading to specifically decrease ability to deacetylate histone H3 at ‘Lys-56’ (H3K56ac).

Activity regulation. Compared to the defatty-acylase activity, the protein deacetylase activity is weak in vitro, and requires activation. The histone deacetylase activity is strongly activated upon binding to nucleosomes and chromatin in vivo. Two molecules of SIRT6 associate with the acidic patch of one nucleosome, while the C-terminal disordered region of SIRT6 associates with nucleosomal DNA, leading to efficient histone deacetylation. The protein-lysine deacetylase activity is also activated by long-chain free fatty-acids. The histone deacetylase activity is specifically repressed by long non-coding RNA lncPRESS1, which binds to SIRT6 and prevents chromatin-binding, thereby promoting stem cell pluripotency. Due to its essential role as tumor suppressor and involvement in DNA repair and life span, extensive research is made for the identification of small compound regulators of SIRT6. Nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) strongly stimulate the protein-lysine deacetylase activity by forming a covalent Michael adduct formation with Cys-18. Activated by UBCS039 (4-(pyridin-3-yl)-4,5- dihydropyrrolo[1,2-a]quinoxaline). Inhibited by non-selective hydroxamate trichostatin A inhibitor. Deacetylase activity is activated by fluvastatin and quercetin-based compounds. The protein-lysine deacetylase activity, but not the defatty-acylase activity, is specifically activated by MDL-800 and MDL-801 activators in vivo, enhancing the histone deacetylase and tumor suppressor activities. MDL-800 and MDL-801 selectively activate SIRT6 and not other members of the sirtuin family. The binding-mode of MDL-801 is however subject to discussion.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The C-terminal disordered region mediates non-specific DNA-binding.

Induction. Down-regulated in a number of cancers, such as pancreatic cancer or colon carcinomas. Post-transcriptionally regulated by miR-766. Expression is post-transcriptionally repressed by miR-122.

Polymorphism. Variability among SIRT6 alleles may account for variations in life span. A minor allele (rs107251) is associated with a decreased life span of 5.5 and 5.9 years when homozygous (TT); when compared to the major allele homozygous (CC) and heterozygous (CT) genotypes, respectively.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N6T7-1	1	yes
Q8N6T7-2	2

RefSeq proteins (9): NP_001180214, NP_001307987, NP_001307988, NP_001307989, NP_001307990, NP_001307991, NP_001307992, NP_001307993, NP_057623* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF02146

Enzyme classification (BRENDA):

• EC 2.3.1.B41 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Catalyzed reactions (Rhea), 5 shown:

• L-arginyl-[protein] + NAD(+) = N(omega)-(ADP-D-ribosyl)-L-arginyl-[protein] + nicotinamide + H(+) (RHEA:19149)
• N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2’’-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein] (RHEA:43636)
• L-lysyl-[protein] + NAD(+) = N(6)-(ADP-D-ribosyl)-L-lysyl-[protein] + nicotinamide + H(+) (RHEA:58220)
• N(6)-hexadecanoyl-L-lysyl-[protein] + NAD(+) + H2O = 2’’-O-hexadecanoyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein] (RHEA:70563)
• N(6)-tetradecanoyl-L-lysyl-[protein] + NAD(+) + H2O = 2’’-O-tetradecanoyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein] (RHEA:70567)

UniProt features (103 total): mutagenesis site 24, binding site 16, strand 16, helix 14, sequence variant 10, modified residue 6, turn 4, sequence conflict 3, compositionally biased region 2, initiator methionine 1, chain 1, domain 1, site 1, region of interest 1, cross-link 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

45 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6HOY	X-RAY DIFFRACTION	1.7
8AK8	X-RAY DIFFRACTION	1.73
6XV6	X-RAY DIFFRACTION	1.75
8CNO	X-RAY DIFFRACTION	1.75
9G7H	X-RAY DIFFRACTION	1.75
8AKD	X-RAY DIFFRACTION	1.76
8AKA	X-RAY DIFFRACTION	1.77
8AK7	X-RAY DIFFRACTION	1.81
8AKE	X-RAY DIFFRACTION	1.82
8AKG	X-RAY DIFFRACTION	1.82
8BL0	X-RAY DIFFRACTION	1.82
8AKC	X-RAY DIFFRACTION	1.83
6QCD	X-RAY DIFFRACTION	1.84
5MF6	X-RAY DIFFRACTION	1.87
8CNM	X-RAY DIFFRACTION	1.88
6QCE	X-RAY DIFFRACTION	1.9
6XV1	X-RAY DIFFRACTION	1.95
8AK9	X-RAY DIFFRACTION	1.95
5X16	X-RAY DIFFRACTION	1.97
8AKF	X-RAY DIFFRACTION	1.97
5MFP	X-RAY DIFFRACTION	1.98
8AK6	X-RAY DIFFRACTION	1.98
3K35	X-RAY DIFFRACTION	2
6QCJ	X-RAY DIFFRACTION	2.01
3PKI	X-RAY DIFFRACTION	2.04
8BL1	X-RAY DIFFRACTION	2.06
5MGN	X-RAY DIFFRACTION	2.07
5MFZ	X-RAY DIFFRACTION	2.1
6QCH	X-RAY DIFFRACTION	2.1
6XVG	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N6T7-F1	87.84	0.79

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 (2): 18 (formation of an covalent adduct with nitro-fatty acid activators); 133 (proton acceptor)

Ligand- & substrate-binding residues (16): 65; 71; 113; 133; 141; 144; 166; 177; 214; 216; 240; 242 …

Post-translational modifications (7): 2, 10, 33, 294, 303, 330, 170

Mutagenesis-validated functional residues (24):

Position	Phenotype
10	abolishes ability to promote dna repair and recruit parp1 to double-strand breaks (dsbs).
10	mimics phosphorylation; increased ability to promote dna repair and recruit parp1 to double-strand breaks (dsbs).
13	increased protein-lysine demyristoylase activity.
15	does not affect acetylation level.
17	does not affect acetylation level.
33	mimics acetylation, leading to impaired ability to recognize and bind double-strand breaks (dsbs) sites.
33	decreased acetylation level.
45	in aaa mutant; strongly decreased nucleosome-binding; when associated with 206-a–a-208.
56	abolished nad-dependent protein deacetylase, defatty-acylase and mono-adp-ribosyltransferase activities.
60	does not affect the nad-dependent protein defatty-acylase activity. abolished nad-dependent protein deacetylase and mono
65	does not affect the mono-adp-ribosyltransferase activity. abolished nad-dependent protein deacetylase and defatty-acylas
82	reduced mdl-800 and mdl-801 compounds-binding.
86	strongly reduced mdl-800 and mdl-801 compounds-binding.
86	slightly reduced mdl-800 and mdl-801 compounds-binding.
133	abolished nad-dependent protein deacetylase, deacylase and mono-adp-ribosyltransferase activities. impaired ability to r
170	decreased ubiquitination.
206–208	in aaa mutant; strongly decreased nucleosome-binding; when associated with a-45.
294	does not affect ability to promote dna repair.
296–300	in 4kr mutant; abolished sumoylation, leading to increased h3k56ac; when associated with r-316 and r-332.
303	does not affect ability to promote dna repair.
316	in 4kr mutant; abolished sumoylation, leading to increased h3k56ac; when associated with 296-r–r-300 and r-332.
330	does not affect ability to promote dna repair.
332	in 4kr mutant; abolished sumoylation, leading to increased h3k56ac; when associated with 296-r–r-300 and r-316.
338	does not affect ability to promote dna repair.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1912422	Pre-NOTCH Expression and Processing
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-73894	DNA Repair

MSigDB gene sets: 429 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, PID_HDAC_CLASSI_PATHWAY, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_MUSCLE_TISSUE_DEVELOPMENT

GO Biological Process (64): negative regulation of transcription by RNA polymerase II (GO:0000122), base-excision repair (GO:0006284), double-strand break repair (GO:0006302), chromatin remodeling (GO:0006338), protein deacetylation (GO:0006476), protein import into nucleus (GO:0006606), negative regulation of cell population proliferation (GO:0008285), determination of adult lifespan (GO:0008340), response to UV (GO:0009411), transposable element silencing (GO:0010526), regulation of double-strand break repair via homologous recombination (GO:0010569), regulation of lipid metabolic process (GO:0019216), pericentric heterochromatin formation (GO:0031508), subtelomeric heterochromatin formation (GO:0031509), protein destabilization (GO:0031648), positive regulation of insulin secretion (GO:0032024), positive regulation of telomere maintenance (GO:0032206), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), circadian regulation of gene expression (GO:0032922), negative regulation of transcription elongation by RNA polymerase II (GO:0034244), ketone biosynthetic process (GO:0042181), negative regulation of protein import into nucleus (GO:0042308), glucose homeostasis (GO:0042593), regulation of circadian rhythm (GO:0042752), positive regulation of fat cell differentiation (GO:0045600), negative regulation of gluconeogenesis (GO:0045721), negative regulation of gene expression, epigenetic (GO:0045814), negative regulation of glycolytic process (GO:0045820), negative regulation of D-glucose import across plasma membrane (GO:0046325), positive regulation of protein export from nucleus (GO:0046827), positive regulation of fibroblast proliferation (GO:0048146), regulation of protein secretion (GO:0050708), regulation of lipid catabolic process (GO:0050994), protein delipidation (GO:0051697), cardiac muscle cell differentiation (GO:0055007), positive regulation of cold-induced thermogenesis (GO:0120162), negative regulation of protein localization to chromatin (GO:0120186), positive regulation of protein localization to chromatin (GO:0120187), DNA repair-dependent chromatin remodeling (GO:0140861), positive regulation of stem cell population maintenance (GO:1902459)

GO Molecular Function (34): DNA binding (GO:0003677), chromatin binding (GO:0003682), damaged DNA binding (GO:0003684), transcription corepressor activity (GO:0003714), NAD+ poly-ADP-ribosyltransferase activity (GO:0003950), zinc ion binding (GO:0008270), nucleotidyltransferase activity (GO:0016779), histone deacetylase activity, NAD-dependent (GO:0017136), chromatin DNA binding (GO:0031490), nucleosome binding (GO:0031491), histone H3K9 deacetylase activity, hydrolytic mechanism (GO:0032129), NAD-dependent protein lysine deacetylase activity (GO:0034979), protein homodimerization activity (GO:0042803), histone H3K9 deacetylase activity, NAD-dependent (GO:0046969), NAD+ binding (GO:0070403), histone H3K18 deacetylase activity, NAD-dependent (GO:0097372), lncRNA binding (GO:0106222), NAD+-protein-arginine ADP-ribosyltransferase activity (GO:0106274), DNA damage sensor activity (GO:0140612), histone H3K56 deacetylase activity, NAD-dependent (GO:0140765), NAD-dependent protein demyristoylase activity (GO:0140773), NAD-dependent protein depalmitoylase activity (GO:0140774), NAD+-protein-lysine ADP-ribosyltransferase activity (GO:0140804), TORC2 complex binding (GO:1904841), NAD+-protein mono-ADP-ribosyltransferase activity (GO:1990404), RNA binding (GO:0003723), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747), glycosyltransferase activity (GO:0016757), enzyme regulator activity (GO:0030234), histone deacetylase regulator activity (GO:0035033), metal ion binding (GO:0046872)

GO Cellular Component (10): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), endoplasmic reticulum (GO:0005783), site of double-strand break (GO:0035861), site of DNA damage (GO:0090734), chromosome, subtelomeric region (GO:0099115), chromosome, telomeric region (GO:0000781), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Pre-NOTCH Expression and Processing	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Signal Transduction	1
Signaling by NOTCH	1
DNA Repair	1
DNA Double-Strand Break Repair	1
Homology Directed Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
histone H3K deacetylase activity	4
histone deacetylase activity, NAD-dependent	3
cellular anatomical structure	3
negative regulation of DNA-templated transcription	2
DNA repair	2
constitutive heterochromatin formation	2
chromosome, telomeric region	2
DNA binding	2
chromatin binding	2
chromosome	2
intracellular membrane-bounded organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
chromatin organization	1
protein deacylation	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
multicellular organismal process	1
response to light stimulus	1
negative regulation of gene expression	1
retrotransposition	1
regulation of DNA recombination	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair	1
lipid metabolic process	1
regulation of primary metabolic process	1
regulation of protein stability	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1

Protein interactions and networks

STRING

2796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIRT6	RELA	Q04206	935
SIRT6	WRN	Q14191	895
SIRT6	BMAL1	O00327	869
SIRT6	HIF1A	Q16665	812
SIRT6	SMARCA5	O60264	809
SIRT6	RBBP8	Q99708	798
SIRT6	FOXO3	O43524	786
SIRT6	JUN	P05412	766
SIRT6	CLOCK	O15516	758
SIRT6	TP53	P04637	746
SIRT6	H3-3A	P06351	744
SIRT6	H3C1	P02295	738
SIRT6	SIRT1	Q96EB6	730
SIRT6	XRCC6	P12956	719
SIRT6	SIRT4	Q9Y6E7	716

IntAct

54 interactions, top by confidence:

A	B	Type	Score
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
SIRT6		psi-mi:“MI:0407”(direct interaction)	0.620
SIRT6		psi-mi:“MI:0202”(depalmitoylation reaction)	0.620
	SIRT6	psi-mi:“MI:0201”(demyristoylation reaction)	0.620
RELA	SIRT6	psi-mi:“MI:0915”(physical association)	0.600
RELA	SIRT6	psi-mi:“MI:0407”(direct interaction)	0.600
CHD3	SIRT6	psi-mi:“MI:0915”(physical association)	0.550
SIRT6	VIM	psi-mi:“MI:0915”(physical association)	0.550
SIRT6	TRIM27	psi-mi:“MI:0914”(association)	0.530
MYC	SIRT6	psi-mi:“MI:0915”(physical association)	0.520
SIRT6	MYC	psi-mi:“MI:0915”(physical association)	0.520
	SIRT6	psi-mi:“MI:0407”(direct interaction)	0.440
SIRT6		psi-mi:“MI:0201”(demyristoylation reaction)	0.440
SIRT6		psi-mi:“MI:0197”(deacetylation reaction)	0.440
CENPA	SIRT6	psi-mi:“MI:0915”(physical association)	0.400
RAX	SIRT6	psi-mi:“MI:0915”(physical association)	0.400
SIRT6	MLF1	psi-mi:“MI:0915”(physical association)	0.400
SIRT6	MLF2	psi-mi:“MI:0915”(physical association)	0.400
HSF2	SIRT6	psi-mi:“MI:0915”(physical association)	0.400
PSMD2	SIRT6	psi-mi:“MI:0915”(physical association)	0.400
	SIRT6	psi-mi:“MI:0915”(physical association)	0.400
SIRT6	FKBPL	psi-mi:“MI:0915”(physical association)	0.400
SIRT6	STUB1	psi-mi:“MI:0915”(physical association)	0.400
AARSD1	SIRT6	psi-mi:“MI:0915”(physical association)	0.400
FAF1	SIRT6	psi-mi:“MI:0915”(physical association)	0.370
UBE2D1	SIRT6	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (749): G3BP1 (Affinity Capture-Western), WDHD1 (Affinity Capture-MS), WAPAL (Affinity Capture-MS), WAC (Affinity Capture-MS), USP7 (Affinity Capture-MS), USP48 (Affinity Capture-MS), UBR5 (Affinity Capture-MS), TXLNA (Affinity Capture-MS), TUBB2A (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), TRIM28 (Affinity Capture-MS), TRIM25 (Affinity Capture-MS), TCP1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TBL1XR1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9UVG7, A0A250YGJ5, A0A2K5TU92, A0A559KX76, A8NWP2, C8V3W5, E1BRE2, E2RDZ6, E9GD30, F4P804, F7DKV7, F7EZ75, G5EB76, I1RN13, J4W6X9, O13492, P0CS88, P16081, P21334, P22945, P27783, P36842, P36858, P38681, P39863, P39869, P43100, P53686, P54898, P59941, Q3ZBQ0, Q57V41, Q59ST1, Q5AI90, Q5AW69, Q5HZN8, Q5R6G3, Q5RBF1, Q5RJQ4, Q68F47

Diamond homologs: A0A0J9UVG7, A0A250YGJ5, A0A2K5TU92, A8MBU4, B2RZ55, B5YJW3, B8ARK7, O07595, O28597, O58669, O67919, P59941, Q0P595, Q4JBN2, Q5JG47, Q5L014, Q6A5T5, Q6MJJ2, Q6N6U0, Q72IV5, Q73KE1, Q7XWV4, Q899G3, Q89LY4, Q8BKJ9, Q8ELR0, Q8N6T7, Q8R104, Q8R984, Q8R9N6, Q8TWG0, Q8U1Q1, Q8XNS6, Q8ZT00, Q8ZU41, Q95Q89, Q974M6, Q97VX5, Q9FE17, Q9I7I7

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
SIRT6	up-regulates	TNF	deacetylation
“Fatty acid”	up-regulates	SIRT6
SIRT6	“up-regulates activity”	CLOCK/BMAL1	binding
SIRT6	“up-regulates activity”	SREBF1	binding
AKT1	“down-regulates activity”	SIRT6	phosphorylation
MDM2	“down-regulates quantity”	SIRT6	ubiquitination
SIRT6	“down-regulates activity”	ME1	deacetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 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
Cell Cycle	5	8.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	59
Likely benign	11
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
929782	NM_016539.4(SIRT6):c.362G>A (p.Arg121His)	Likely pathogenic

SpliceAI

1140 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4174942:CGGTC:C	acceptor_gain	1.0000
19:4174945:TC:T	acceptor_gain	1.0000
19:4174946:CC:C	acceptor_gain	1.0000
19:4174947:C:CA	acceptor_loss	1.0000
19:4174947:C:CC	acceptor_gain	1.0000
19:4174948:T:C	acceptor_loss	1.0000
19:4174951:C:CT	acceptor_gain	1.0000
19:4175024:CTAC:C	donor_loss	1.0000
19:4175025:TA:T	donor_loss	1.0000
19:4175026:A:AC	donor_gain	1.0000
19:4175027:C:CC	donor_gain	1.0000
19:4175027:CG:C	donor_gain	1.0000
19:4175027:CGT:C	donor_gain	1.0000
19:4175027:CGTG:C	donor_gain	1.0000
19:4175756:CTCCC:C	acceptor_gain	1.0000
19:4175759:CC:C	acceptor_gain	1.0000
19:4175760:CC:C	acceptor_gain	1.0000
19:4175934:CTGC:C	acceptor_gain	1.0000
19:4175944:C:CT	acceptor_gain	1.0000
19:4177074:CTCA:C	donor_loss	1.0000
19:4177076:CACG:C	donor_loss	1.0000
19:4177077:A:AC	donor_gain	1.0000
19:4177078:C:CC	donor_gain	1.0000
19:4177078:CGT:C	donor_gain	1.0000
19:4177085:CA:C	donor_gain	1.0000
19:4177134:TGTCC:T	acceptor_gain	1.0000
19:4177135:GTCC:G	acceptor_gain	1.0000
19:4177136:TCC:T	acceptor_gain	1.0000
19:4177137:CC:C	acceptor_gain	1.0000
19:4177137:CCC:C	acceptor_gain	1.0000

AlphaMissense

2279 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4175730:C:A	W188C	1.000
19:4175730:C:G	W188C	1.000
19:4175732:A:G	W188R	1.000
19:4175732:A:T	W188R	1.000
19:4177115:C:T	G134E	1.000
19:4179268:C:A	W71C	1.000
19:4179268:C:G	W71C	1.000
19:4179270:A:G	W71R	1.000
19:4179270:A:T	W71R	1.000
19:4180782:C:A	R65M	1.000
19:4180782:C:G	R65T	1.000
19:4180784:G:C	F64L	1.000
19:4180784:G:T	F64L	1.000
19:4180786:A:G	F64L	1.000
19:4175046:G:C	N240K	0.999
19:4175046:G:T	N240K	0.999
19:4175110:A:G	I219T	0.999
19:4175116:A:G	L217P	0.999
19:4175731:C:G	W188S	0.999
19:4177105:A:C	F137L	0.999
19:4177105:A:T	F137L	0.999
19:4177107:A:G	F137L	0.999
19:4177111:G:C	N135K	0.999
19:4177111:G:T	N135K	0.999
19:4177115:C:A	G134V	0.999
19:4177116:C:A	G134W	0.999
19:4177117:G:C	H133Q	0.999
19:4177117:G:T	H133Q	0.999
19:4177119:G:C	H133D	0.999
19:4177119:G:T	H133N	0.999

dbSNP variants (sampled 300 via entrez): RS1000986632 (19:4183007 C>G), RS1001220975 (19:4178152 G>A,C), RS1001329127 (19:4183982 A>C), RS1001330851 (19:4184119 C>T), RS1001430687 (19:4183713 A>T), RS1001573642 (19:4174081 T>C), RS1001611981 (19:4183904 G>A), RS1001655241 (19:4178573 A>G), RS1001759771 (19:4173982 C>A), RS1001892612 (19:4180160 A>G), RS1001958679 (19:4178786 G>A,C), RS1003665577 (19:4183153 A>G), RS1004004433 (19:4182454 G>C), RS1004115065 (19:4176658 C>T), RS1004300197 (19:4176952 C>A,G,T)

Disease associations

OMIM: gene MIM:606211 | disease phenotypes:

GenCC curated gene-disease

Mondo (3): long QT syndrome (MONDO:0002442), syndromic complex neurodevelopmental disorder (MONDO:0800439), primary ovarian failure (MONDO:0005387)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2163182 (SINGLE PROTEIN), CHEMBL4742301 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,442,816 (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
CHEMBL1140	NIACINAMIDE	4	231,688
CHEMBL2220442	FLUVASTATIN	4	53,699
CHEMBL50	QUERCETIN	3	74,559
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL267476	LINOLEIC ACID	2	323,195
CHEMBL8659	OLEIC ACID	2	713,838
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
MDL-800	Activation	4.99	pEC50
AKK(thioAc)LM21	Inhibition	4.33	pIC50

Binding affinities (BindingDB)

3 measured of 9 human assays (9 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

46 potent at pChembl≥5 of 106 total, top 39 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.60	IC50	250	nM	CHEMBL4438193
6.59	IC50	256	nM	CHEMBL5277251
6.55	IC50	282	nM	CHEMBL5274589
6.50	IC50	319	nM	CHEMBL5281352
6.50	IC50	319	nM	CHEMBL5267327
6.43	IC50	368	nM	CHEMBL5280037
6.30	IC50	495	nM	CHEMBL5270531
5.77	IC50	1700	nM	CHEMBL4645806
5.72	IC50	1900	nM	LUTEOLIN
5.72	IC50	1900	nM	QUERCETIN
5.70	Ki	2000	nM	TRICHOSTATIN
5.70	Ki	2020	nM	TRICHOSTATIN
5.60	IC50	2500	nM	(-)-CATECHINGALLATE
5.55	IC50	2800	nM	CHEMBL4128547
5.51	EC50	3100	nM	OLEOYLETHANOLAMIDE
5.33	Ki	4620	nM	TRICHOSTATIN
5.31	IC50	4930	nM	CHEMBL1370863
5.28	EC50	5300	nM	CHEMBL5275868
5.27	EC50	5350	nM	CHEMBL4636189
5.27	IC50	5400	nM	GALLOCATECHIN GALLATE
5.26	EC50	5490	nM	CHEMBL4636189
5.26	Kd	5520	nM	CHEMBL4636189
5.25	IC50	5680	nM	CHEMBL6120377
5.24	EC50	5700	nM	CHEMBL4440358
5.24	EC50	5700	nM	CHEMBL5275868
5.17	IC50	6700	nM	CHEMBL5281841
5.15	EC50	7100	nM	FLUVASTATIN
5.15	EC50	7100	nM	CHEMBL350239
5.12	EC50	7500	nM	CHEMBL5277451
5.10	IC50	7900	nM	CHEMBL4440955
5.09	IC50	8100	nM	CHEMBL5270371
5.05	EC50	8910	nM	CHEMBL4636189
5.05	Kd	8850	nM	CHEMBL4636189
5.04	IC50	9090	nM	CHEMBL4638368
5.02	IC50	9460	nM	CHEMBL4636099
5.02	Kd	9510	nM	CHEMBL4551664
5.01	Kd	9760	nM	CHEMBL1370863
5.00	Kd	1e+04	nM	CHEMBL1370863
5.00	EC50	1e+04	nM	CHEMBL4440358

PubChem BioAssay actives

45 with measured affinity, of 819 total; 28 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
(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	1509514: Inhibition of recombinant human N-terminal polyhis-tagged SIRT6 (1 to 355 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	0.2500	uM
(2S,3R)-2-[[(2S,5S,8S,29S)-29-acetamido-2-[3-(diaminomethylideneamino)propyl]-3,6,14,17,20,23,30-heptaoxo-5-[4-(undecylcarbamothioylamino)butyl]-1,4,7,13,16,21,24-heptazacyclotriacontane-8-carbonyl]amino]-3-hydroxybutanoic acid	1924885: Inhibition of SIRT6 (unknown origin)	ic50	0.2560	uM
(2S,3R)-2-[[(2S,5S,8S,29S)-29-acetamido-2-[3-(diaminomethylideneamino)propyl]-3,6,14,17,20,23,30-heptaoxo-5-[4-(tetradecylcarbamothioylamino)butyl]-1,4,7,13,16,21,24-heptazacyclotriacontane-8-carbonyl]amino]-3-hydroxybutanoic acid	1924885: Inhibition of SIRT6 (unknown origin)	ic50	0.2820	uM
(2S,3R)-2-[[(2S,5S,8S,33S)-33-acetamido-2-[3-(diaminomethylideneamino)propyl]-3,6,14,17,24,27,34-heptaoxo-5-[4-(tetradecylcarbamothioylamino)butyl]-1,4,7,13,16,25,28-heptazacyclotetratriacontane-8-carbonyl]amino]-3-hydroxybutanoic acid	1924885: Inhibition of SIRT6 (unknown origin)	ic50	0.3190	uM
(2S,3R)-2-[[(2S,5S,8S,27S)-27-acetamido-2-[3-(diaminomethylideneamino)propyl]-3,6,14,21,28-pentaoxo-5-[4-(tetradecylcarbamothioylamino)butyl]-1,4,7,13,22-pentazacyclooctacosane-8-carbonyl]amino]-3-hydroxybutanoic acid	1924885: Inhibition of SIRT6 (unknown origin)	ic50	0.3190	uM
(2S,3R)-2-[[(2S,5S,8S,33S)-33-acetamido-2-[3-(diaminomethylideneamino)propyl]-3,6,14,17,24,27,34-heptaoxo-5-[4-(undecylcarbamothioylamino)butyl]-1,4,7,13,16,25,28-heptazacyclotetratriacontane-8-carbonyl]amino]-3-hydroxybutanoic acid	1924885: Inhibition of SIRT6 (unknown origin)	ic50	0.3680	uM
(2S,3R)-2-[[(2S,5S,8S,27S)-27-acetamido-2-[3-(diaminomethylideneamino)propyl]-3,6,14,21,28-pentaoxo-5-[4-(undecylcarbamothioylamino)butyl]-1,4,7,13,22-pentazacyclooctacosane-8-carbonyl]amino]-3-hydroxybutanoic acid	1924885: Inhibition of SIRT6 (unknown origin)	ic50	0.4950	uM
(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-aminopropanoyl]pyrrolidine-2-carbonyl]amino]-6-(tetradecanoylamino)hexanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxybutanoic acid	1652960: Inhibition of sirtuin 6 (unknown origin)	ic50	1.7000	uM
Quercetin	1924878: Inhibition of human SIRT6 using H3K9 myristoyl-peptide substrate	ic50	1.9000	uM
2-(3,4-dihydroxyphenyl)-5,7-dihydroxychromen-4-one	1924878: Inhibition of human SIRT6 using H3K9 myristoyl-peptide substrate	ic50	1.9000	uM
(2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide	1423498: Inhibition of full length SIRT6 (unknown origin) using acetylated H3K9 peptide as substrate after 2 hrs in presence of NAD	ki	2.0000	uM
[(2S,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate	1924893: Inhibition of GST-SIRT6 (unknown origin) assessed as deacetylation reaction using calf thymus histone as substrate by Western blot analysis	ic50	2.5000	uM
2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-6-(tetradecanethioylamino)hexanoyl]amino]-3-hydroxybutanoyl]amino]acetic acid	1498680: Inhibition of human SIRT6 (1 to 294 residues) expressed in Escherichia coli Rosetta (DE3) using H3K9AcWW as substrate preincubated for 15 mins followed by substrate addition measured after 1 hr by HPLC analysis	ic50	2.8000	uM
(Z)-N-(2-hydroxyethyl)octadec-9-enamide	1924881: Activation of human SIRT6 deacetylase activity expressed in Escherichia coli BL21(DE3) expressed in Escherichia coli using H3K9Ac peptide substrate	ec50	3.1000	uM
5-(4-methylpiperazin-1-yl)-2-nitroaniline	1664130: Inhibition of SIRT6 (unknown origin) using Ac-RYQK(Ac)-AMC as substrate by Fluor de Lys assay	ic50	4.9300	uM
N-(5-bromo-4-fluoro-2-methylphenyl)-4-[(3,5-dichlorophenyl)sulfonylamino]-2-[[(3R)-3-methylmorpholin-4-yl]methyl]benzenesulfonamide	2002418: Activation of SIRT6 (unknown origin) deacetylase activity	ec50	5.3000	uM
N-benzhydryl-2-(1-benzofuran-2-yl)quinoline-4-carboxamide	1665222: Activation of N-terminal his-tagged human SIRT6 expressed in Escherichia coli M15 [pREP4] assessed as increase in peptide demyristoylation incubated for 120 mins using Ac-EALPKK(Myr)-AMC substrate by FDL assay relative to control	ec50	5.3500	uM
[(2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate	1924924: Inhibition of GST-tagged SIRT6 (unknown origin) deacetylase activity using H3K9Ac peptide substrate by reversed-phase HPLC	ic50	5.4000	uM
2-[(5-bromo-4-fluoro-2-methylphenyl)sulfamoyl]-5-[(3,5-dichlorophenyl)sulfonylamino]benzoic acid	1607627: Inhibition of SIRT6 (unknown origin)	ec50	5.7000	uM
2,4-dioxo-1-[2-oxo-2-[[(2S)-3-oxo-3-(propylamino)-2-[3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)propanoylamino]propyl]amino]ethyl]pyrimidine-5-carboxamide	1924894: Inhibition of GST-SIRT6 (unknown origin) assessed as deacetylation reaction demyristoylation assay	ic50	6.7000	uM
Fluvastatin	1924900: Activation of human SIRT6 in human HepG2 cells assessed as decrease in H3K9 acetylation	ec50	7.1000	uM
(E)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoic acid	1726066: Activation of recombinant SIRT6 (unknown origin) using fluoro substrate peptide incubated for 1 hr in presence of NAD by Fluor de Lys assay based fluorometric analysis	ec50	7.1000	uM
N-(2-hydroxyethyl)tetradecanamide	1924882: Activation of recombinant His-tagged SIRT6 (unknown origin) deacetylase activity expressed in Escherichia coli using H3K9Ac peptide substrate	ec50	7.5000	uM
(3S,6S,23S)-6-[3-(diaminomethylideneamino)propyl]-3-[4-(dodecylcarbamothioylamino)butyl]-2,5,8,11,14,17-hexaoxo-1,4,7,10,15,18-hexazacyclotricosane-23-carboxamide	1575169: Inhibition of demyristoylation activity of recombinant human full length N-terminal His6-tagged SIRT6 expressed in Escherichia coli using H2N-EALPK-[Nepsilon-myristoyl-lysine]-TGGPQ-CONH2 as substrate measured after 12 mins by HPLC analysis	ic50	7.9000	uM
(2S,3R)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-amino-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-6-(tetradecanethioylamino)hexanoyl]amino]-3-hydroxybutanoic acid	1924878: Inhibition of human SIRT6 using H3K9 myristoyl-peptide substrate	ic50	8.1000	uM
1-(3-methoxy-4-nitrophenyl)-4-methylpiperazine	1664130: Inhibition of SIRT6 (unknown origin) using Ac-RYQK(Ac)-AMC as substrate by Fluor de Lys assay	ic50	9.0900	uM
methyl 5-(4-methylpiperazin-1-yl)-2-nitrobenzoate	1664130: Inhibition of SIRT6 (unknown origin) using Ac-RYQK(Ac)-AMC as substrate by Fluor de Lys assay	ic50	9.4600	uM
methyl 2-[(5-bromo-4-fluoro-2-methylphenyl)sulfamoyl]-5-[(3,5-dichlorophenyl)sulfonylamino]benzoate	1665228: Binding affinity to N-terminal his-tagged human SIRT6 expressed in Escherichia coli M15 [pREP4] by SPR assay	kd	9.5100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
aristolochic acid I	increases expression	1
STF-118804	decreases reaction, increases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
quinone	decreases expression, decreases reaction	1
triphenyl phosphate	affects expression	1
hesperetin	affects cotreatment, increases expression	1
beta-lapachone	increases expression	1
cupric oxide	increases expression	1
norcantharidin	decreases expression	1
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride	increases expression, affects cotreatment	1
abrine	increases expression	1
N-(4-(2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl)-2-pyridyl)benzamide	increases expression	1
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide	decreases activity	1
malondialdehyde-low density lipoprotein, human	decreases reaction, increases reaction, increases expression, decreases expression	1
Resveratrol	affects reaction, increases expression, decreases reaction	1
Air Pollutants	affects expression, increases abundance	1
Asbestos	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1
Curcumin	decreases expression, decreases reaction, increases reaction, increases expression	1
Disulfiram	affects binding, decreases expression	1
Hydrogen Peroxide	increases expression, decreases abundance	1
Ozone	affects expression, increases abundance	1
Paraquat	decreases response to substance, decreases reaction, affects binding, increases reaction	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Thiram	increases expression	1

ChEMBL screening assays

244 unique, capped per target: 240 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2166659	Binding	Activity of human SIRT6 assessed as decrotonylation of compound at 50 uM after 1 hr by trypsin developer-based fluorescence assay	Substrates for efficient fluorometric screening employing the NAD-dependent sirtuin 5 lysine deacylase (KDAC) enzyme. — J Med Chem
CHEMBL4626138	Functional	In-vivo activation of SIRT6 in BALB/c nude mouse xenografted with human PANC1 cells assessed as reduction in Lin28b expression at 150 mg/kg/day, po for 30 days by IHC analysis	Discovery of Potent Small-Molecule SIRT6 Activators: Structure-Activity Relationship and Anti-Pancreatic Ductal Adenocarcinoma Activity. — J Med Chem

Cellosaurus cell lines

12 cell lines: 7 cancer cell line, 3 embryonic stem cell, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A6E2	SEES3-1V human SIRT6, clone1	Embryonic stem cell	Male
CVCL_A6E3	SEES3-1V human SIRT6, clone2	Embryonic stem cell	Male
CVCL_A6E4	SEES3-1V human SIRT6, clone3	Embryonic stem cell	Male
CVCL_B2FG	Abcam HeLa SIRT6 KO	Cancer cell line	Female
CVCL_B8PG	Abcam HCT 116 SIRT6 KO	Cancer cell line	Male
CVCL_B9RV	Abcam A-549 SIRT6 KO	Cancer cell line	Male
CVCL_D2HA	Abcam MCF-7 SIRT6 KO	Cancer cell line	Female
CVCL_D8AB	Ubigene A-549 SIRT6 KO	Cancer cell line	Male
CVCL_TL35	HAP1 SIRT6 (-) 1	Cancer cell line	Male
CVCL_TL36	HAP1 SIRT6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy