SIRT5 is an NAD+-dependent protein lysine deacylase of the sirtuin family that preferentially removes negatively charged acyl groups (succinyl, malonyl and glutaryl) from lysine residues, transferring the acyl group to ADP-ribose and releasing nicotinamide. Tyr102 and Arg105 in its acyl-binding pocket recognize the acyl carboxylate, and its deacetylase activity is weak by comparison. Synthesized with an N-terminal mitochondrial transit peptide, it acts mainly in the mitochondrial matrix (also the intermembrane space), with a substantial cytosolic pool and a minor nuclear pool. It is a major regulator of cellular lysine succinylation and glutarylation; characterized substrates include CPS1 (activated, supporting urea-cycle ammonia disposal during fasting), HMGCS2 (ketogenesis), SHMT2 (serine catabolism), SOD1 (antioxidant defence), and the pyruvate dehydrogenase and succinate dehydrogenase complexes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000050 urea cycle | TAS Reactome:R-HSA-70635 | KEEP AS NON CORE | Summary: SIRT5 regulates the urea cycle by activating CPS1 through desuccinylation and deglutarylation; it performs no urea-cycle reaction itself. Reason: SIRT5 does not catalyse a step of the urea cycle; it removes inhibitory succinyl and glutaryl groups from CPS1, the first enzyme of the cycle, increasing its activity (mouse KO and human cell knockdown). GO has no 'regulation of urea cycle' term, so the Reactome pathway-membership TAS is retained as a non-core regulatory involvement rather than refined. It is not a core function: the core activity is the deacylase reaction on CPS1. Supporting Evidence: PMID:24703693 Glutarylation of CPS1 inhibits its activity, but can be reserved by SIRT5. Reactome:R-HSA-9955504 Knockdown of SIRT5 leads to hyperglutarylation of CPS1 and reduced CPS1 enzymatic activity, consistent with a role for SIRT5 in activating the enzyme. PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice |
| GO:0003950 NAD+ poly-ADP-ribosyltransferase activity | TAS NOT PMID:17456799 Sirtuin functions in health and disease. | ACCEPT | Summary: NOT NAD+ poly-ADP-ribosyltransferase activity: no sirtuin, and specifically not SIRT5, has been shown to synthesize poly-ADP-ribose. Reason: The curator's negative statement from this review (abstract-only in our cache) is consistent with the biochemistry: SIRT5 uses NAD+ as an acyl acceptor (forming 2'-O-acyl-ADP-ribose) in a deacylation reaction, the same mechanism as class I sirtuin deacetylation, and the ADP-ribosyltransferase activities reported in the family are attributed to other members (SIRT4/SIRT6 and bacterial CobB nodes in PAINT), not to the SIRT5 subfamily node PTN000119399. We have no evidence contradicting the curator, so the NOT is accepted. Supporting Evidence: PMID:17456799 Certain sirtuins have in addition an ADP-ribosyltransferase activity. PMID:22076378 Thus, the mechanism for Sirt5-catalyzed desuccinylation or demalonylation is similar to the deacetylation mechanism of Class I sirtuins. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Minor nuclear pool of SIRT5; secondary to its principal mitochondrial location. Reason: Endogenous SIRT5 is mainly mitochondrial, with a minor nuclear pool detectable by fractionation (most evident in mouse liver), and Sirt5 loss increases histone lysine succinylation. A nuclear presence is therefore real but minor. The IBA comes from a deep ancestral node (PTN008492176) seeded by the nuclear sirtuins; the PAINT curator did not place nucleus on the SIRT5-subfamily node itself (which carries mitochondrion and cytosol), so this is an inherited ancestral location that survives in SIRT5 only as a small secondary pool. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN008492176 SUPPORTS SOURCE BUT NOT TARGET Deep sirtuin node seeded by nuclear members (SIRT1/6/7, yeast Sir2/Hst). SIRT5 has a transit peptide and is predominantly mitochondrial; only a minor nuclear pool is observed, so the transfer holds weakly and is non-core. Supporting Evidence: PMID:23806337 A very small amount of SIRT5 was also detected in the nuclear fraction, which was particularly evident in the liver samples file:human/SIRT5/SIRT5-uniprot.txt and very small amounts also detected in the nucleus. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Minor nuclear pool of SIRT5 (UniProt subcellular-location mapping). Reason: Endogenous SIRT5 is mainly mitochondrial, with a minor nuclear pool detectable by fractionation (most evident in mouse liver), and Sirt5 loss increases histone lysine succinylation. A nuclear presence is therefore real but minor. The IBA comes from a deep ancestral node (PTN008492176) seeded by the nuclear sirtuins; the PAINT curator did not place nucleus on the SIRT5-subfamily node itself (which carries mitochondrion and cytosol), so this is an inherited ancestral location that survives in SIRT5 only as a small secondary pool. Supporting Evidence: PMID:23806337 A very small amount of SIRT5 was also detected in the nuclear fraction, which was particularly evident in the liver samples file:human/SIRT5/SIRT5-uniprot.txt and very small amounts also detected in the nucleus. |
| GO:0005634 nucleus | TAS PMID:23806337 SIRT5-mediated lysine desuccinylation impacts diverse metabo... | KEEP AS NON CORE | Summary: Park et al. detected a very small nuclear SIRT5 fraction; retained as a minor location. Reason: Endogenous SIRT5 is mainly mitochondrial, with a minor nuclear pool detectable by fractionation (most evident in mouse liver), and Sirt5 loss increases histone lysine succinylation. A nuclear presence is therefore real but minor. The IBA comes from a deep ancestral node (PTN008492176) seeded by the nuclear sirtuins; the PAINT curator did not place nucleus on the SIRT5-subfamily node itself (which carries mitochondrion and cytosol), so this is an inherited ancestral location that survives in SIRT5 only as a small secondary pool. Supporting Evidence: PMID:23806337 A very small amount of SIRT5 was also detected in the nuclear fraction, which was particularly evident in the liver samples |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Correct but general; the extramitochondrial pool is specifically cytosolic. Reason: Fractionation of human cells places a significant fraction of endogenous SIRT5 in the cytosol; GO:0005829 cytosol, which the gene already carries (IBA, IDA, IEA), is the specific supported child of cytoplasm. Proposed replacements: cytosol Supporting Evidence: PMID:23806337 Subcellular fractionation revealed that a significant fraction of endogenous SIRT5 was present cytosolically both in human cells |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MODIFY | Summary: Mitochondrial localization is correct; refine to the matrix and intermembrane space sub-compartments. Reason: SIRT5 is unequivocally mitochondrial (imaging, fractionation, high-confidence mitochondrial proteome, N-terminal transit peptide), but the term is less specific than the evidence: in vitro import places it in both the matrix and the intermembrane space, and its physiological substrates (CPS1, SHMT2, PDC, SDH, HMGCS2) are matrix enzymes. Both specific sub-compartments are already annotated to the gene, so this is refined to them rather than kept as a general term. Proposed replacements: mitochondrial matrix mitochondrial intermembrane space Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | MODIFY | Summary: Mitochondrial localization is correct and inherited within the SIRT5 subfamily; refine to matrix and intermembrane space. Reason: SIRT5 is unequivocally mitochondrial (imaging, fractionation, high-confidence mitochondrial proteome, N-terminal transit peptide), but the term is less specific than the evidence: in vitro import places it in both the matrix and the intermembrane space, and its physiological substrates (CPS1, SHMT2, PDC, SDH, HMGCS2) are matrix enzymes. Both specific sub-compartments are already annotated to the gene, so this is refined to them rather than kept as a general term. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade, taxon Eukaryota) carrying the IBD; human SIRT5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER Mouse Sirt5 (Q8K2C6), the orthologous experimental seed in the same subfamily. UniProtKB:Q9NXA8 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences the PAINT curator used; expected, not circular. Proposed replacements: mitochondrial matrix mitochondrial intermembrane space Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix PMID:16079181 SIRT3, SIRT4, and SIRT5 are localized in mitochondria |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | MODIFY | Summary: Mitochondrial localization is correct; refine to the matrix and intermembrane space sub-compartments. Reason: SIRT5 is unequivocally mitochondrial (imaging, fractionation, high-confidence mitochondrial proteome, N-terminal transit peptide), but the term is less specific than the evidence: in vitro import places it in both the matrix and the intermembrane space, and its physiological substrates (CPS1, SHMT2, PDC, SDH, HMGCS2) are matrix enzymes. Both specific sub-compartments are already annotated to the gene, so this is refined to them rather than kept as a general term. Proposed replacements: mitochondrial matrix mitochondrial intermembrane space Supporting Evidence: PMID:23806337 SIRT5 (green) partially colocalized with MitoTracker Red to produce a yellow signal. |
| GO:0005739 mitochondrion | IDA GO_REF:0000054 | MODIFY | Summary: Mitochondrial localization is correct; refine to the matrix and intermembrane space sub-compartments. Reason: SIRT5 is unequivocally mitochondrial (imaging, fractionation, high-confidence mitochondrial proteome, N-terminal transit peptide), but the term is less specific than the evidence: in vitro import places it in both the matrix and the intermembrane space, and its physiological substrates (CPS1, SHMT2, PDC, SDH, HMGCS2) are matrix enzymes. Both specific sub-compartments are already annotated to the gene, so this is refined to them rather than kept as a general term. Proposed replacements: mitochondrial matrix mitochondrial intermembrane space Supporting Evidence: PMID:16079181 SIRT3, SIRT4, and SIRT5 are localized in mitochondria |
| GO:0005739 mitochondrion | IDA PMID:16079181 Evolutionarily conserved and nonconserved cellular localizat... | MODIFY | Summary: Mitochondrial localization is correct; refine to the matrix and intermembrane space sub-compartments. Reason: SIRT5 is unequivocally mitochondrial (imaging, fractionation, high-confidence mitochondrial proteome, N-terminal transit peptide), but the term is less specific than the evidence: in vitro import places it in both the matrix and the intermembrane space, and its physiological substrates (CPS1, SHMT2, PDC, SDH, HMGCS2) are matrix enzymes. Both specific sub-compartments are already annotated to the gene, so this is refined to them rather than kept as a general term. Proposed replacements: mitochondrial matrix mitochondrial intermembrane space Supporting Evidence: PMID:16079181 SIRT3, SIRT4, and SIRT5 are localized in mitochondria |
| GO:0005739 mitochondrion | IDA PMID:23806337 SIRT5-mediated lysine desuccinylation impacts diverse metabo... | MODIFY | Summary: Mitochondrial localization is correct; refine to the matrix and intermembrane space sub-compartments. Reason: SIRT5 is unequivocally mitochondrial (imaging, fractionation, high-confidence mitochondrial proteome, N-terminal transit peptide), but the term is less specific than the evidence: in vitro import places it in both the matrix and the intermembrane space, and its physiological substrates (CPS1, SHMT2, PDC, SDH, HMGCS2) are matrix enzymes. Both specific sub-compartments are already annotated to the gene, so this is refined to them rather than kept as a general term. Proposed replacements: mitochondrial matrix mitochondrial intermembrane space Supporting Evidence: PMID:23806337 SIRT5 (green) partially colocalized with MitoTracker Red to produce a yellow signal. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | MODIFY | Summary: Mitochondrial localization is correct; refine to the matrix and intermembrane space sub-compartments. Reason: SIRT5 is unequivocally mitochondrial (imaging, fractionation, high-confidence mitochondrial proteome, N-terminal transit peptide), but the term is less specific than the evidence: in vitro import places it in both the matrix and the intermembrane space, and its physiological substrates (CPS1, SHMT2, PDC, SDH, HMGCS2) are matrix enzymes. Both specific sub-compartments are already annotated to the gene, so this is refined to them rather than kept as a general term. Proposed replacements: mitochondrial matrix mitochondrial intermembrane space Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Inner-membrane 'part_of' is not supported; SIRT5 is a soluble matrix/intermembrane-space enzyme. Reason: SIRT5 has no transmembrane segment, is imported into the matrix and intermembrane space, and is assayed as a soluble enzyme. Acting on membrane-associated substrates (e.g. respiratory complexes, SDH) does not make it a component of the inner membrane. This Ensembl Compara projection from mouse is retained only as an over-annotation pending direct sub-mitochondrial fractionation evidence. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:18680753 Substrates and regulation mechanisms for the human mitochond... | KEEP AS NON CORE | Summary: SIRT5 can be imported into the intermembrane space; supported secondary location. Reason: A mitochondrial import assay shows human SIRT5 can be translocated into the intermembrane space as well as the matrix, and its in vitro deacetylation substrate cytochrome c resides there. This is a supported but secondary sub-compartment; the metabolically important substrates are in the matrix. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix PMID:18680753 Instead, it can deacetylate cytochrome c, a protein of the mitochondrial intermembrane space |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Intermembrane-space location from UniProt subcellular mapping; supported secondary location. Reason: A mitochondrial import assay shows human SIRT5 can be translocated into the intermembrane space as well as the matrix, and its in vitro deacetylation substrate cytochrome c resides there. This is a supported but secondary sub-compartment; the metabolically important substrates are in the matrix. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005759 mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial matrix is the principal site of SIRT5 deacylase activity. Reason: The matrix is where SIRT5 meets its principal substrates (CPS1, SHMT2, PDC, SDH); import assays place SIRT5 in the matrix. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000872307 SUPPORTS TRANSFER Vertebrate SIRT5 node carrying the matrix IBD; human SIRT5 descends from it. UniProtKB:Q9NXA8 SUPPORTS TRANSFER Target's own experimental annotation is the descendant evidence; expected, not circular. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix PMID:29180469 SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. |
| GO:0005759 mitochondrial matrix | IDA PMID:18680753 Substrates and regulation mechanisms for the human mitochond... | ACCEPT | Summary: Import assay places SIRT5 in the matrix. Reason: The matrix is where SIRT5 meets its principal substrates (CPS1, SHMT2, PDC, SDH); import assays place SIRT5 in the matrix. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Matrix location (UniProt subcellular mapping) is supported. Reason: The matrix is where SIRT5 meets its principal substrates (CPS1, SHMT2, PDC, SDH); import assays place SIRT5 in the matrix. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5688294 | ACCEPT | Summary: Matrix location is supported for SIRT5 (Reactome reaction context). Reason: The matrix is where SIRT5 meets its principal substrates (CPS1, SHMT2, PDC, SDH); import assays place SIRT5 in the matrix. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9955504 | ACCEPT | Summary: SIRT5 deglutarylates matrix CPS1, consistent with matrix activity. Reason: The matrix is where SIRT5 meets its principal substrates (CPS1, SHMT2, PDC, SDH); import assays place SIRT5 in the matrix. Supporting Evidence: Reactome:R-HSA-9955504 Knockdown of SIRT5 leads to hyperglutarylation of CPS1 and reduced CPS1 enzymatic activity, consistent with a role for SIRT5 in activating the enzyme. PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: A significant cytosolic SIRT5 pool is established and inherited in the SIRT5 subfamily. Reason: Fractionation and immunofluorescence of endogenous SIRT5 in human cells show a significant cytosolic fraction, consistent with SIRT5-dependent desuccinylation of cytosolic proteins such as SOD1. PAINT placed cytosol on the SIRT5-subfamily node. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade, taxon Eukaryota) carrying the IBD; human SIRT5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER Mouse Sirt5 (Q8K2C6), the orthologous experimental seed in the same subfamily. UniProtKB:Q9NXA8 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences the PAINT curator used; expected, not circular. Supporting Evidence: PMID:23806337 Subcellular fractionation revealed that a significant fraction of endogenous SIRT5 was present cytosolically both in human cells PMID:24140062 SIRT5 binds to, desuccinylates and activates SOD1. |
| GO:0005829 cytosol | IDA PMID:23806337 SIRT5-mediated lysine desuccinylation impacts diverse metabo... | ACCEPT | Summary: Endogenous SIRT5 fractionates substantially to the cytosol in human cells. Reason: Fractionation and immunofluorescence of endogenous SIRT5 in human cells show a significant cytosolic fraction, consistent with SIRT5-dependent desuccinylation of cytosolic proteins such as SOD1. PAINT placed cytosol on the SIRT5-subfamily node. Supporting Evidence: PMID:23806337 Subcellular fractionation revealed that a significant fraction of endogenous SIRT5 was present cytosolically both in human cells |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Cytosolic SIRT5 is supported experimentally. Reason: Fractionation and immunofluorescence of endogenous SIRT5 in human cells show a significant cytosolic fraction, consistent with SIRT5-dependent desuccinylation of cytosolic proteins such as SOD1. PAINT placed cytosol on the SIRT5-subfamily node. Supporting Evidence: PMID:23806337 Subcellular fractionation revealed that a significant fraction of endogenous SIRT5 was present cytosolically both in human cells |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000108 | REMOVE | Summary: Chromatin remodeling is inferred only from the inherited histone-deacetylase IBA, which does not hold for SIRT5. Reason: This is a logical inference from GO:0017136 (histone deacetylase activity, NAD-dependent), which this review refines away from SIRT5 because its deacetylase activity is ~500-fold weaker than SIRT1 and it does not affect global acetylation in vivo. No study shows SIRT5 participates in chromatin remodeling; increased histone succinylation in Sirt5 KO cells does not establish a remodeling role. Removing the derived process is an argument about the electronic inference, not an experimental annotation. Supporting Evidence: PMID:22076378 The catalytic efficiency (kcat/Km) of Sirt5 was about 500-fold lower than that of Sirt1. PMID:23806337 SIRT5 deficiency does not significantly impact global Lys acetylation |
| GO:0006476 protein deacetylation | IDA PMID:18680753 Substrates and regulation mechanisms for the human mitochond... | MARK AS OVER ANNOTATED | Summary: In vitro deacetylation of cytochrome c does not establish a physiological protein-deacetylation role for SIRT5. Reason: Schlicker et al. found SIRT5 deacetylated none of the matrix proteins tested and only cytochrome c in vitro; Reactome notes the significance is unknown. Later work shows deacetylation is 29 to >1000-fold less efficient than desuccinylation/demalonylation and that Sirt5 loss does not change global lysine acetylation or CPS1 K44/K287 acetylation in vivo. The weak activity is captured by the MF term GO:0034979 (kept non-core); the process claim overstates it. A curator NOT for the same process exists (PMID:22076378). Supporting Evidence: PMID:18680753 Sirt5, in contrast to Sirt3, deacetylates none of the mitochondrial matrix proteins tested. PMID:18680753 Instead, it can deacetylate cytochrome c, a protein of the mitochondrial intermembrane space Reactome:R-HSA-5688294 The functional significance of this is unknown (Bao & Sack 2010). PMID:23806337 SIRT5 deficiency does not significantly impact global Lys acetylation |
| GO:0006476 protein deacetylation | IDA NOT PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: NOT protein deacetylation: SIRT5 loss does not change acetylation of CPS1 or global acetylation in vivo. Reason: The curator's negation is supported by the full text: in Sirt5 KO mouse liver, acetylation of CPS1 Lys44 and Lys287 is unchanged while succinylation of Lys1291 rises sharply, and the measured deacetylation rate is ~500-fold below SIRT1. Independent SILAC data show no global acetylation change in Sirt5-null cells. The weak in vitro deacetylase activity is a molecular-function property (GO:0034979), not physiological participation in protein deacetylation. Supporting Evidence: PMID:22076378 For Lys44 and Lys287, the levels of acetylation and succinylation did not change significantly in Sirt5 KO mice PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice PMID:22076378 The catalytic efficiency (kcat/Km) of Sirt5 was about 500-fold lower than that of Sirt1. PMID:23806337 SIRT5 deficiency does not significantly impact global Lys acetylation |
| GO:0007005 mitochondrion organization | TAS Reactome:R-HSA-1592230 | MARK AS OVER ANNOTATED | Summary: No evidence that SIRT5 organizes mitochondria; inclusion in the Reactome mitochondrial-biogenesis pathway reflects its weak cytochrome c deacetylation. Reason: SIRT5 regulates mitochondrial metabolic enzymes by deacylation; it is not known to act in mitochondrial biogenesis, fission/fusion or other organelle organization. Reactome's own reaction for SIRT5 (cytochrome c deacetylation) states that its functional significance is unknown. Pathway membership is not process participation. Supporting Evidence: Reactome:R-HSA-5688294 The functional significance of this is unknown (Bao & Sack 2010). PMID:18680753 Instead, it can deacetylate cytochrome c, a protein of the mitochondrial intermembrane space |
| GO:0008270 zinc ion binding | IDA PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | KEEP AS NON CORE | Summary: SIRT5 binds one structural zinc in the conserved sirtuin zinc-ribbon subdomain. Reason: UniProt curates one Zn(2+) per subunit citing this structural study (crystal structures of human SIRT5 with peptide and NAD), and the four zinc-ligand cysteines (C166/C169/C207/C212) are conserved in the sirtuin fold. Zinc is a structural cofactor, true but peripheral to the deacylase function. Supporting Evidence: file:human/SIRT5/SIRT5-uniprot.txt Note=Binds 1 zinc ion per subunit. PMID:22076378 Thus, Tyr102 and Arg105 were important for binding succinyl and malonyl groups. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: Structural zinc binding (UniRule) is correct; non-core. Reason: UniRule/HAMAP MF_03160 assigns the conserved sirtuin zinc site; consistent with curated cofactor data. Structural, non-core. Supporting Evidence: file:human/SIRT5/SIRT5-uniprot.txt Note=Binds 1 zinc ion per subunit. |
| GO:0010566 regulation of ketone biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of ketogenesis via HMGCS2 desuccinylation (ortholog evidence); non-core. Reason: Mouse Sirt5 desuccinylates and activates HMGCS2, the rate-limiting ketogenic enzyme; UniProt records this by similarity. Mouse Sirt5 is the 1:1 ortholog in the same PANTHER subfamily (PTHR11085:SF10) and PAINT node (PTN000119399), so transfer of this substrate-specific regulatory role to human is phylogenetically justified, but it is one downstream consequence of the core desuccinylase activity. Supporting Evidence: file:human/SIRT5/SIRT5-uniprot.txt and activation of HMGCS2 (By similarity). Has weak NAD-dependent |
| GO:0010566 regulation of ketone biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of ketogenesis via HMGCS2 desuccinylation (ortholog evidence); non-core. Reason: Mouse Sirt5 desuccinylates and activates HMGCS2, the rate-limiting ketogenic enzyme; UniProt records this by similarity. Mouse Sirt5 is the 1:1 ortholog in the same PANTHER subfamily (PTHR11085:SF10) and PAINT node (PTN000119399), so transfer of this substrate-specific regulatory role to human is phylogenetically justified, but it is one downstream consequence of the core desuccinylase activity. Supporting Evidence: file:human/SIRT5/SIRT5-uniprot.txt and activation of HMGCS2 (By similarity). Has weak NAD-dependent |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cardiomyocyte survival is a tissue phenotype downstream of SIRT5 metabolic regulation, projected from rat. Reason: This Ensembl Compara projection transfers a rat cardiomyocyte apoptosis phenotype. SIRT5's direct activity is deacylation of metabolic enzymes; reduced cardiomyocyte apoptosis is an indirect organismal/cellular consequence of that metabolic and redox control, not participation in the regulation of the apoptotic machinery. No human evidence was found. Supporting Evidence: PMID:23806337 SIRT5 is a central regulator of Lys succinylation in mammalian cells |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000117 | MODIFY | Summary: Correct but uninformative parent; SIRT5's acyl-transfer-to-ADP-ribose deacylase activities are the specific terms. Reason: In GO the NAD-dependent sirtuin deacylase activities are classified under acyltransferase activity (the acyl group is transferred to ADP-ribose, forming 2'-O-acyl-ADP-ribose). The ARBA-derived parent is therefore correct but should be refined to the specific, experimentally supported activities the gene already carries: desuccinylase, demalonylase and deglutarylase. Proposed replacements: protein-succinyllysine desuccinylase activity protein-malonyllysine demalonylase activity protein-glutaryllysine deglutarylase activity Supporting Evidence: PMID:22076378 Thus, the mechanism for Sirt5-catalyzed desuccinylation or demalonylation is similar to the deacetylation mechanism of Class I sirtuins. PMID:22076378 Our data suggest that Sirt5 is an NAD-dependent demalonylase and desuccinylase. PMID:24703693 Using this assay, we found SIRT5 is the only HDAC exhibiting significant lysine deglutarylase activity in vitro |
| GO:0017136 histone deacetylase activity, NAD-dependent | IBA GO_REF:0000033 | MODIFY | Summary: SIRT5 inherits a family-wide histone deacetylase IBD, but its acyl pocket is specialized for acidic acyl groups; refine to its desuccinylase/demalonylase/deglutarylase activities. Reason: The IBD sits on a deep sirtuin node (PTN008718612) seeded by robust deacetylases (SIRT1-3, SIRT6, yeast Sir2/Hst proteins); no SIRT5 data were among the seeds. On the SIRT5-subfamily node itself (PTN000119399) the PAINT curator placed desuccinylase, demalonylase and deglutarylase, not deacetylase. SIRT5 shows target-specific divergence: Tyr102/Arg105 in the acyl pocket bind carboxylate acyl groups, deacetylation is ~500-fold weaker than SIRT1, and no physiological histone deacetylation is established. The term is refined to the acidic deacylase activities rather than removed, since weak in vitro H3K9ac peptide deacetylation was measured. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN008718612 SUPPORTS SOURCE BUT NOT TARGET Deep sirtuin node; the deacetylase IBD is well grounded in class I/IV sirtuins but SIRT5 diverged to acidic-acyl specificity (Tyr102/Arg105). Proposed replacements: protein-succinyllysine desuccinylase activity protein-malonyllysine demalonylase activity protein-glutaryllysine deglutarylase activity Supporting Evidence: PMID:22076378 The catalytic efficiency (kcat/Km) of Sirt5 was about 500-fold lower than that of Sirt1. PMID:22076378 Thus, Tyr102 and Arg105 were important for binding succinyl and malonyl groups. PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SIRT5-dependent CPS1 activation responds to fasting; a physiological context of the core activity. Reason: SIRT5 activates CPS1 during fasting through NAD-dependent desuccinylation/deglutarylation, and lysine succinylation rises with fasting. The response to nutrient levels is a real but contextual consequence of the NAD-sensing deacylase activity (projected from rat). Supporting Evidence: PMID:24703693 Glutarylation of CPS1 inhibits its activity, but can be reserved by SIRT5. PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice |
| GO:0034979 NAD-dependent protein lysine deacetylase activity | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: Weak but measurable NAD-dependent lysine deacetylase activity; non-core. Reason: Purified human SIRT5 deacetylates a subset of acetyl peptides and cytochrome c in vitro, but with catalytic efficiency about 500-fold below SIRT1 and 29 to >1000-fold below its own desuccinylase/demalonylase activity. The molecular activity is real and is kept, but it is not the core function. Supporting Evidence: PMID:22076378 The catalytic efficiency (kcat/Km) of Sirt5 was about 500-fold lower than that of Sirt1. PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation |
| GO:0034979 NAD-dependent protein lysine deacetylase activity | TAS Reactome:R-HSA-5688294 | KEEP AS NON CORE | Summary: Cytochrome c deacetylation in vitro; functional significance unknown; non-core. Reason: Purified human SIRT5 deacetylates a subset of acetyl peptides and cytochrome c in vitro, but with catalytic efficiency about 500-fold below SIRT1 and 29 to >1000-fold below its own desuccinylase/demalonylase activity. The molecular activity is real and is kept, but it is not the core function. Supporting Evidence: PMID:18680753 Instead, it can deacetylate cytochrome c, a protein of the mitochondrial intermembrane space Reactome:R-HSA-5688294 The functional significance of this is unknown (Bao & Sack 2010). PMID:22076378 The catalytic efficiency (kcat/Km) of Sirt5 was about 500-fold lower than that of Sirt1. |
| GO:0036046 protein demalonylation | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: SIRT5 removes malonyl groups from proteins; demalonylase kinetics measured. Reason: Tan et al. measured SIRT5 demalonylase, desuccinylase and deglutarylase kinetics on acylated peptides; demalonylation is one of the three core acidic deacylation reactions. Supporting Evidence: PMID:24703693 were significantly higher for desuccinylation and deglutarylation compared to the demalonylase activity PMID:21908771 we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo |
| GO:0036047 peptidyl-lysine demalonylation | IDA PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: SIRT5 demalonylates lysine residues in vitro and in vivo. Reason: Two independent studies identified SIRT5 as a lysine demalonylase, with efficiency far exceeding its deacetylase activity. Supporting Evidence: PMID:21908771 we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo |
| GO:0036047 peptidyl-lysine demalonylation | IDA PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: SIRT5 demalonylates lysine residues in vitro and in vivo. Reason: Two independent studies identified SIRT5 as a lysine demalonylase, with efficiency far exceeding its deacetylase activity. Supporting Evidence: PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation PMID:22076378 Our data suggest that Sirt5 is an NAD-dependent demalonylase and desuccinylase. |
| GO:0036048 protein desuccinylation | IDA PMID:24140062 SIRT5 desuccinylates and activates SOD1 to eliminate ROS. | ACCEPT | Summary: SIRT5 desuccinylates specific protein substrates. Reason: Desuccinylation of specific substrates (SOD1, SHMT2 K280, CPS1) by SIRT5 is directly demonstrated; desuccinylation is the most efficient SIRT5 reaction. Supporting Evidence: PMID:24140062 SIRT5 binds to, desuccinylates and activates SOD1. |
| GO:0036048 protein desuccinylation | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: SIRT5 desuccinylates specific protein substrates. Reason: Desuccinylation of specific substrates (SOD1, SHMT2 K280, CPS1) by SIRT5 is directly demonstrated; desuccinylation is the most efficient SIRT5 reaction. Supporting Evidence: PMID:24703693 were significantly higher for desuccinylation and deglutarylation compared to the demalonylase activity |
| GO:0036048 protein desuccinylation | IDA PMID:29180469 SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferat... | ACCEPT | Summary: SIRT5 desuccinylates specific protein substrates. Reason: Desuccinylation of specific substrates (SOD1, SHMT2 K280, CPS1) by SIRT5 is directly demonstrated; desuccinylation is the most efficient SIRT5 reaction. Supporting Evidence: PMID:29180469 SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. |
| GO:0036049 peptidyl-lysine desuccinylation | IDA PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: SIRT5 removes succinyl groups from lysine residues in vitro and in vivo. Reason: Lysine desuccinylation by SIRT5 is shown biochemically and by increased CPS1 K1291 succinylation in Sirt5 KO mice. Supporting Evidence: PMID:21908771 we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo |
| GO:0036049 peptidyl-lysine desuccinylation | IDA PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: SIRT5 removes succinyl groups from lysine residues in vitro and in vivo. Reason: Lysine desuccinylation by SIRT5 is shown biochemically and by increased CPS1 K1291 succinylation in Sirt5 KO mice. Supporting Evidence: PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice |
| GO:0036054 protein-malonyllysine demalonylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Demalonylase activity, inherited from the SIRT5-subfamily node. Reason: Human SIRT5 has robust NAD-dependent lysine demalonylase activity, far more efficient than its deacetylase activity; core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade, taxon Eukaryota) carrying the IBD; human SIRT5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER Mouse Sirt5 (Q8K2C6), the orthologous experimental seed in the same subfamily. UniProtKB:Q9NXA8 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences the PAINT curator used; expected, not circular. Supporting Evidence: PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation PMID:21908771 we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo |
| GO:0036054 protein-malonyllysine demalonylase activity | IDA PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: Directly measured protein-malonyllysine demalonylase activity. Reason: Human SIRT5 has robust NAD-dependent lysine demalonylase activity, far more efficient than its deacetylase activity; core function. Supporting Evidence: PMID:21908771 we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo |
| GO:0036054 protein-malonyllysine demalonylase activity | IDA PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: Directly measured protein-malonyllysine demalonylase activity. Reason: Human SIRT5 has robust NAD-dependent lysine demalonylase activity, far more efficient than its deacetylase activity; core function. Supporting Evidence: PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation PMID:22076378 Our data suggest that Sirt5 is an NAD-dependent demalonylase and desuccinylase. |
| GO:0036054 protein-malonyllysine demalonylase activity | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Directly measured protein-malonyllysine demalonylase activity. Reason: Human SIRT5 has robust NAD-dependent lysine demalonylase activity, far more efficient than its deacetylase activity; core function. Supporting Evidence: PMID:24703693 were significantly higher for desuccinylation and deglutarylation compared to the demalonylase activity |
| GO:0036054 protein-malonyllysine demalonylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Demalonylase activity (UniRule/Rhea); experimentally supported. Reason: Human SIRT5 has robust NAD-dependent lysine demalonylase activity, far more efficient than its deacetylase activity; core function. Supporting Evidence: PMID:22076378 Our data suggest that Sirt5 is an NAD-dependent demalonylase and desuccinylase. |
| GO:0036055 protein-succinyllysine desuccinylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Desuccinylase activity, inherited from the SIRT5-subfamily node. Reason: Desuccinylation is the most efficient SIRT5 reaction; Tyr102/Arg105 bind the succinyl carboxylate, and SIRT5 controls global lysine succinylation in cells and activates CPS1, SOD1 and SHMT2 by desuccinylation; core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade, taxon Eukaryota) carrying the IBD; human SIRT5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER Mouse Sirt5 (Q8K2C6), the orthologous experimental seed in the same subfamily. UniProtKB:Q9NXA8 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences the PAINT curator used; expected, not circular. Supporting Evidence: PMID:22076378 Thus, Tyr102 and Arg105 were important for binding succinyl and malonyl groups. PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation |
| GO:0036055 protein-succinyllysine desuccinylase activity | IDA PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: Directly demonstrated protein-succinyllysine desuccinylase activity. Reason: Desuccinylation is the most efficient SIRT5 reaction; Tyr102/Arg105 bind the succinyl carboxylate, and SIRT5 controls global lysine succinylation in cells and activates CPS1, SOD1 and SHMT2 by desuccinylation; core function. Supporting Evidence: PMID:21908771 we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo |
| GO:0036055 protein-succinyllysine desuccinylase activity | IDA PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: Directly demonstrated protein-succinyllysine desuccinylase activity. Reason: Desuccinylation is the most efficient SIRT5 reaction; Tyr102/Arg105 bind the succinyl carboxylate, and SIRT5 controls global lysine succinylation in cells and activates CPS1, SOD1 and SHMT2 by desuccinylation; core function. Supporting Evidence: PMID:22076378 With all three peptide sequences, the catalytic efficiencies for demalonylation and desuccinylation were much (29 to >1000 fold) higher than that for deacetylation PMID:22076378 Thus, Tyr102 and Arg105 were important for binding succinyl and malonyl groups. |
| GO:0036055 protein-succinyllysine desuccinylase activity | IDA PMID:24140062 SIRT5 desuccinylates and activates SOD1 to eliminate ROS. | ACCEPT | Summary: Directly demonstrated protein-succinyllysine desuccinylase activity. Reason: Desuccinylation is the most efficient SIRT5 reaction; Tyr102/Arg105 bind the succinyl carboxylate, and SIRT5 controls global lysine succinylation in cells and activates CPS1, SOD1 and SHMT2 by desuccinylation; core function. Supporting Evidence: PMID:24140062 SIRT5 binds to, desuccinylates and activates SOD1. |
| GO:0036055 protein-succinyllysine desuccinylase activity | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Directly demonstrated protein-succinyllysine desuccinylase activity. Reason: Desuccinylation is the most efficient SIRT5 reaction; Tyr102/Arg105 bind the succinyl carboxylate, and SIRT5 controls global lysine succinylation in cells and activates CPS1, SOD1 and SHMT2 by desuccinylation; core function. Supporting Evidence: PMID:24703693 were significantly higher for desuccinylation and deglutarylation compared to the demalonylase activity |
| GO:0036055 protein-succinyllysine desuccinylase activity | IDA PMID:29180469 SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferat... | ACCEPT | Summary: Directly demonstrated protein-succinyllysine desuccinylase activity. Reason: Desuccinylation is the most efficient SIRT5 reaction; Tyr102/Arg105 bind the succinyl carboxylate, and SIRT5 controls global lysine succinylation in cells and activates CPS1, SOD1 and SHMT2 by desuccinylation; core function. Supporting Evidence: PMID:29180469 SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. |
| GO:0036055 protein-succinyllysine desuccinylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Desuccinylase activity (UniRule/Rhea); experimentally supported. Reason: Desuccinylation is the most efficient SIRT5 reaction; Tyr102/Arg105 bind the succinyl carboxylate, and SIRT5 controls global lysine succinylation in cells and activates CPS1, SOD1 and SHMT2 by desuccinylation; core function. Supporting Evidence: PMID:22076378 Our data suggest that Sirt5 is an NAD-dependent demalonylase and desuccinylase. |
| GO:0061697 protein-glutaryllysine deglutarylase activity | EXP PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Deglutarylase activity demonstrated experimentally. Reason: SIRT5 is the only HDAC/sirtuin with significant lysine deglutarylase activity in vitro, and it deglutarylates and activates CPS1; core function. Supporting Evidence: PMID:24703693 Using this assay, we found SIRT5 is the only HDAC exhibiting significant lysine deglutarylase activity in vitro PMID:24703693 were significantly higher for desuccinylation and deglutarylation compared to the demalonylase activity |
| GO:0061697 protein-glutaryllysine deglutarylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Deglutarylase activity, inherited from the SIRT5-subfamily node. Reason: SIRT5 is the only HDAC/sirtuin with significant lysine deglutarylase activity in vitro, and it deglutarylates and activates CPS1; core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade, taxon Eukaryota) carrying the IBD; human SIRT5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER Mouse Sirt5 (Q8K2C6), the orthologous experimental seed in the same subfamily. UniProtKB:Q9NXA8 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences the PAINT curator used; expected, not circular. Supporting Evidence: PMID:24703693 Using this assay, we found SIRT5 is the only HDAC exhibiting significant lysine deglutarylase activity in vitro |
| GO:0061697 protein-glutaryllysine deglutarylase activity | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Deglutarylase activity measured on peptides and CPS1. Reason: SIRT5 is the only HDAC/sirtuin with significant lysine deglutarylase activity in vitro, and it deglutarylates and activates CPS1; core function. Supporting Evidence: PMID:24703693 Using this assay, we found SIRT5 is the only HDAC exhibiting significant lysine deglutarylase activity in vitro PMID:24703693 Glutarylation of CPS1 inhibits its activity, but can be reserved by SIRT5. |
| GO:0061697 protein-glutaryllysine deglutarylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Deglutarylase activity (UniRule/Rhea); experimentally supported. Reason: SIRT5 is the only HDAC/sirtuin with significant lysine deglutarylase activity in vitro, and it deglutarylates and activates CPS1; core function. Supporting Evidence: PMID:24703693 Using this assay, we found SIRT5 is the only HDAC exhibiting significant lysine deglutarylase activity in vitro |
| GO:0061698 protein deglutarylation | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: SIRT5 deglutarylates CPS1 and other proteins. Reason: SIRT5 is the only HDAC/sirtuin with significant lysine deglutarylase activity in vitro, and it deglutarylates and activates CPS1; core function. Supporting Evidence: PMID:24703693 Glutarylation of CPS1 inhibits its activity, but can be reserved by SIRT5. |
| GO:0070403 NAD+ binding | IDA PMID:21908771 The first identification of lysine malonylation substrates a... | KEEP AS NON CORE | Summary: NAD+ co-substrate binding; non-core. Reason: NAD+ is the obligatory co-substrate of the SIRT5 deacylation reaction (consumed to 2'-O-acyl-ADP-ribose and nicotinamide), and crystal structures show NAD bound in the Rossmann-fold site. True, but the binding is entailed by the deacylase activity; non-core. Supporting Evidence: PMID:24703693 NAD+ is required for SIRT5-dependent desuccinylation and demalonylation reactions |
| GO:0070403 NAD+ binding | IDA PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | KEEP AS NON CORE | Summary: NAD+ co-substrate binding shown structurally; non-core. Reason: NAD+ is the obligatory co-substrate of the SIRT5 deacylation reaction (consumed to 2'-O-acyl-ADP-ribose and nicotinamide), and crystal structures show NAD bound in the Rossmann-fold site. True, but the binding is entailed by the deacylase activity; non-core. Supporting Evidence: PMID:22076378 Thus, the mechanism for Sirt5-catalyzed desuccinylation or demalonylation is similar to the deacetylation mechanism of Class I sirtuins. PMID:22076378 Our data suggest that Sirt5 is an NAD-dependent demalonylase and desuccinylase. |
| GO:0070403 NAD+ binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: NAD+ binding (InterPro/UniRule); non-core. Reason: NAD+ is the obligatory co-substrate of the SIRT5 deacylation reaction (consumed to 2'-O-acyl-ADP-ribose and nicotinamide), and crystal structures show NAD bound in the Rossmann-fold site. True, but the binding is entailed by the deacylase activity; non-core. Supporting Evidence: PMID:22076378 Our data suggest that Sirt5 is an NAD-dependent demalonylase and desuccinylase. |
| GO:1990404 NAD+-protein mono-ADP-ribosyltransferase activity | TAS NOT PMID:17456799 Sirtuin functions in health and disease. | ACCEPT | Summary: NOT mono-ADP-ribosyltransferase activity: no ADP-ribosyltransferase activity has been reported for SIRT5. Reason: The family review notes that only certain sirtuins have ADP-ribosyltransferase activity; in PAINT that activity sits on the SIRT4/SIRT6 and bacterial nodes, not on the SIRT5-subfamily node. SIRT5 uses NAD+ for acyl transfer to ADP-ribose in deacylation. No evidence contradicts the curator's negation (abstract-only cache), so it is accepted. Supporting Evidence: PMID:17456799 Certain sirtuins have in addition an ADP-ribosyltransferase activity. PMID:22076378 Thus, the mechanism for Sirt5-catalyzed desuccinylation or demalonylation is similar to the deacetylation mechanism of Class I sirtuins. |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | IDA PMID:24140062 SIRT5 desuccinylates and activates SOD1 to eliminate ROS. | KEEP AS NON CORE | Summary: SIRT5 lowers ROS by desuccinylating and activating SOD1; a substrate-specific consequence of the core activity. Reason: SIRT5 binds, desuccinylates and activates SOD1, and SOD1-mediated ROS reduction increases when SIRT5 is co-expressed. SIRT5 acts upstream of SOD1 rather than in ROS metabolism itself; the regulatory term is appropriate but non-core. Supporting Evidence: PMID:24140062 SIRT5 binds to, desuccinylates and activates SOD1. PMID:24140062 SOD1-mediated ROS reduction is increased when SIRT5 is co-expressed. |
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Download this section (compressed HTML)Q: Should GO provide a 'regulation of urea cycle' term so that SIRT5 (a CPS1-activating deacylase) can be annotated as a regulator rather than as involved_in the urea cycle itself?
Q: Does the weak in vitro deacetylase activity of SIRT5 (cytochrome c, H3K9ac peptide) have any physiological substrate, given that Sirt5 loss does not alter global or CPS1 acetylation?
Experiment: Quantitative sub-mitochondrial fractionation (matrix vs intermembrane space vs inner membrane) of endogenous SIRT5 in human hepatocytes, to settle the inner-membrane projection and the size of the IMS pool.
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