| Function / biochemical activity | Reaction / substrate scope | Key substrates / pathways | Subcellular localization / contexts | Key mouse in vivo evidence / phenotypes (quantitative) | Recent 2023–2024 developments / applications | Key citations (year; DOI / URL) |
|---|---|---|---|---|---|---|
| NAD+-dependent lysine deacetylase / deacylase; core sirtuin-family enzyme | Consumes NAD+ to remove lysine acyl groups, yielding deacylated protein, nicotinamide, and 2′-O-acyl-ADP-ribose; reported acyl scope includes acetyl, propionyl, butyryl, hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl, crotonyl, methacryl, lipoyl, benzoyl, lactoyl, and 4-oxononanoyl groups; extended C pocket accommodates long acyl chains (pqac-00000008, pqac-00000006) | α-tubulin K40 deacetylation is a canonical substrate/function; additional biochemical substrate examples include H3K9/H3K18, PDH-E2 K259, PKM2 K305; inflammatory and signaling targets reported include p65/NF-κB, NLRP3, FOXO1, p38, p53, FOXO3a, NFATc4 (pqac-00000003, pqac-00000008, pqac-00000010) | Mainly cytosolic; colocalizes with microtubules; shuttles nucleus↔cytosol depending on stimulus; mouse isoforms SIRT2.1/2.2 predominantly cytoplasmic but can accumulate in nucleus; ischemia and infection can increase nuclear localization (pqac-00000003, pqac-00000005, pqac-00000007) | In mouse liver, male Sirt2−/− mice showed reduced adipose tissue (N=11 KO vs N=8 WT; p<0.05), reduced fat/lean ratio (p<0.001), fasting hypoglycemia (N=8; p<0.05), lower hepatic triglycerides, impaired lactate/pyruvate/glycerol-driven gluconeogenesis, and reduced OCR/FAO in hepatocytes; pyruvate test differences at 75 min p<0.0005, 85 min p<0.005, 100 min p<0.05; glycerol test reduced at 30/60/120 min p<0.05 (pqac-00000017, pqac-00000015) | 2024 inhibitor-screen paper emphasized separable deacetylase vs demyristoylase pharmacology; exemplar compound inhibited deacetylase with IC50 7 μM and demyristoylase with IC50 37 μM, supporting dual-activity targeting (pqac-00000006) | Schmidt et al. 2024, doi:10.3390/biom14091160, https://doi.org/10.3390/biom14091160; Lu et al. 2023, doi:10.3389/fimmu.2023.1174180, https://doi.org/10.3389/fimmu.2023.1174180; Yang et al. 2024, doi:10.1371/journal.pone.0305000, https://doi.org/10.1371/journal.pone.0305000; Shenk et al. 2024, doi:10.3390/ph17101298, https://doi.org/10.3390/ph17101298 |
| Microtubule / cytoskeleton regulator via tubulin deacetylation | Deacetylates α-tubulin at Lys40, linking SIRT2 to microtubule acetylation state, stabilization, and remodeling (pqac-00000000, pqac-00000003) | α-tubulin K40; microtubule dynamics; cytoskeletal remodeling (pqac-00000000, pqac-00000003) | Cytoplasm / microtubules; stimulus-dependent nuclear shuttling but dominant cytosolic function under basal conditions (pqac-00000003, pqac-00000005) | Mouse-relevant liver fractionation detected major Sirt2 isoforms in nuclear and cytosolic fractions but not in purified mitochondria or peroxisomes (N=3), supporting extra-mitochondrial control of many downstream effects (pqac-00000020) | SIRT2 degraders and inhibitors use α-tubulin acetylation as a downstream cellular readout; 2023 PROTAC review notes SIRT2 degradation in MCF7 cells at 0.5 μM for 48 h with increased α-tubulin acetylation (pqac-00000020) | Schmidt et al. 2024, doi:10.3390/biom14091160, https://doi.org/10.3390/biom14091160; Zhang et al. 2023, doi:10.15212/amm-2023-0039, https://doi.org/10.15212/amm-2023-0039 |
| Metabolic regulator in liver / gluconeogenesis / acetylome control | Deacetylates metabolic regulators; literature cited in mouse liver study links SIRT2 to stabilization of HNF4α and Pepck1/PEPCK1 deacetylation; acetylome data indicate strong sex-specific hepatic targeting (pqac-00000016) | HNF4α, Pepck1/PEPCK1, Ldha and many hepatic acetyl-sites; pathways: gluconeogenesis, glycolysis-linked lactate utilization, mitochondrial respiration, fatty-acid oxidation (pqac-00000016, pqac-00000017, pqac-00000015) | Nuclear + cytosolic presence; despite many mitochondrial target-site changes, Sirt2 antigen was not detected in purified WT liver mitochondria, implying indirect or pre-import regulation of mitochondrial proteins (pqac-00000016, pqac-00000020) | 2452 acetylated peptides quantified; in male Sirt2−/− liver mean acetylation increased ~8-fold (average log2FC=3), with 317 peptides / 306 sites (~13%) significantly hyperacetylated (p<0.01, FC>1.5); target-site distribution: mitochondria 44%, cytosol 32%, nucleus 8%, peroxisomes 6%; females showed little change (pqac-00000018, pqac-00000016) | 2024 mouse study reframed Sirt2 as a sex-specific hepatic acetylome regulator, highlighting strong male-selective metabolic phenotypes and many putative targets outside the nucleus; useful for functional annotation because it directly interrogated the mouse gene product in vivo (pqac-00000016, pqac-00000018) | Schmidt et al. 2024, doi:10.3390/biom14091160, https://doi.org/10.3390/biom14091160 |
| Context-dependent regulator of inflammation / autophagy / neurodegeneration | Deacetylates p65/NF-κB and NLRP3; binds/deacetylates FOXO1; effects can be anti- or pro-inflammatory depending on CNS vs peripheral context and model (pqac-00000010) | NF-κB/p65, NLRP3 inflammasome, FOXO1-autophagy axis; pathways include neuroinflammation, autophagic-lysosomal function, oxidative stress, microglial Aβ engulfment (pqac-00000010, pqac-00000011) | Brain-enriched expression reported, especially in oligodendrocytes / myelin-rich regions; can translocate into neuronal nuclei in injury contexts (pqac-00000003, pqac-00000010) | In APP/PS1 AD mice, SIRT2 inhibitor 33i improved cognition and LTP, reduced amyloid pathology and hippocampal neuroinflammation, and increased microglial Aβ engulfment; however it increased peripheral IL-1β, TNF, IL-6, and MCP-1. BBB-impermeable AGK-2 worsened cognition and systemic inflammation. In prior aging work cited, 2-year-old Sirt2−/− mice had impaired GTT and increased peripheral inflammation (pqac-00000011, pqac-00000012) | AD-targeting perspective sharpened in 2023–2024: central SIRT2 inhibition can be neuroprotective, but peripheral inhibition may be harmful; 33i was reported non-mutagenic/non-genotoxic in Ames and comet assays, supporting preclinical tractability (pqac-00000011, pqac-00000012, pqac-00000013) | Sola-Sevilla et al. 2023, doi:10.1007/s11481-023-10084-9, https://doi.org/10.1007/s11481-023-10084-9; Sola-Sevilla & Puerta 2024, doi:10.4103/1673-5374.375315, https://doi.org/10.4103/1673-5374.375315 |
| Druggable deacylase with separable deacetylase vs defatty-acylase pharmacology | Allosteric / substrate-competitive modulators can preferentially inhibit deacetylation while sparing demyristoylation; EC/selectivity pocket is central to selectivity (pqac-00000009, pqac-00000014) | Long-chain acyl recognition via EC pocket; inhibitor classes include SirReal-derived ligands, FLS-359, AGK2, oxadiazoles; 1,2,4-oxadiazoles described as substrate-competitive and NAD+-noncompetitive (pqac-00000009, pqac-00000014) | Structural studies focus on catalytic core plus induced selectivity pocket; useful for isoform-selective pharmacology (pqac-00000008, pqac-00000014) | Not a mouse phenotype row per se, but mouse pharmacology exists: FLS-359 showed favorable mouse PK in BALB/c mice and no overt toxicity over 14 days at 50 mg/kg b.i.d. (pqac-00000009) | 2023 JCI: FLS-359 showed broad antiviral activity and in BALB/c mice had plasma t1/2 ~6 h, Cmax 89 μM, AUC 713 μM·h/mL after 50 mg/kg p.o.; 14-day dosing at 50 mg/kg b.i.d. caused no weight loss/clinical signs and reduced virus production in humanized mouse HCMV models. 2024 JMC: oxadiazole scaffold optimized from Kinetobox; initial hit inhibited SmSirt2 at IC50 14.0 ± 2.0 μM; crystal structure confirmed binding mode. 2024 assay paper enabled parallel discovery of deacetylase- and defatty-acylase-directed inhibitors (pqac-00000009, pqac-00000014, pqac-00000006) | Roche et al. 2023, doi:10.1172/JCI158978, https://doi.org/10.1172/JCI158978; Colcerasa et al. 2024, doi:10.1021/acs.jmedchem.4c00229, https://doi.org/10.1021/acs.jmedchem.4c00229; Yang et al. 2024, doi:10.1371/journal.pone.0305000, https://doi.org/10.1371/journal.pone.0305000 |
| Evidence support for functional annotation confidence | Multiple independent 2023–2024 sources converge on same identity: NAD+-dependent lysine deacylase, tubulin K40 deacetylase, cytosol-dominant enzyme with nuclear shuttling, broad acyl chemistry, and context-dependent disease relevance (pqac-00000000, pqac-00000003, pqac-00000005, pqac-00000008) | UniProt-consistent annotation is supported by mouse-specific genetics and modern structural/pharmacology literature (pqac-00000000, pqac-00000016, pqac-00000014) | Cytosol, nucleus, microtubules; oligodendrocyte/myelin enrichment in CNS contexts; no convincing liver mitochondrial residence despite many mitochondrial acetylation changes (pqac-00000003, pqac-00000020) | Strongest direct mouse evidence in this run comes from whole-body Sirt2−/− liver phenotyping and APP/PS1 pharmacology; both show that Sirt2 function is highly context- and tissue-dependent (pqac-00000017, pqac-00000011) | Research frontier in 2023–2024 centers on separating central vs peripheral effects, and deacetylase vs defatty-acylase targeting, rather than treating SIRT2 as a single uniform activity (pqac-00000009, pqac-00000011, pqac-00000014) | Bursch et al. 2024, doi:10.3390/molecules29051185, https://doi.org/10.3390/molecules29051185; Schmidt et al. 2024, doi:10.3390/biom14091160, https://doi.org/10.3390/biom14091160; Shenk et al. 2024, doi:10.3390/ph17101298, https://doi.org/10.3390/ph17101298 |


*Table: This table condenses the strongest evidence gathered for mouse Sirt2 (UniProt Q8VDQ8), covering its enzymatic activities, substrates, localization, mouse phenotypes, and 2023–2024 translational developments. It is designed as a citation-ready functional annotation aid anchored only to evidence retrieved in this run.*