PNC1 encodes the zinc-dependent nicotinamidase Pnc1, the yeast enzyme that deamidates nicotinamide to nicotinate and ammonia in the NAD+ salvage pathway. By clearing nicotinamide, a Sir2 inhibitor, Pnc1 supports nicotinate nucleotide salvage and indirectly promotes Sir2-dependent telomeric and rDNA heterochromatin functions, lifespan responses to calorie restriction, and regulation of rDNA copy-number amplification. Pnc1 is cytoplasmic, nuclear, and peroxisomal, with stress-responsive regulation and peroxisomal enrichment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000781 chromosome, telomeric region | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: This computational logical inference derives from PNC1 involvement in subtelomeric heterochromatin formation. The literature supports nuclear Pnc1 activity and effects on telomeric silencing, but not direct localization of Pnc1 to telomeric chromatin. Reason: Pnc1 regulates telomeric silencing by removing nicotinamide and thereby supporting Sir2 activity. A telomeric-region cellular component annotation overstates the evidence because Pnc1 is not shown to be a telomere-bound chromatin protein. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to nucleus is consistent with direct Pnc1 localization evidence and its nuclear role in Sir2-dependent silencing. Reason: Nuclear localization is supported experimentally and is mechanistically consistent with Pnc1 effects on rDNA and telomeric silencing. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated cytoplasmic localization is consistent with direct microscopy evidence and Pnc1's general metabolic role. Reason: Pnc1 is observed in the cytoplasm and participates in cellular nicotinamide salvage. |
| GO:0005777 peroxisome | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt peroxisome mapping is consistent with direct evidence that Pnc1 concentrates in peroxisomal foci, particularly in stress contexts. Reason: Peroxisomal localization is supported by experimental localization studies and is part of Pnc1's condition-dependent subcellular distribution. |
| GO:0008936 nicotinamidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment of nicotinamidase activity matches Pnc1's core enzymatic activity and EC 3.5.1.19. The crystal structure of yeast nicotinamidase Pnc1p (PDB 2H0R), solved with its active-site Zn2+, structurally confirms this enzyme. Reason: Pnc1 catalyzes hydrolysis of nicotinamide to nicotinate and ammonia, the central molecular function of this gene product. Supporting Evidence: file:yeast/PNC1/PNC1-deep-research-falcon.md PNC1 (gene YGL037C) encodes nicotinamidase (EC 3.5.1.19) PMID:17382284 The yeast nicotinamidase Pnc1p acts in transcriptional silencing by reducing levels of nicotinamide, an inhibitor of the histone deacetylase Sir2p PMID:17382284 Pnc1p also acts on pyrazinamide, a substrate analog converted by the nicotinamidase |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | MODIFY | Summary: Hydrolase activity is a true but generic parent of nicotinamidase activity. The specific nicotinamidase term is already present. Reason: For curation, GO:0008936 captures the actual enzyme activity and should be preferred over the broad hydrolase parent. Proposed replacements: nicotinamidase activity |
| GO:0019363 pyridine nucleotide biosynthetic process | IEA GO_REF:0000043 | MODIFY | Summary: Pnc1 participates in pyridine nucleotide salvage by converting nicotinamide to nicotinate, but the more precise existing process term is nicotinate nucleotide salvage. Reason: Pnc1 is not a broad de novo pyridine nucleotide biosynthesis factor. It catalyzes the nicotinamide entry step into the nicotinate salvage route, which is captured by GO:0019358. Proposed replacements: nicotinate nucleotide salvage |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: Metal ion binding is accurate but generic; Pnc1 specifically binds zinc as part of its nicotinamidase active site. Reason: The more informative term is zinc ion binding, already supported by curated evidence and structural/mechanistic context. Proposed replacements: zinc ion binding |
| GO:0008270 zinc ion binding | RCA PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc pr... | ACCEPT | Summary: Rapid curated annotation from yeast zinc proteome analysis is consistent with the known zinc-dependent nicotinamidase active site of Pnc1. Reason: Zinc binding is mechanistically appropriate for Pnc1's catalytic function. Supporting Evidence: PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc proteome. |
| GO:0031509 subtelomeric heterochromatin formation | IMP PMID:11901108 Telomeric and rDNA silencing in Saccharomyces cerevisiae are... | KEEP AS NON CORE | Summary: pnc1 deletion causes telomeric silencing defects through impaired nicotinamide clearance and reduced Sir2-dependent chromatin function. Reason: The phenotype is well supported, but it is a downstream chromatin outcome of Pnc1's core nicotinamidase/NAD salvage activity rather than an independent chromatin-binding function. Supporting Evidence: PMID:11901108 Deletion of another NAD(+) salvage pathway gene called PNC1 caused a less severe silencing defect |
| GO:0019358 nicotinate nucleotide salvage | IMP PMID:11901108 Telomeric and rDNA silencing in Saccharomyces cerevisiae are... | ACCEPT | Summary: Genetic evidence supports Pnc1 as a component of the NAD+ salvage pathway, converting nicotinamide to nicotinate for reuse. Reason: This is the core biological process associated with Pnc1's enzymatic activity and explains the Sir2-related phenotypes. Supporting Evidence: PMID:11901108 Pnc1p and Npt1p function together in recycling the nuclear nicotinamide |
| GO:0005737 cytoplasm | HDA PMID:22842922 Dissecting DNA damage response pathways by analysing protein... | ACCEPT | Summary: High-throughput direct assay evidence supports cytoplasmic localization. Reason: This is consistent with direct localization studies and Pnc1's metabolic role in nicotinamide salvage. Supporting Evidence: PMID:22842922 Dissecting DNA damage response pathways by analysing protein localization |
| GO:1904524 negative regulation of DNA amplification | IMP PMID:26195783 Regulation of ribosomal DNA amplification by the TOR pathway... | KEEP AS NON CORE | Summary: The rDNA amplification study reports that TOR/caloric-excess regulation reduces PNC1 expression and that PNC1 overexpression substantially reduces rDNA amplification rate. Reason: The annotation is experimentally supported, but it is an indirect regulatory consequence of Pnc1 effects on Sir2/Hst deacetylase activity and rDNA chromatin rather than the core enzymatic function. Supporting Evidence: PMID:26195783 overexpression of PNC1 substantially reduces ribosomal DNA amplification rate |
| GO:0000183 rDNA heterochromatin formation | IMP PMID:11901108 Telomeric and rDNA silencing in Saccharomyces cerevisiae are... | KEEP AS NON CORE | Summary: Genetic evidence supports a role for Pnc1 in rDNA silencing through the nuclear NAD+ salvage pathway and Sir2-dependent chromatin regulation. Reason: This is a well-supported downstream biological process, but Pnc1 acts through nicotinamide salvage rather than as a structural chromatin factor. Supporting Evidence: PMID:11901108 Telomeric and rDNA silencing in Saccharomyces cerevisiae are dependent on a nuclear NAD(+) salvage pathway |
| GO:0005634 nucleus | IDA PMID:12736687 Nicotinamide and PNC1 govern lifespan extension by calorie r... | ACCEPT | Summary: Direct localization evidence places Pnc1 in the nucleus. Reason: Nuclear localization is consistent with Pnc1's role in modulating Sir2-dependent silencing through nicotinamide clearance. Supporting Evidence: file:yeast/PNC1/PNC1-deep-research-falcon.md Pnc1-GFP shows nuclear/cytosolic distribution with discrete peroxisomal foci |
| GO:0005737 cytoplasm | IDA PMID:12736687 Nicotinamide and PNC1 govern lifespan extension by calorie r... | ACCEPT | Summary: Direct localization evidence places Pnc1 in the cytoplasm. Reason: Cytoplasmic localization is consistent with Pnc1's NAD salvage enzyme function. Supporting Evidence: file:yeast/PNC1/PNC1-deep-research-falcon.md Pnc1-GFP shows nuclear/cytosolic distribution with discrete peroxisomal foci |
| GO:0005777 peroxisome | IDA PMID:12736687 Nicotinamide and PNC1 govern lifespan extension by calorie r... | ACCEPT | Summary: Direct localization evidence supports peroxisomal Pnc1 foci and condition-dependent peroxisomal enrichment. Reason: Peroxisome localization is experimentally supported and is a recurring feature of Pnc1 stress-responsive distribution. Supporting Evidence: file:yeast/PNC1/PNC1-deep-research-falcon.md Pnc1 localizes to cytosol and nucleus and to discrete peroxisomal foci |
| GO:0008936 nicotinamidase activity | IMP PMID:19381334 The yeast PNC1 longevity gene is up-regulated by mRNA mistra... | ACCEPT | Summary: The mistranslation study measured increased Pnc1 expression and activity and used nicotinamidase assays to connect stress to Pnc1/Sir2 activation. The crystal structure of yeast nicotinamidase Pnc1p (PDB 2H0R), determined with its active-site Zn2+, independently confirms the enzyme identity. Reason: This experimental annotation reinforces the core nicotinamidase activity of Pnc1 under stress conditions. Supporting Evidence: PMID:19381334 Our results showed that up-regulation of Pnc1p expression (Figs 1 and 2) resulted in increased Pnc1p and Sir2p activity PMID:17382284 The Pnc1p structure was determined at 2.9 Å resolution using MAD and MIRAS phasing methods |
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Download this section (compressed HTML)Q: What determines condition-specific partitioning of Pnc1 between cytosol, nucleus, and peroxisomes, and how much of the Sir2-regulatory effect depends on each pool?
Experiment: Endogenous Pnc1 localization mutants that selectively disrupt peroxisomal enrichment, followed by nicotinamide, NAD+, Sir2 silencing, and rDNA amplification assays under stress and calorie-restriction conditions.
Hypothesis: Nuclear and cytosolic Pnc1 provide most Sir2-regulatory activity, while stress-enhanced peroxisomal Pnc1 contributes condition-specific nicotinamide handling.
Type: localization/genetics/metabolomics
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