SIRT5

UniProt ID: F6S899
Organism: Equus caballus
Review Status: COMPLETE
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Gene Description

Horse SIRT5 is the mitochondrial NAD-dependent protein lysine deacylase of sirtuin class III (PANTHER PTHR11085:SF10), which by orthology to human and mouse SIRT5 removes succinyl, malonyl and glutaryl groups from lysines of mitochondrial and cytosolic metabolic enzymes, consuming NAD+ and releasing nicotinamide. The UniProt record F6S899 (282 aa) is a defective Ensembl gene model of this gene: it matches human SIRT5 through the N-terminal targeting sequence, the NAD-binding GAG loop, the Tyr102/Arg105 acyl pocket, the catalytic His158 and the first zinc-ligand cysteine pair, but its transcript skips a 124-nt coding exon, so the C-terminal third is translated out of frame and lacks the second zinc-ligand cysteine pair and the C-terminal NAD-contacting segments. Full-length products of the same horse gene (A0A9L0T9B1, 310 aa, 88% identical to human SIRT5) retain every catalytic element.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0070403 NAD+ binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: NAD+ binding from the InterPro sirtuin signature (IPR003000). True of the horse SIRT5 gene product, whose deacylase reaction consumes NAD+; F6S899 retains the N-terminal NAD-binding GAG loop and QNID motif, but its frameshifted C-terminus lacks the later NAD-contacting segments, so the exact F6S899 translation is an incomplete model.
Reason: NAD+ is the co-substrate of SIRT5-family deacylation, and the InterPro sirtuin domain match is sound for the gene: PANTHER places F6S899 in PTHR11085:SF10, the SIRT5 subfamily, and full-length products of the same Ensembl gene (ENSECAG00000026898; A0A9L0T9B1) keep all mapped human NAD-contacting residues. The term is kept because it describes the gene product, but as non-core: it is a cofactor-binding consequence of the catalytic activity (protein-succinyllysine desuccinylase), not the function itself. The F6S899 sequence keeps the N-terminal Rossmann NAD loop (human 58-77) and QNID (140-143) but loses GTS 249-251, NTE 275-277 and Cys293 to an out-of-frame C-terminus caused by a skipped 124-nt exon; whether that truncated translation folds and binds NAD is not established, and it is best treated as a gene-model defect rather than a functional variant.
Supporting Evidence:
file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
| BINDING | 140-143 | NAD(+) | QNID | QNID | QNID | QNID |
file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
- Exon in the canonical A0A9L0T6A9 transcript but not in F6S899: 13742662-13742785, 124 nt (length mod 3 = 1).
file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
- F6S899: 282 residues; 189/280 paired residues identical (67.5%); Ensembl transcript ENSECAT00000028843 of gene ENSECAG00000026898, 10 exons.
file:human/SIRT5/SIRT5-uniprot.txt
CC -!- FUNCTION: NAD-dependent lysine demalonylase, desuccinylase and CC deglutarylase that specifically removes malonyl, succinyl and glutaryl CC groups on target proteins (PubMed:21908771, PubMed:22076378, CC PubMed:24703693, PubMed:29180469). Activates CPS1 and contributes to CC the regulation of blood ammonia levels during prolonged fasting: acts CC by mediating desuccinylation and deglutarylation of CPS1, thereby CC increasing CPS1 activity in response to elevated NAD levels during CC fasting (PubMed:22076378, PubMed:24703693). Activates SOD1 by mediating CC its desuccinylation, leading to reduced reactive oxygen species CC (PubMed:24140062). Activates SHMT2 by mediating its desuccinylation CC (PubMed:29180469). Modulates ketogenesis through the desuccinylation CC and activation of HMGCS2 (By similarity). Has weak NAD-dependent CC protein deacetylase activity; however this activity may not be CC physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) CC and a number of other proteins in vitro such as UOX. CC {ECO:0000250|UniProtKB:Q8K2C6, ECO:0000269|PubMed:18680753, CC ECO:0000269|PubMed:21908771, ECO:0000269|PubMed:22076378, CC ECO:0000269|PubMed:24140062, ECO:0000269|PubMed:24703693, CC ECO:0000269|PubMed:29180469}.

Core Functions

NAD-dependent removal of succinyl groups from protein lysines of mitochondrial metabolic enzymes, the principal activity of the horse SIRT5 gene. Assigned to the gene by PANTHER PTHR11085:SF10 membership and the PAINT node PTN000119399 (seeded by human SIRT5 and mouse Sirt5), which already propagates this term to the full-length horse product A0A9L0T9B1. The F6S899 translation itself lacks the second zinc-ligand pair.

Molecular Function:
protein-succinyllysine desuccinylase activity
Cellular Locations:
mitochondrial matrix
Supporting Evidence:
  • PMID:22076378
    is an efficient protein lysine desuccinylase and demalonylase in vitro
  • file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
    GO:0036055 IBA GO_REF:0000033 [MGI:MGI:1915596, PANTHER:PTN000119399, UniProtKB:Q9NXA8]
  • file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
    | BINDING | 207-207 | Zn(2+) | C | W | C | C |
  • file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
    - A0A9L0T9B1: 310 residues; 273/310 paired residues identical (88.1%); Ensembl transcript ENSECAT00000146678 of gene ENSECAG00000026898, 9 exons.

NAD-dependent removal of malonyl groups from protein lysines, assigned by the same SIRT5-subfamily PAINT node.

Molecular Function:
protein-malonyllysine demalonylase activity
Cellular Locations:
mitochondrial matrix
Supporting Evidence:
  • PMID:22076378
    is an efficient protein lysine desuccinylase and demalonylase in vitro
  • file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
    GO:0005759 IBA GO_REF:0000033 [PANTHER:PTN000872307, UniProtKB:Q9NXA8]

NAD-dependent removal of glutaryl groups from protein lysines, for example on CPS1, assigned by the same SIRT5-subfamily PAINT node.

Molecular Function:
protein-glutaryllysine deglutarylase activity
Cellular Locations:
mitochondrial matrix
Supporting Evidence:
  • PMID:24703693
    We then showed that SIRT5 catalyzes lysine deglutarylation both in vitro and in vivo.
  • file:HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md
    GO:0005759 IBA GO_REF:0000033 [PANTHER:PTN000872307, UniProtKB:Q9NXA8]

References

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Suggested Questions for Experts

Q: Should GO annotations for horse SIRT5 be anchored on a full-length product of ENSECAG00000026898 (A0A9L0T9B1, which already carries the PAINT IBAs) rather than on F6S899, whose transcript skips a 124-nt exon and whose C-terminal third is out of frame? Is there RNA-seq support for the F6S899 exon structure, including its 3-nt gap between the last two exons?

Suggested Experiments

Experiment: RT-PCR or long-read sequencing across exons 6-8 of horse SIRT5 in liver or muscle to test whether any transcript skips the 124-nt exon; recombinant expression of the full-length horse protein with a succinyl-lysine peptide assay to confirm desuccinylase activity.

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · SIRT5-protnlm-predictions-review.yaml · Review status: COMPLETE

Assessment of 1 ProtNLM2 GO prediction for horse SIRT5 (F6S899). The single prediction, metal ion binding, is true of the horse SIRT5 gene but is scored NPI for this product, because F6S899 is a defective gene model whose frameshifted C-terminus lacks the second zinc-ligand cysteine pair of the sirtuin zinc ribbon.

Source documents: genes/human/SIRT5/SIRT5-uniprot.txt · genes/HORSE/SIRT5/SIRT5-bioinformatics/RESULTS.md · genes/HORSE/SIRT5/SIRT5-bioinformatics/RESULTS-rereview.md · genes/HORSE/SIRT5__A0A9L0T9B1/SIRT5__A0A9L0T9B1-uniprot.txt · projects/PROTNLM_EVALUATION/mammal-benchmark/horse40-predictions.csv · genes/HORSE/SIRT5/SIRT5-hypotheses/horse40-nad-dependent-desuccinylation/openscientist.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0046872 metal ion binding GO_MF
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
DOMAIN ARCHITECTURE MISMATCH
Review rationale: Metal ion binding is true of the horse SIRT5 gene: sirtuins bind one structural zinc ion through a four-cysteine zinc ribbon, human SIRT5 is curated as binding one Zn(2+) per subunit (PMID:22076378), and the full-length horse product A0A9L0T9B1 retains all four zinc-ligand cysteines and carries GO:0008270 zinc ion binding. This accession, however, lacks the feature the activity depends on. F6S899 is a defective gene model whose transcript skips a 124-nt coding exon, so its C-terminal third is translated out of frame; mapping the human zinc ligands onto it shows Cys166 and Cys169 retained but Trp at the positions of Cys207 and Cys212. With half of the tetrathiolate zinc site missing, this exact sequence has no established metal-binding site, and no other metal site is known for the family. The prediction is therefore incorrect for the product scored.
Supporting Evidence:

Deep Research

Cyberian

(SIRT5-deep-research-cyberian.md)

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OpenScientist

(SIRT5-hypotheses/horse40-nad-dependent-desuccinylation/openscientist.md)

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📚 Additional Documentation

Notes

(SIRT5-notes.md)

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Bioinformatics Results

(RESULTS.md)

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Protnlm Function Review

(SIRT5-protnlm-function-review.md)

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📄 View Raw YAML

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