Sirt5 is an NAD+-dependent protein lysine deacylase of the sirtuin family (class III) that preferentially removes negatively charged acyl groups (succinyl, malonyl and glutaryl) from lysine residues, transferring the acyl group to ADP-ribose and releasing nicotinamide; its deacetylase activity is weak. Tyr102 and Arg105 in the acyl-binding pocket recognize the acyl carboxylate. The protein carries an N-terminal mitochondrial transit peptide and acts mainly in the mitochondrial matrix, with a substantial cytosolic pool and a trace nuclear pool. In mouse, loss of Sirt5 causes widespread lysine hypersuccinylation and hyperglutarylation in liver, embryonic fibroblasts and heart without changing lysine acetylation. Characterized mouse substrates include CPS1, whose activation by Sirt5 supports urea-cycle ammonia disposal during fasting, HMGCS2 (ketogenesis), and subunits of the pyruvate dehydrogenase and succinate dehydrogenase complexes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002931 response to ischemia | IMP PMID:26388266 Characterization of the cardiac succinylome and its role in ... | MARK AS OVER ANNOTATED | Summary: Sirt5 knockout hearts suffer greater ischemia-reperfusion injury; this is a downstream phenotype, not a response process Sirt5 executes. Reason: The IMP shows that Sirt5-/- hearts have larger infarcts after ischemia-reperfusion, rescued by the SDH inhibitor dimethyl malonate, implicating SDH hypersuccinylation. Sirt5 is a constitutive mitochondrial desuccinylase; it is not shown to be induced by or to carry out a response to ischemia. The annotation records an organismal consequence of loss of its desuccinylase activity and is retained only as an over-annotation of the acts-upstream phenotype. Supporting Evidence: PMID:26388266 Strikingly, dimethyl malonate treatment of Sirt5β/β hearts restored RPP recovery to WT levels PMID:26388266 Taken together, these data are consistent with the hypothesis that Sirt5 functions as a desuccinylase in cardiac mitochondria. |
| GO:0005515 protein binding | IPI PMID:19410549 SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regu... | REMOVE | Summary: Endogenous Sirt5 co-immunoprecipitates CPS1 from mouse liver mitochondria; generic protein binding is uninformative. Reason: The interaction is real (CPS1, Q8C196, co-IPs with Sirt5 but not Sirt4), but CPS1 is a deacylation substrate, and that function is already captured by the desuccinylase and deglutarylase activity terms. Removal follows the protein-binding policy and does not dispute the interaction. Supporting Evidence: PMID:19410549 CPS1 was co-immunoprecipitated by antibody to SIRT5 but not SIRT4 PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A very small nuclear pool of Sirt5 is detectable in mouse liver; secondary to its mitochondrial location. Reason: Fractionation of mouse liver detected a very small amount of Sirt5 in the nuclear fraction, so the location is real but minor. The IBA comes from a deep node seeded by nuclear sirtuins; the PAINT curator did not place nucleus on the SIRT5-subfamily node PTN000119399, which carries mitochondrion and cytosol. 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 sirtuins (SIRT1/6/7, yeast Sir2/Hst); not placed on the SIRT5 node. Sirt5 has a transit peptide and only a trace nuclear 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:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A very small nuclear pool of Sirt5 is detectable in mouse liver; secondary to its mitochondrial location. Reason: Fractionation of mouse liver detected a very small amount of Sirt5 in the nuclear fraction, so the location is real but minor. The IBA comes from a deep node seeded by nuclear sirtuins; the PAINT curator did not place nucleus on the SIRT5-subfamily node PTN000119399, which carries mitochondrion and cytosol. 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:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol 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: A very small nuclear pool of Sirt5 is detectable in mouse liver; secondary to its mitochondrial location. Reason: Fractionation of mouse liver detected a very small amount of Sirt5 in the nuclear fraction, so the location is real but minor. The IBA comes from a deep node seeded by nuclear sirtuins; the PAINT curator did not place nucleus on the SIRT5-subfamily node PTN000119399, which carries mitochondrion and cytosol. 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:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | HDA PMID:18614015 A mitochondrial protein compendium elucidates complex I dise... | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:18614015 we performed mass spectrometry, GFP tagging, and machine learning to create a mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade) carrying the IBD; mouse Sirt5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences used for the IBD; expected, not circular. UniProtKB:Q9NXA8 SUPPORTS TRANSFER Human SIRT5, the 1:1 ortholog and second experimental seed in the same subfamily. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | IDA PMID:17923681 Mammalian Sir2 homolog SIRT3 regulates global mitochondrial ... | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:17923681 no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5 PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | IDA PMID:23806337 SIRT5-mediated lysine desuccinylation impacts diverse metabo... | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | IDA PMID:26388266 Characterization of the cardiac succinylome and its role in ... | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:26388266 To determine if Sirt5 functions as a desuccinylase in heart mitochondria, we analyzed the total succinylated lysine content of mitochondria isolated from mouse hearts. PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | IDA PMID:26767982 Nutritional stress exacerbates hepatic steatosis induced by ... | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | IMP PMID:26388266 Characterization of the cardiac succinylome and its role in ... | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:26388266 To determine if Sirt5 functions as a desuccinylase in heart mitochondria, we analyzed the total succinylated lysine content of mitochondria isolated from mouse hearts. PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | ISO GO_REF:0000119 | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9NXA8 SUPPORTS TRANSFER Human SIRT5, 1:1 ortholog in PTHR11085:SF10; mitochondrial location holds for mouse, refined to matrix by mouse fractionation. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | MODIFY | Summary: Sirt5 is mitochondrial; the specific compartment established in mouse is the matrix. Reason: Mitochondrion is correct but less specific than the mouse evidence: fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where its substrates CPS1, HMGCS2, PDC and SDH reside. Refined to mitochondrial matrix (already carried by this gene). An intermembrane-space pool is reported only for human SIRT5 (in vitro import), so it is not added here as a mouse-established refinement. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:18054327 Localization of mouse mitochondrial SIRT proteins: shift of ... | UNDECIDED | Summary: Inner-membrane location from an abstract-only localization study; not reconcilable with the matrix fractionation here. Reason: The cached record for PMID:18054327 is abstract-only and says only that the three mitochondrial sirtuins occupy different compartments. Mouse liver fractionation in PMID:19410549 placed Sirt5 in the soluble matrix, and Sirt5 has no transmembrane segment. Without the full text the inner-membrane assignment can be neither confirmed nor rejected, so the curator's call is left undecided. Supporting Evidence: PMID:18054327 SIRT3, SIRT4, and SIRT5 proteins were localized in different compartments of the mitochondria. PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Intermembrane-space pool inferred from human SIRT5; not established for mouse Sirt5. Reason: Human SIRT5 can be imported into the intermembrane space as well as the matrix in an in vitro import assay, where it can act on cytochrome c. Mouse Sirt5 is a 1:1 ortholog in the same PANTHER subfamily, so the transfer is evolutionarily sound, but no mouse experiment shows an IMS pool. Kept as a non-core, inferred location. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005758 mitochondrial intermembrane space | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Intermembrane-space pool inferred from human SIRT5; not established for mouse Sirt5. Reason: Human SIRT5 can be imported into the intermembrane space as well as the matrix in an in vitro import assay, where it can act on cytochrome c. Mouse Sirt5 is a 1:1 ortholog in the same PANTHER subfamily, so the transfer is evolutionarily sound, but no mouse experiment shows an IMS pool. Kept as a non-core, inferred location. Supporting Evidence: PMID:18680753 Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix |
| GO:0005758 mitochondrial intermembrane space | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Intermembrane-space pool inferred from human SIRT5; not established for mouse Sirt5. Reason: Human SIRT5 can be imported into the intermembrane space as well as the matrix in an in vitro import assay, where it can act on cytochrome c. Mouse Sirt5 is a 1:1 ortholog in the same PANTHER subfamily, so the transfer is evolutionarily sound, but no mouse experiment shows an IMS pool. Kept as a non-core, inferred location. 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 action in mouse. Reason: Fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where it desuccinylates and deglutarylates matrix enzymes such as CPS1 and HMGCS2. Core location. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000872307 SUPPORTS TRANSFER Metazoan SIRT5-lineage node seeded by human SIRT5 matrix evidence; consistent with mouse fractionation. Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: Mitochondrial matrix is the principal site of Sirt5 action in mouse. Reason: Fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where it desuccinylates and deglutarylates matrix enzymes such as CPS1 and HMGCS2. Core location. Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005759 mitochondrial matrix | ISO GO_REF:0000119 | ACCEPT | Summary: Mitochondrial matrix is the principal site of Sirt5 action in mouse. Reason: Fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where it desuccinylates and deglutarylates matrix enzymes such as CPS1 and HMGCS2. Core location. Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial matrix is the principal site of Sirt5 action in mouse. Reason: Fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where it desuccinylates and deglutarylates matrix enzymes such as CPS1 and HMGCS2. Core location. Supporting Evidence: PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-MMU-9955513 | ACCEPT | Summary: Mitochondrial matrix is the principal site of Sirt5 action in mouse. Reason: Fractionation of mouse liver mitochondria placed endogenous Sirt5 in the matrix, where it desuccinylates and deglutarylates matrix enzymes such as CPS1 and HMGCS2. Core location. Supporting Evidence: Reactome:R-MMU-9955513 Sirt5 desuccinylates Cps1 at residue K1291, activating the enzyme PMID:19410549 These results all indicate that SIRT5 is a mitochondrial matrix protein. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: A substantial fraction of endogenous Sirt5 is cytosolic in mouse liver. Reason: Subcellular fractionation of mouse liver showed a significant cytosolic pool of endogenous Sirt5, consistent with Sirt5-dependent succinylation of cytosolic proteins (e.g. glycolytic enzymes) in knockout MEFs and liver. The PAINT curator 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) carrying the IBD; mouse Sirt5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences used for the IBD; expected, not circular. UniProtKB:Q9NXA8 SUPPORTS TRANSFER Human SIRT5, the 1:1 ortholog and second experimental seed in the same subfamily. Supporting Evidence: PMID:23806337 Subcellular fractionation revealed that a significant fraction of endogenous SIRT5 was present cytosolically both in human cells (Figure 5A) and mouse liver (Figure 5B). file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005829 cytosol | IDA PMID:23806337 SIRT5-mediated lysine desuccinylation impacts diverse metabo... | ACCEPT | Summary: A substantial fraction of endogenous Sirt5 is cytosolic in mouse liver. Reason: Subcellular fractionation of mouse liver showed a significant cytosolic pool of endogenous Sirt5, consistent with Sirt5-dependent succinylation of cytosolic proteins (e.g. glycolytic enzymes) in knockout MEFs and liver. The PAINT curator 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 (Figure 5A) and mouse liver (Figure 5B). file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: A substantial fraction of endogenous Sirt5 is cytosolic in mouse liver. Reason: Subcellular fractionation of mouse liver showed a significant cytosolic pool of endogenous Sirt5, consistent with Sirt5-dependent succinylation of cytosolic proteins (e.g. glycolytic enzymes) in knockout MEFs and liver. The PAINT curator 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 (Figure 5A) and mouse liver (Figure 5B). file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: A substantial fraction of endogenous Sirt5 is cytosolic in mouse liver. Reason: Subcellular fractionation of mouse liver showed a significant cytosolic pool of endogenous Sirt5, consistent with Sirt5-dependent succinylation of cytosolic proteins (e.g. glycolytic enzymes) in knockout MEFs and liver. The PAINT curator 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 (Figure 5A) and mouse liver (Figure 5B). file:mouse/Sirt5/Sirt5-uniprot.txt Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus. |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000108 | REMOVE | Summary: Chromatin remodeling is inferred only from the deep-node histone deacetylase IBA; no chromatin role for Sirt5. Reason: This IEA is a logical inference from GO:0017136 (NAD-dependent histone deacetylase activity), itself an inherited ancestral IBA that Sirt5 has diverged from. Sirt5 is mainly mitochondrial and cytosolic with only a trace nuclear pool, and no chromatin-remodeling activity has been shown in mouse or human. 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:23806337 A very small amount of SIRT5 was also detected in the nuclear fraction, which was particularly evident in the liver samples |
| GO:0006476 protein deacetylation | ISO GO_REF:0000119 | REMOVE | Summary: Positive protein deacetylation transferred from human; contradicted by mouse knockout data and by the accepted NOT annotation. Reason: Sirt5 deacetylates peptides only weakly in vitro (about 500-fold less efficiently than SIRT1 on H3K9ac), and in mouse its loss changes succinylation and glutarylation but not acetylation. The original claim that Sirt5 activates CPS1 by deacetylation (PMID:19410549) was superseded by desuccinylation and deglutarylation. The process annotation overstates a weak in vitro side activity. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:Q9NXA8 SUPPORTS SOURCE BUT NOT TARGET Donor is human SIRT5's weak in vitro deacetylation; mouse KO data show no physiological deacetylation, and the same donor also carries a NOT for this process. Supporting Evidence: PMID:22076378 The catalytic efficiency (kcat/Km) of Sirt5 was about 500-fold lower than that of Sirt1. PMID:23806337 our data showed that SIRT5 deficiency does not significantly impact global Lys acetylation PMID:22076378 In contrast, acetylation levels of Lys1291 did not change in Sirt5 KO compared with wt |
| GO:0006476 protein deacetylation | ISS NOT GO_REF:0000024 | ACCEPT | Summary: NOT protein deacetylation: Sirt5 loss does not change global or site-specific lysine acetylation in mouse. Reason: The NOT is transferred from human SIRT5, and mouse data independently support it: Sirt5 knockout mice show no mitochondrial hyperacetylation, Sirt5 KO MEFs show unchanged global acetylation, and CPS1 K1291 acetylation is unchanged while its succinylation rises. Weak in vitro deacetylation of peptides by the human enzyme does not amount to a physiological deacetylation process. Supporting Evidence: PMID:23806337 our data showed that SIRT5 deficiency does not significantly impact global Lys acetylation PMID:17923681 no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5 PMID:22076378 In contrast, acetylation levels of Lys1291 did not change in Sirt5 KO compared with wt PMID:18680753 Sirt5, in contrast to Sirt3, deacetylates none of the mitochondrial matrix proteins tested. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Structural zinc bound by the conserved sirtuin Cys4 zinc-ribbon. Reason: Sirtuins bind one structural zinc ion through four cysteines in the small domain; the four cysteines (C166, C169, C207, C212) are conserved in mouse Sirt5. Zinc binding is structural, not catalytic, so the term is true but non-core. Supporting Evidence: file:mouse/Sirt5/Sirt5-uniprot.txt Binds 1 zinc ion per subunit. file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md the four zinc-binding cysteines (C166, C169, C207, C212) are identical |
| GO:0008270 zinc ion binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Structural zinc bound by the conserved sirtuin Cys4 zinc-ribbon. Reason: Sirtuins bind one structural zinc ion through four cysteines in the small domain; the four cysteines (C166, C169, C207, C212) are conserved in mouse Sirt5. Zinc binding is structural, not catalytic, so the term is true but non-core. Supporting Evidence: file:mouse/Sirt5/Sirt5-uniprot.txt Binds 1 zinc ion per subunit. file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md the four zinc-binding cysteines (C166, C169, C207, C212) are identical |
| GO:0010566 regulation of ketone biosynthetic process | IMP PMID:24315375 SIRT5 regulates the mitochondrial lysine succinylome and met... | KEEP AS NON CORE | Summary: Sirt5 knockout mice have decreased ketone body production and hypersuccinylated, less active HMGCS2. Reason: Sirt5 regulates ketogenesis by desuccinylating HMGCS2, the rate-limiting enzyme; succinyl-mimetic mutations at K83/K310 inhibit HMGCS2. This is a real regulatory consequence of the core desuccinylase activity on one substrate, so it is kept as non-core. Supporting Evidence: PMID:24315375 In addition, we show that hypersuccinylation occurs on almost all proteins involved in fatty acid Ξ²-oxidation and ketogenesis in the absence of SIRT5, and that this switch in the succinylation state is associated with accumulation of both medium and long chain acylcarnitines as well as decreased ketone body production during fasting. PMID:24315375 our data support the model that lysine succinylation and desuccinylation by SIRT5 can regulate HMGCS2 activity through disrupting and restoring the binding pocket for phosphate groups of acetyl-CoA respectively |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Anti-apoptotic role in cardiomyocytes transferred from rat; indirect consequence of mitochondrial deacylation. Reason: The ISO/IEA rows transfer a rat cardiomyocyte annotation. In mouse, Sirt5 loss worsens cardiac ischemia-reperfusion injury through SDH hypersuccinylation, a metabolic effect several steps removed from regulation of the apoptotic program. Sirt5 is not shown to act on apoptotic machinery, so this is an over-annotation of an indirect phenotype. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: ROLE CONFLATION Sources checked: RGD:1303285 SOURCE WEAK OR INFERRED Rat Sirt5 cardiomyocyte annotation; a downstream survival phenotype rather than direct regulation of apoptosis. Supporting Evidence: PMID:26388266 Strikingly, dimethyl malonate treatment of Sirt5β/β hearts restored RPP recovery to WT levels |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Anti-apoptotic role in cardiomyocytes transferred from rat; indirect consequence of mitochondrial deacylation. Reason: The ISO/IEA rows transfer a rat cardiomyocyte annotation. In mouse, Sirt5 loss worsens cardiac ischemia-reperfusion injury through SDH hypersuccinylation, a metabolic effect several steps removed from regulation of the apoptotic program. Sirt5 is not shown to act on apoptotic machinery, so this is an over-annotation of an indirect phenotype. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: ROLE CONFLATION Sources checked: RGD:1303285 SOURCE WEAK OR INFERRED Rat Sirt5 cardiomyocyte annotation; a downstream survival phenotype rather than direct regulation of apoptosis. Supporting Evidence: PMID:26388266 Strikingly, dimethyl malonate treatment of Sirt5β/β hearts restored RPP recovery to WT levels |
| GO:0017136 histone deacetylase activity, NAD-dependent | IBA GO_REF:0000033 | MODIFY | Summary: Inherited family-wide histone deacetylase IBD; Sirt5's acyl pocket is specialized for acidic acyl groups. Reason: The IBD sits on a deep node seeded by class I/IV deacetylases. On the SIRT5-subfamily node PTN000119399 the PAINT curator placed desuccinylase, demalonylase and deglutarylase, not deacetylase. Sirt5 shows target-specific divergence: Tyr102/Arg105 (conserved in mouse) bind carboxylate acyl groups, deacetylation is 29 to >1000-fold less efficient than desuccinylation/demalonylation, and Sirt5 loss in mouse does not change acetylation. Refined to the three acidic deacylase activities, consistent with the human SIRT5 review. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN008718612 SUPPORTS SOURCE BUT NOT TARGET Deep sirtuin node seeded by robust deacetylases (SIRT1-3, SIRT6, yeast Sir2/Hst); no SIRT5 seed. SIRT5 diverged to acidic-acyl specificity via Tyr102/Arg105. Proposed replacements: protein-succinyllysine desuccinylase activity protein-malonyllysine demalonylase activity protein-glutaryllysine deglutarylase 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 Thus, Tyr102 and Arg105 were important for binding succinyl and malonyl groups. file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 PMID:23806337 our data showed that SIRT5 deficiency does not significantly impact global Lys acetylation |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Sirt5-dependent CPS1 activation is required for ammonia disposal during fasting. Reason: Sirt5 KO mice fail to upregulate CPS1 activity and develop hyperammonemia after a 48 h fast, and CPS1 is hypersuccinylated/hyperglutarylated in KO liver. Sirt5 thus contributes to the metabolic adaptation to nutrient limitation through its deacylase activity; a broad, non-core process. Supporting Evidence: PMID:19410549 On the contrary, after 48 hours fasting, SIRT5 mice showed significantly elevated blood ammonia levels compared to wild type PMID:24703693 Hyperglutarylation was associated with reduced hepatic CPS1 enzymatic activity in SIRT5KO mouse liver |
| GO:0034979 NAD-dependent protein lysine deacetylase activity | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: Weak NAD-dependent deacetylase activity exists in vitro but is not the physiological function. Reason: SIRT5 deacetylates some peptides in vitro, but about 500-fold less efficiently than SIRT1, and Sirt5 loss in mouse does not alter lysine acetylation. The activity is real but minor and kept as non-core; the related process-level NOT (protein deacetylation) records that it has no demonstrated physiological role. Supporting Evidence: PMID:22076378 The catalytic efficiency (kcat/Km) of Sirt5 was about 500-fold lower than that of Sirt1. PMID:23806337 our data showed that SIRT5 deficiency does not significantly impact global Lys acetylation |
| GO:0036046 protein demalonylation | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Sirt5 removes malonyl groups from protein lysines in vitro and in vivo. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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:0036046 protein demalonylation | ISO GO_REF:0000119 | ACCEPT | Summary: Sirt5 removes malonyl groups from protein lysines in vitro and in vivo. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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:0036047 peptidyl-lysine demalonylation | IMP PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: Sirt5 removes malonyl groups from protein lysines in vitro and in vivo. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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:0036047 peptidyl-lysine demalonylation | ISO GO_REF:0000119 | ACCEPT | Summary: Sirt5 removes malonyl groups from protein lysines in vitro and in vivo. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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:0036048 protein desuccinylation | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:24703693 To validate the results of the in vitro studies, we examined lysine glutarylation and lysine succinylation in Sirt5+/+ (WT) and Sirt5β/β (KO) mouse tissues. |
| GO:0036048 protein desuccinylation | IMP PMID:23806337 SIRT5-mediated lysine desuccinylation impacts diverse metabo... | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:23806337 These data showed that SIRT5 deficiency significantly impacted Ksucc levels, suggesting that SIRT5 is a central regulator of Lys succinylation in mammalian cells |
| GO:0036048 protein desuccinylation | IMP PMID:24315375 SIRT5 regulates the mitochondrial lysine succinylome and met... | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:24315375 In addition, we show that hypersuccinylation occurs on almost all proteins involved in fatty acid Ξ²-oxidation and ketogenesis in the absence of SIRT5, and that this switch in the succinylation state is associated with accumulation of both medium and long chain acylcarnitines as well as decreased ketone body production during fasting. |
| GO:0036048 protein desuccinylation | ISO GO_REF:0000119 | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice PMID:23806337 These data showed that SIRT5 deficiency significantly impacted Ksucc levels, suggesting that SIRT5 is a central regulator of Lys succinylation in mammalian cells |
| GO:0036049 peptidyl-lysine desuccinylation | IMP PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. 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:0036049 peptidyl-lysine desuccinylation | IMP PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice |
| GO:0036049 peptidyl-lysine desuccinylation | IMP PMID:26388266 Characterization of the cardiac succinylome and its role in ... | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:26388266 Taken together, these data are consistent with the hypothesis that Sirt5 functions as a desuccinylase in cardiac mitochondria. |
| GO:0036049 peptidyl-lysine desuccinylation | ISO GO_REF:0000119 | ACCEPT | Summary: Sirt5 is the principal lysine desuccinylase in mouse tissues. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice PMID:23806337 These data showed that SIRT5 deficiency significantly impacted Ksucc levels, suggesting that SIRT5 is a central regulator of Lys succinylation in mammalian cells |
| GO:0036054 protein-malonyllysine demalonylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Protein-malonyllysine demalonylase activity. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade) carrying the IBD; mouse Sirt5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences used for the IBD; expected, not circular. UniProtKB:Q9NXA8 SUPPORTS TRANSFER Human SIRT5, the 1:1 ortholog and second experimental seed in the same subfamily. 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 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 file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0036054 protein-malonyllysine demalonylase activity | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Protein-malonyllysine demalonylase activity. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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 file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0036054 protein-malonyllysine demalonylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein-malonyllysine demalonylase activity. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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 file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0036054 protein-malonyllysine demalonylase activity | IMP PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: Protein-malonyllysine demalonylase activity. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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 file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0036054 protein-malonyllysine demalonylase activity | ISO GO_REF:0000119 | ACCEPT | Summary: Protein-malonyllysine demalonylase activity. Reason: Peng et al. showed Sirt5-catalysed demalonylation in vitro and in vivo (Sirt5-deficient cells); the malonyl preference is explained by the conserved Tyr102/Arg105 acyl pocket. Core activity, although fewer physiological malonyl substrates are characterized than for succinyl. 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 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 file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0036055 protein-succinyllysine desuccinylase activity | EXP PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice 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 | IBA GO_REF:0000033 | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade) carrying the IBD; mouse Sirt5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences used for the IBD; expected, not circular. UniProtKB:Q9NXA8 SUPPORTS TRANSFER Human SIRT5, the 1:1 ortholog and second experimental seed in the same subfamily. 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 file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0036055 protein-succinyllysine desuccinylase activity | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:24703693 To validate the results of the in vitro studies, we examined lysine glutarylation and lysine succinylation in Sirt5+/+ (WT) and Sirt5β/β (KO) mouse tissues. |
| GO:0036055 protein-succinyllysine desuccinylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. 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 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0036055 protein-succinyllysine desuccinylase activity | IMP PMID:21908771 The first identification of lysine malonylation substrates a... | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. 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 | IMP PMID:22076378 Sirt5 is a NAD-dependent protein lysine demalonylase and des... | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:22076378 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice 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 | IMP PMID:23806337 SIRT5-mediated lysine desuccinylation impacts diverse metabo... | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:23806337 These data showed that SIRT5 deficiency significantly impacted Ksucc levels, suggesting that SIRT5 is a central regulator of Lys succinylation in mammalian cells PMID:23806337 Our finding that SIRT5 desuccinylates PDC subunits to inhibit PDC activity reveals a previously unappreciated aspect of PDC regulation |
| GO:0036055 protein-succinyllysine desuccinylase activity | IMP PMID:24315375 SIRT5 regulates the mitochondrial lysine succinylome and met... | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:24315375 our data support the model that lysine succinylation and desuccinylation by SIRT5 can regulate HMGCS2 activity through disrupting and restoring the binding pocket for phosphate groups of acetyl-CoA respectively |
| GO:0036055 protein-succinyllysine desuccinylase activity | IMP PMID:26388266 Characterization of the cardiac succinylome and its role in ... | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. Core function. Supporting Evidence: PMID:26388266 Taken together, these data are consistent with the hypothesis that Sirt5 functions as a desuccinylase in cardiac mitochondria. |
| GO:0036055 protein-succinyllysine desuccinylase activity | ISO GO_REF:0000119 | ACCEPT | Summary: Protein-succinyllysine desuccinylase activity, the most efficient Sirt5 reaction. Reason: Desuccinylation is the most efficient Sirt5 reaction. In mouse, Sirt5 knockout causes broad lysine hypersuccinylation in liver, MEFs and heart mitochondria, including CPS1 K1291 and HMGCS2, without changing acetylation at the same sites. The acyl-pocket Tyr102/Arg105 that bind the succinyl carboxylate are conserved between mouse and human. 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 For Lys1291, succinylation level increased dramatically in Sirt5 KO mice compared with the level in wt mice file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:0061697 protein-glutaryllysine deglutarylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Protein-glutaryllysine deglutarylase activity. Reason: Sirt5 knockout mouse liver shows marked protein hyperglutarylation, including CPS1, with reduced CPS1 activity; SIRT5 was the only one of 18 recombinant HDACs with significant deglutarylase activity. Core function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000119399 SUPPORTS TRANSFER SIRT5-subfamily node (PTHR11085:SF10 clade) carrying the IBD; mouse Sirt5 descends directly from it. MGI:MGI:1915596 SUPPORTS TRANSFER The target's own experimental annotation is one of the descendant evidences used for the IBD; expected, not circular. UniProtKB:Q9NXA8 SUPPORTS TRANSFER Human SIRT5, the 1:1 ortholog and second experimental seed in the same subfamily. Supporting Evidence: PMID:24703693 Hyperglutarylation was associated with reduced hepatic CPS1 enzymatic activity in SIRT5KO mouse liver PMID:24703693 Further, Sirt5 is only one of the 18 recombinant HDACs that showed significant deglutarylation activity |
| GO:0061697 protein-glutaryllysine deglutarylase activity | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Protein-glutaryllysine deglutarylase activity. Reason: Sirt5 knockout mouse liver shows marked protein hyperglutarylation, including CPS1, with reduced CPS1 activity; SIRT5 was the only one of 18 recombinant HDACs with significant deglutarylase activity. Core function. Supporting Evidence: PMID:24703693 Hyperglutarylation was associated with reduced hepatic CPS1 enzymatic activity in SIRT5KO mouse liver PMID:24703693 Further, Sirt5 is only one of the 18 recombinant HDACs that showed significant deglutarylation activity |
| GO:0061697 protein-glutaryllysine deglutarylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein-glutaryllysine deglutarylase activity. Reason: Sirt5 knockout mouse liver shows marked protein hyperglutarylation, including CPS1, with reduced CPS1 activity; SIRT5 was the only one of 18 recombinant HDACs with significant deglutarylase activity. Core function. Supporting Evidence: PMID:24703693 Hyperglutarylation was associated with reduced hepatic CPS1 enzymatic activity in SIRT5KO mouse liver PMID:24703693 Further, Sirt5 is only one of the 18 recombinant HDACs that showed significant deglutarylation activity |
| GO:0061697 protein-glutaryllysine deglutarylase activity | ISO GO_REF:0000119 | ACCEPT | Summary: Protein-glutaryllysine deglutarylase activity. Reason: Sirt5 knockout mouse liver shows marked protein hyperglutarylation, including CPS1, with reduced CPS1 activity; SIRT5 was the only one of 18 recombinant HDACs with significant deglutarylase activity. Core function. Supporting Evidence: PMID:24703693 Hyperglutarylation was associated with reduced hepatic CPS1 enzymatic activity in SIRT5KO mouse liver PMID:24703693 Further, Sirt5 is only one of the 18 recombinant HDACs that showed significant deglutarylation activity |
| GO:0061698 protein deglutarylation | IDA PMID:24703693 Lysine glutarylation is a protein posttranslational modifica... | ACCEPT | Summary: Sirt5 removes glutaryl groups from protein lysines in mouse liver. Reason: Sirt5 knockout mouse liver shows marked protein hyperglutarylation, including CPS1, with reduced CPS1 activity; SIRT5 was the only one of 18 recombinant HDACs with significant deglutarylase activity. Core function. Supporting Evidence: PMID:24703693 Hyperglutarylation was associated with reduced hepatic CPS1 enzymatic activity in SIRT5KO mouse liver PMID:24703693 Further, Sirt5 is only one of the 18 recombinant HDACs that showed significant deglutarylation activity |
| GO:0061698 protein deglutarylation | ISO GO_REF:0000119 | ACCEPT | Summary: Sirt5 removes glutaryl groups from protein lysines in mouse liver. Reason: Sirt5 knockout mouse liver shows marked protein hyperglutarylation, including CPS1, with reduced CPS1 activity; SIRT5 was the only one of 18 recombinant HDACs with significant deglutarylase activity. Core function. Supporting Evidence: PMID:24703693 Hyperglutarylation was associated with reduced hepatic CPS1 enzymatic activity in SIRT5KO mouse liver PMID:24703693 Further, Sirt5 is only one of the 18 recombinant HDACs that showed significant deglutarylation activity |
| GO:0070403 NAD+ binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: NAD+ is the co-substrate of Sirt5 deacylation. Reason: Sirt5 consumes NAD+ as the acyl acceptor, producing nicotinamide and 2'-O-acyl-ADP-ribose; NAD+ binding is part of the catalytic mechanism already implied by the deacylase activity terms, so it is true but non-core. 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 file:mouse/Sirt5/Sirt5-uniprot.txt Belongs to the sirtuin family. Class III subfamily. |
| GO:0070403 NAD+ binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: NAD+ is the co-substrate of Sirt5 deacylation. Reason: Sirt5 consumes NAD+ as the acyl acceptor, producing nicotinamide and 2'-O-acyl-ADP-ribose; NAD+ binding is part of the catalytic mechanism already implied by the deacylase activity terms, so it is true but non-core. 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 file:mouse/Sirt5/Sirt5-uniprot.txt Belongs to the sirtuin family. Class III subfamily. |
| GO:0141218 NAD-dependent protein lysine deacylase activity | IEA GO_REF:0000117 | TOO GENERAL | Summary: NAD-dependent protein lysine deacylase activity is the parent of the three specific Sirt5 activities. Reason: True of Sirt5, but GO:0036055 desuccinylase, GO:0036054 demalonylase and GO:0061697 deglutarylase activity, all accepted here, are is_a descendants of this term and say which acyl groups Sirt5 removes. 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 |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from human: SIRT5 desuccinylates and activates SOD1, lowering ROS. Reason: Shown for human SIRT5 in cultured cells (SOD1 desuccinylation increases SOD1-mediated ROS reduction). Mouse Sirt5 is the 1:1 ortholog in the same PANTHER subfamily with an identical acyl pocket, so the transfer is sound, but there is no mouse-specific evidence. A regulatory consequence of desuccinylation; non-core. Supporting Evidence: PMID:24140062 SOD1-mediated ROS reduction is increased when SIRT5 is co-expressed. file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Transferred from human: SIRT5 desuccinylates and activates SOD1, lowering ROS. Reason: Shown for human SIRT5 in cultured cells (SOD1 desuccinylation increases SOD1-mediated ROS reduction). Mouse Sirt5 is the 1:1 ortholog in the same PANTHER subfamily with an identical acyl pocket, so the transfer is sound, but there is no mouse-specific evidence. A regulatory consequence of desuccinylation; non-core. Supporting Evidence: PMID:24140062 SOD1-mediated ROS reduction is increased when SIRT5 is co-expressed. file:mouse/Sirt5/Sirt5-bioinformatics/RESULTS.md mouse Y102 and R105 match human Y102 and R105 |
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Download this section (compressed HTML)Q: Does mouse Sirt5 have a physiologically relevant intermembrane-space pool, as reported for human SIRT5 in import assays, or is the IMS assignment species- or assay-specific?
Q: What compartment did Nakamura et al. (PMID:18054327) assign to mouse Sirt5, and can the inner-membrane annotation be reconciled with matrix fractionation?
Experiment: Protease-protection and sub-mitochondrial fractionation of endogenous Sirt5 in mouse liver and heart, to quantify matrix, intermembrane-space and inner-membrane pools.
Experiment: Kinetic characterization of recombinant mouse Sirt5 with acetyl, succinyl, malonyl and glutaryl peptides, so that species-matched activity data replace the human-enzyme kinetics.
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