Sirt5 (mouse, Q8K2C6) notes

2026-10-20 — Full re-review, independent of the ProtNLM2 predictions

No ProtNLM2 output was consulted for this review.

Deep research

just deep-research-falcon mouse Sirt5 --fallback perplexity-lite failed: falcon
returned "Failed to authenticate" and the perplexity-lite fallback returned HTTP 401
(insufficient quota). No deep-research file exists; the review is built from the
cached GOA references (all in publications/), the UniProt record and the existing
human SIRT5 review's references.

Evolutionary grounding

• Mouse Sirt5 is in PANTHER PTHR11085:SF10 with human SIRT5 (UniProt DR lines).
• PAINT node PTN000119399 (SIRT5 subfamily) carries IBDs for mitochondrion
  (GO:0005739), cytosol (GO:0005829), demalonylase (GO:0036054), desuccinylase
  (GO:0036055) and deglutarylase (GO:0061697); its seeds are MGI:1915596 (this gene)
  and human Q9NXA8 (interpro/panther/PTHR11085/PTHR11085-paint.tsv).
• Nucleus (GO:0005634) and NAD-dependent histone deacetylase (GO:0017136) IBAs come
  from deep sirtuin nodes (PTN008492176, PTN008718612) seeded by the nuclear/class I
  deacetylases, not from the SIRT5 node. The PAINT curator placed neither on the
  SIRT5 node.
• Gapless comparison mouse vs human: 86.1% identity; Y102, R105 (acyl pocket), H158
  and the four Zn cysteines identical (Sirt5-bioinformatics/RESULTS.md).

What is established in mouse itself (vs inferred)

Mouse-experimental:
- Desuccinylation in vivo: Sirt5 KO mice show CPS1 K1291 hypersuccinylation
without change in K1291 acetylation PMID:22076378;
global hypersuccinylation in KO MEFs and liver PMID:23806337; liver mitochondrial
succinylome, HMGCS2 hypersuccinylation and decreased beta-hydroxybutyrate
PMID:24315375; cardiac mitochondrial hypersuccinylation PMID:26388266.
- Deglutarylation in vivo: KO liver hyperglutarylation, CPS1 hyperglutarylation and
reduced CPS1 activity PMID:24703693.
- Demalonylation: Peng et al. report demalonylation in vitro and in vivo
[PMID:21908771, abstract-only in cache].
- No effect on global acetylation: PMID:23806337; PMID:17923681.
- Localization: mitochondrial matrix by mouse liver mitochondrial fractionation
PMID:19410549; substantial cytosolic and a very small nuclear pool in mouse liver
PMID:23806337.
- Endogenous interaction with CPS1 in mouse liver mitochondrial matrix PMID:19410549.
The original deacetylation-of-CPS1 interpretation was superseded by Du et al. 2011.

Inferred only (from human, via ortholog/PAINT):
- Weak in vitro deacetylase activity and the kinetics showing 29->1000-fold preference
for malonyl/succinyl (measured with human enzyme, PMID:22076378).
- Intermembrane-space pool (human: PMID:18680753).
- SOD1 activation / ROS reduction (human cells, PMID:24140062).

Decisions worth flagging

• GO:0005743 inner membrane IDA from PMID:18054327 is abstract-only and conflicts with
  matrix fractionation in PMID:19410549 -> UNDECIDED.
• GO:0002931 response to ischemia (IMP, cardiac I/R): KO phenotype attributed to SDH
  hypersuccinylation; marked over-annotated rather than a process Sirt5 executes.
• Protein binding (CPS1, IPI) removed per protein-binding policy; CPS1 is a deacylation
  substrate and the activity is captured by the deacylase MF terms.
• GO:0006476 protein deacetylation: the NOT (ISS) row is accepted on mouse KO
  acetylation data; the positive ISO row from human is removed, so the review does not
  keep both a claim and its negation.
• The deep-node NAD-dependent histone deacetylase IBA (PTN008718612) is refined to the
  three acidic deacylase activities, matching the human SIRT5 review.

Validation: just validate mouse Sirt5 passes with no warnings.