Rgn

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004341 gluconolactonase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation correctly identifies the core enzymatic function. Strongly supported by experimental evidence in PMID:16585534 showing gluconolactonase activity is essential for vitamin C biosynthesis. This is a primary molecular function of the protein. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md 1. Primary biochemical function: Rat Rgn encodes regucalcin/SMP30, a metal-dependent gluconolactonase/lactonase (EC 3.1.1.17) with a six-bladed β‑propeller active site coordinating a divalent metal (Glu18/Asn154/Asp204; Asn103 important for catalysis). file:rat/Rgn/Rgn-deep-research-falcon.md A central, experimentally supported biochemical activity of regucalcin/SMP30 is gluconolactonase (EC 3.1.1.17) activity, requiring a divalent metal ion (e.g., Zn2+ and Mn2+ are cited as activators) and showing activity on multiple aldonolactones in vitro (e.g., D/L‑glucono‑γ‑lactone, D/L‑gulono‑γ‑lactone, D/L‑galactono‑γ‑lactone).
GO:0005509 calcium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation correctly identifies calcium binding as a core function. Strongly supported by experimental evidence dating back to PMID:699201 and confirmed by structural studies. Essential for both its enzymatic activity and calcium homeostasis regulatory functions. Falcon deep research notes regucalcin is a Ca2+-binding/Ca2+-signaling protein but is explicitly NOT an EF-hand protein; the divalent metal (including Ca2+/Mg2+) is coordinated at the catalytic active site (Glu18/Asn154/Asp204). Reason: Calcium binding is retained on direct biochemical/structural evidence (classic rat regucalcin Ca2+-binding studies; active-site divalent-metal coordination); note that the IBA itself is stale — the current PANTHER PAINT release no longer carries an IBD for this term in PTHR10907. GOA no longer carries this row. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTHR10907 · regucalcin/SMP30 family (PAINT) SOURCE STALE OR MISSING No IBD for GO:0005509 remains in the current PTHR10907 PAINT slice (snapshot 20251127); the remaining IBDs at PTN004208435 are GO:0004341, nucleus, cytoplasm, and GO:0050848 only. PAINT has withdrawn or re-scoped this function assertion; the ACCEPT here rests on the direct rat biochemical evidence, not on the IBA. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Regucalcin is also widely described as a multifunctional Ca2+-signaling regulator (not an EF‑hand protein), acting as a cytoplasmic regulator and capable of nuclear translocation, with inhibitory effects on multiple kinases/phosphatases and on DNA/RNA/protein synthesis, thereby influencing cell-cycle progression and apoptosis sensitivity in various rat cell systems.
GO:0019853 L-ascorbic acid biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation correctly identifies involvement in vitamin C biosynthesis. Strongly supported by PMID:16585534 showing this enzyme catalyzes the penultimate step. This is a core biological function. Reason: The ascorbate-biosynthesis role is retained on direct experimental evidence (PMID:16585534; SMP30/GNL knockout mice develop scurvy); note that the IBA itself is stale — the current PANTHER PAINT release no longer carries an IBD for this term in PTHR10907. GOA no longer carries this row. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTHR10907 · regucalcin/SMP30 family (PAINT) SOURCE STALE OR MISSING No IBD for GO:0019853 remains in the current PTHR10907 PAINT slice (snapshot 20251127); the remaining IBDs at PTN004208435 are GO:0004341, nucleus, cytoplasm, and GO:0050848 only. PAINT has withdrawn or re-scoped this process assertion; the ACCEPT here rests on the direct rodent experimental evidence, not on the IBA. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Ascorbate/vitamin C pathway role (in non‑primates): SMP30/GNL is implicated in the ascorbic acid biosynthesis pathway by catalyzing formation of the γ‑lactone ring from L‑gulonate (i.e., producing L‑gulono‑γ‑lactone, which is then converted to ascorbic acid by downstream enzymes). Genetic/physiological support includes SMP30/GNL knockout mice developing scurvy on vitamin C‑deficient diets.
GO:0005509 calcium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of the IBA annotation above, both are correct. IEA based on InterPro domains aligns with experimental evidence. Calcium binding is a well-established core function. Supporting Evidence: UniProtKB:Q03336 The physiological cofactor for gluconolactonase activity is most likely Ca(2+) or Mg(2+).
GO:0030234 enzyme regulator activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Enzyme regulator activity from the InterPro regucalcin family mapping. Regucalcin has been reported to modulate many enzymes in rat liver and kidney extracts, activating Ca2+-ATPases and suppressing aminoacyl-tRNA synthetase, kinases, phosphatases and nitric oxide synthase, so the generic term is consistent with the literature but uninformative. Reason: The term does not overshoot the evidence; it is simply generic. Regucalcin acts on targets in both directions (activation of Ca2+-ATPases, inhibition of others), so neither enzyme inhibitor activity nor enzyme activator activity alone fits, and whether these in vitro effects are direct protein-enzyme regulation or a consequence of Ca2+ binding is unresolved. Changed from MARK_AS_OVER_ANNOTATED at the 2026 re-review; the previously proposed NEW enzyme inhibitor activity row was withdrawn because it is a descendant of this term and the mechanism is unsettled. Supporting Evidence: PMID:2280766 the protein (1.0-2.0 microM) caused a remarkable decrease in the enzyme activity. PMID:16786169 This study demonstrates that regucalcin has an activating effect on Ca2+-ATPase in rat heart mitochondria
GO:0004341 gluconolactonase activity	IEA GO_REF:0000120	ACCEPT	Summary: Another correct annotation of gluconolactonase activity. IEA from multiple sources confirms this core enzymatic function. Supporting Evidence: UniProtKB:Q03336 Reaction=D-glucono-1,5-lactone + H2O = D-gluconate + H(+)
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Cytoplasmic localization is well-established. Protein is predominantly cytoplasmic. Reason: GOA no longer carries this row. Supporting Evidence: UniProtKB:Q03336 SUBCELLULAR LOCATION: Cytoplasm.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	TOO GENERAL	Summary: This is too general. The protein has specific gluconolactonase activity (GO:0004341) which is already annotated. This broad parent term adds no informative value. Reason: GOA no longer carries this row. TOO_GENERAL rather than REMOVE: gluconolactonase activity, kept in this review, entails this term, so the claim is true but less informative. Supporting Evidence: UniProtKB:Q03336 Reaction=D-glucono-1,5-lactone + H2O = D-gluconate + H(+)
GO:0019853 L-ascorbic acid biosynthetic process	IEA GO_REF:0000043	ACCEPT	Summary: Duplicate annotation of vitamin C biosynthesis with IEA evidence. This core function is well-established. Reason: GOA no longer carries this row. Supporting Evidence: UniProtKB:Q03336 Catalyzes a key step in ascorbic acid (vitamin C) biosynthesis.
GO:0046872 metal ion binding	IEA GO_REF:0000043	TOO GENERAL	Summary: Too general. The protein specifically binds calcium (GO:0005509) and zinc (GO:0008270) ions, which are already annotated with more specific terms. Reason: GOA no longer carries this row. TOO_GENERAL rather than REMOVE: calcium ion binding and zinc ion binding, kept in this review, entail this term, so the claim is true but less informative. Supporting Evidence: UniProtKB:Q03336 Note=Binds 1 divalent metal cation per subunit. Most active with Zn(2+) and Mn(2+) ions.
GO:0010558 negative regulation of macromolecule biosynthetic process	IDA PMID:2280766 Effect of calcium-binding protein regucalcin on hepatic prot...	MODIFY	Summary: This term is too general. The experimental evidence specifically shows inhibition of aminoacyl-tRNA synthetase activity, affecting protein synthesis. Should be replaced with GO:0017148 (negative regulation of translation) or GO:0031127 (negative regulation of aminoacyl-tRNA ligase activity) for specificity. Reason: GOA no longer carries this row. GOA has since replaced this row with the proposed GO:0017148 negative regulation of translation (IDA, same paper). Proposed replacements: negative regulation of translation Supporting Evidence: PMID:2280766 the protein caused a remarkable decrease in hepatic protein synthesis file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus; maintains intracellular Ca2+ homeostasis by activating Ca2+ pumps in plasma membrane, mitochondria, and ER; inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression; summarizes rat liver, kidney, prostate, and hepatoma studies showing anti-proliferative and homeostatic roles
GO:1903011 negative regulation of bone development	IMP PMID:11129957 Role of endogenous regucalcin in protein tyrosine phosphatas...	KEEP AS NON CORE	Summary: This IMP annotation cites PMID:11129957, whose cached abstract concerns regucalcin regulation of protein tyrosine phosphatase activity in cloned rat hepatoma cells (H4-II-E) and does not mention bone; the cache is abstract-only, so the specific supporting evidence cannot be re-verified from the accessible text and the curator's full-text reading is deferred to. The term itself is genuinely established for Rgn by the parallel IDA annotation citing PMID:12239582 (bone loss induced in regucalcin transgenic rats), so the annotation is kept, but as a secondary systemic phenotype rather than a core function, consistent with the treatment of the IDA row for the same term. Reason: The bone-loss phenotype of regucalcin overexpression is real but is a downstream physiological consequence of regucalcin's Ca2+-homeostasis and signaling-suppressor roles, not a core molecular function; aligned with the KEEP_AS_NON_CORE call on the IDA annotation of the same term. The abstract-only cache of PMID:11129957 prevents verifying this row's specific assay, so per curation guidelines the curator is not overruled. Supporting Evidence: PMID:11129957 Role of endogenous regucalcin in protein tyrosine phosphatase regulation in the cloned rat hepatoma cells (H4-II-E).
GO:1903011 negative regulation of bone development	IDA PMID:12239582 Role of endogenous regucalcin in bone metabolism: bone loss ...	KEEP AS NON CORE	Summary: Duplicate annotation showing bone loss in Rgn transgenic rats. Secondary effect rather than core function. Supporting Evidence: PMID:12239582 This study demonstrates that bone loss is induced in the femoral tissue of regucalcin transgenic rats
GO:1903625 negative regulation of DNA catabolic process	IDA PMID:2001740 Inhibitory effect of calcium-binding protein regucalcin on C...	ACCEPT	Summary: Evidence shows inhibition of Ca2+-activated DNA fragmentation. This anti-apoptotic function is part of the broader cellular protection role. Supporting Evidence: PMID:2001740 The Ca2+ (10 microM)-activated DNA fragmentation was inhibited by the presence of Ca2(+)-binding protein regucalcin isolated from rat liver cytosol. The inhibitory effect of regucalcin was complete at 0.5 microM.
GO:0010867 positive regulation of triglyceride biosynthetic process	IDA PMID:16817230 Overexpression of regucalcin enhances glucose utilization an...	KEEP AS NON CORE	Summary: Evidence from overexpression studies shows enhanced lipid production. This metabolic regulatory function is supported but represents a secondary function. Supporting Evidence: PMID:16817230 This study demonstrates that overexpression of regucalcin enhances glucose utilization and lipid production in the cloned rat hepatoma H4-II-E cells
GO:0010907 positive regulation of glucose metabolic process	IDA PMID:16817230 Overexpression of regucalcin enhances glucose utilization an...	KEEP AS NON CORE	Summary: Enhanced glucose utilization shown in overexpression studies. Secondary metabolic regulatory function. Supporting Evidence: PMID:16817230 This study demonstrates that overexpression of regucalcin enhances glucose utilization and lipid production in the cloned rat hepatoma H4-II-E cells
GO:0043066 negative regulation of apoptotic process	IDA PMID:15806309 Overexpression of regucalcin suppresses apoptotic cell death...	ACCEPT	Summary: Well-documented anti-apoptotic effect in hepatoma cells treated with sulforaphane. This cytoprotective function is important for cell survival. Supporting Evidence: PMID:15806309 This study demonstrates that sulforaphane induces cell death and apoptosis in the cloned rat hepatoma H4-II-E cells, and that overexpression of regucalcin suppresses sulforaphane-induced apoptotic cell death which is partly mediated through caspase-3.
GO:0045723 positive regulation of fatty acid biosynthetic process	IDA PMID:16817230 Overexpression of regucalcin enhances glucose utilization an...	KEEP AS NON CORE	Summary: Related to lipid metabolism regulation shown in the same study. Secondary metabolic function. Supporting Evidence: PMID:16817230 This study demonstrates that overexpression of regucalcin enhances glucose utilization and lipid production in the cloned rat hepatoma H4-II-E cells
GO:0050680 negative regulation of epithelial cell proliferation	IDA PMID:16142398 Overexpression of regucalcin suppresses cell proliferation o...	ACCEPT	Summary: Suppression of kidney epithelial cell proliferation demonstrated. Part of the general anti-proliferative regulatory function. Supporting Evidence: PMID:16142398 Cell numbers of transfectants were significantly suppressed as compared with that of wild- and mock-type.
GO:0001822 kidney development	IEP PMID:8794449 Gene regulation of senescence marker protein-30 (SMP30): coo...	KEEP AS NON CORE	Summary: Expression pattern during kidney development shown. While expressed during development, this is not a core function but reflects tissue expression pattern. Supporting Evidence: PMID:8794449 The high expression of SMP30 in the tissue-maturing process and adulthood suggests that SMP30 may be required for the maintenance of highly differentiated hepatic and renal functions
GO:0001889 liver development	IEP PMID:8794449 Gene regulation of senescence marker protein-30 (SMP30): coo...	KEEP AS NON CORE	Summary: Expression pattern during liver development. Not a core function but reflects developmental expression pattern. Supporting Evidence: PMID:8794449 The high expression of SMP30 in the tissue-maturing process and adulthood suggests that SMP30 may be required for the maintenance of highly differentiated hepatic and renal functions
GO:0004341 gluconolactonase activity	IDA PMID:16585534 Senescence marker protein 30 functions as gluconolactonase i...	ACCEPT	Summary: Direct experimental evidence proving gluconolactonase activity and its essential role in vitamin C biosynthesis. Knockout mice lacking this enzyme develop scurvy. This is a core enzymatic function. Supporting Evidence: PMID:16585534 SMP30 purified from the rat liver had lactonase activity toward various aldonolactones, such as d- and l-glucono-delta-lactone, d- and l-gulono-gamma-lactone, and d- and l-galactono-gamma-lactone, with a requirement for Zn(2+) or Mn(2+) as a cofactor. Furthermore, in SMP30 knockout mice, no GNL activity was detectable in the liver. Thus, we conclude that SMP30 is a unique GNL in the liver. file:rat/Rgn/Rgn-deep-research-falcon.md A central, experimentally supported biochemical activity of regucalcin/SMP30 is gluconolactonase (EC 3.1.1.17) activity, requiring a divalent metal ion (e.g., Zn2+ and Mn2+ are cited as activators) and showing activity on multiple aldonolactones in vitro (e.g., D/L‑glucono‑γ‑lactone, D/L‑gulono‑γ‑lactone, D/L‑galactono‑γ‑lactone).
GO:0007283 spermatogenesis	IDA PMID:23615721 Sperm parameters and epididymis function in transgenic rats ...	KEEP AS NON CORE	Summary: Evidence from RGN-overexpressing transgenic rats (lower sperm counts and motility, altered epididymis) points to a role in epididymal sperm maturation. While documented, this is a tissue-specific function rather than core. Supporting Evidence: PMID:23615721 Tg-RGN animals displayed an altered morphology of epididymis and lower sperm counts and motility PMID:23615721 suggest a role for RGN in sperm maturation
GO:0043066 negative regulation of apoptotic process	IDA PMID:16167335 Overexpression of regucalcin suppresses apoptotic cell death...	ACCEPT	Summary: Duplicate annotation showing anti-apoptotic effects in kidney epithelial cells. Consistent cytoprotective function. Supporting Evidence: PMID:16167335 this DNA fragmentation was significantly suppressed in transfectants
GO:0097421 liver regeneration	IEP PMID:7759556 Enhanced expression of calcium-binding protein regucalcin mR...	KEEP AS NON CORE	Summary: Enhanced expression during liver regeneration. While involved, this is a context-specific response rather than core function. Supporting Evidence: PMID:7759556 These findings demonstrate that the expression of hepatic regucalcin mRNA is enhanced in regenerating rat liver
GO:1901318 negative regulation of flagellated sperm motility	IDA PMID:23615721 Sperm parameters and epididymis function in transgenic rats ...	KEEP AS NON CORE	Summary: Overexpression (Tg-RGN rats) lowers sperm motility, consistent with the negative-regulation sign of the term. Tissue-specific effect related to calcium handling in the epididymal lumen. Supporting Evidence: PMID:23615721 Tg-RGN animals displayed an altered morphology of epididymis and lower sperm counts and motility
GO:1902679 negative regulation of RNA biosynthetic process	IMP PMID:12397604 Role of endogenous regucalcin in nuclear regulation of regen...	ACCEPT	Summary: Evidence shows suppression of RNA synthesis in regenerating liver. Part of the core regulatory function on nucleic acid biosynthesis and cell proliferation control. Supporting Evidence: PMID:12397604 The present study demonstrates that endogenous regucalcin has a suppressive effect on the enhancement of RNA synthesis activity in the nucleus of regenerating rat liver with proliferative cells. file:rat/Rgn/Rgn-deep-research-falcon.md Regucalcin is also widely described as a multifunctional Ca2+-signaling regulator (not an EF‑hand protein), acting as a cytoplasmic regulator and capable of nuclear translocation, with inhibitory effects on multiple kinases/phosphatases and on DNA/RNA/protein synthesis, thereby influencing cell-cycle progression and apoptosis sensitivity in various rat cell systems.
GO:2000279 negative regulation of DNA biosynthetic process	IMP PMID:11500948 Regulatory role of endogenous regucalcin in the enhancement ...	ACCEPT	Summary: Well-documented suppression of DNA synthesis in hepatoma cells. This is part of the core regulatory function on nucleic acid biosynthesis and cell proliferation control. Supporting Evidence: PMID:11500948 The present study demonstrates that endogenous regucalcin plays a suppressive role in the enhancement of nuclear DNA synthesis with proliferative cells.
GO:1903052 obsolete positive regulation of proteolysis involved in protein catabolic process	IDA PMID:1513338 Calcium-binding protein regucalcin increases calcium-indepen...	MODIFY	Summary: This GO term is obsolete (verified via OLS; term_replaced_by GO:0045732). The experimental evidence (PMID:1513338) shows regucalcin increases Ca2+-independent proteolytic activity in rat liver cytosol and activates a neutral cysteinyl-proteinase, i.e. it positively regulates protein catabolism. MODIFY to the official replacement term GO:0045732 (positive regulation of protein catabolic process), which preserves the original BP aspect. Reason: GOA no longer carries this row. GOA now carries the replacement term GO:0045732 (IDA, same paper) as a separate row. Proposed replacements: positive regulation of protein catabolic process Supporting Evidence: PMID:1513338 The present findings suggest that regucalcin increases proteolytic activity in rat liver cytosol, and that regucalcin may activate Ca(2+)-independent neutral cysteinyl-proteinase.
GO:0001889 liver development	IEP PMID:9546611 Expression of calcium-binding protein regucalcin mRNA in fet...	KEEP AS NON CORE	Summary: Duplicate annotation of expression during liver development. Non-core developmental expression pattern. Supporting Evidence: PMID:9546611 These findings demonstrate that the expression of hepatic regucalcin mRNA is increased with fetal development
GO:0045019 negative regulation of nitric oxide biosynthetic process	IMP PMID:12686401 Inhibitory role of regucalcin in the regulation of nitric ox...	ACCEPT	Summary: Inhibits nitric oxide synthase activity in brain. Part of the broader regulatory function on cellular signaling. Supporting Evidence: PMID:12686401 The present study demonstrates that endogenous regucalcin has an inhibitory effect on NO synthase activity in the brain cytosol of young and aged rats. file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus; maintains intracellular Ca2+ homeostasis by activating Ca2+ pumps in plasma membrane, mitochondria, and ER; inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression; summarizes rat liver, kidney, prostate, and hepatoma studies showing anti-proliferative and homeostatic roles
GO:0004341 gluconolactonase activity	ISS GO_REF:0000024	ACCEPT	Summary: Another duplicate gluconolactonase annotation. This core function is well-established. Supporting Evidence: UniProtKB:Q03336 Reaction=D-glucono-1,5-lactone + H2O = D-gluconate + H(+)
GO:0004341 gluconolactonase activity	ISO GO_REF:0000096	ACCEPT	Summary: Another duplicate gluconolactonase annotation based on orthology. Consistent with experimental evidence. Reason: GOA no longer carries this row. Supporting Evidence: UniProtKB:Q03336 Reaction=D-glucono-1,5-lactone + H2O = D-gluconate + H(+)
GO:0019853 L-ascorbic acid biosynthetic process	ISS GO_REF:0000024	ACCEPT	Summary: Another duplicate of vitamin C biosynthesis annotation. Consistent with experimental evidence. Supporting Evidence: UniProtKB:Q03336 Catalyzes a key step in ascorbic acid (vitamin C) biosynthesis.
GO:0019853 L-ascorbic acid biosynthetic process	ISO GO_REF:0000096	ACCEPT	Summary: Another duplicate vitamin C biosynthesis annotation based on orthology. Well-supported core function. Reason: GOA no longer carries this row. Supporting Evidence: UniProtKB:Q03336 Catalyzes a key step in ascorbic acid (vitamin C) biosynthesis.
GO:0005509 calcium ion binding	ISO GO_REF:0000096	ACCEPT	Summary: Another duplicate calcium binding annotation with ISO evidence. Calcium binding is a core function. Reason: GOA no longer carries this row. Supporting Evidence: UniProtKB:Q03336 The physiological cofactor for gluconolactonase activity is most likely Ca(2+) or Mg(2+).
GO:0008270 zinc ion binding	ISS GO_REF:0000024	ACCEPT	Summary: Correct annotation. Zinc is a cofactor for gluconolactonase activity as shown in PMID:16585534. The protein can use Zn2+ or Mn2+ as cofactors for its enzymatic activity. Supporting Evidence: UniProtKB:Q03336 Note=Binds 1 divalent metal cation per subunit. Most active with Zn(2+) and Mn(2+) ions.
GO:0008270 zinc ion binding	ISO GO_REF:0000096	ACCEPT	Summary: Duplicate annotation with different evidence code. Zinc binding is confirmed as a cofactor for enzymatic activity. Reason: GOA no longer carries this row. Supporting Evidence: UniProtKB:Q03336 Note=Binds 1 divalent metal cation per subunit. Most active with Zn(2+) and Mn(2+) ions.
GO:0005509 calcium ion binding	IDA PMID:699201 Purification of calcium binding substance from soluble fract...	ACCEPT	Summary: Direct experimental evidence from the original 1978 paper identifying this as a calcium-binding protein. This is foundational evidence for a core molecular function. Supporting Evidence: PMID:699201 Purification of calcium binding substance from soluble fraction of normal rat liver.
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: Nuclear localization is supported by functional studies showing regulation of nuclear processes (DNA/RNA synthesis). Valid cellular component. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Duplicate cytoplasmic localization annotation. Well-supported. Supporting Evidence: UniProtKB:Q03336 SUBCELLULAR LOCATION: Cytoplasm.
GO:0006874 intracellular calcium ion homeostasis	IDA PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitoc...	ACCEPT	Summary: Direct evidence for regulation of calcium homeostasis through Ca2+-ATPase modulation in mitochondria. This is a core biological function. Supporting Evidence: PMID:16786169 This study demonstrates that regucalcin has an activating effect on Ca2+-ATPase in rat heart mitochondria, suggesting its role in the regulation of heart mitochondrial function. file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus; maintains intracellular Ca2+ homeostasis by activating Ca2+ pumps in plasma membrane, mitochondria, and ER; inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression; summarizes rat liver, kidney, prostate, and hepatoma studies showing anti-proliferative and homeostatic roles
GO:0032781 positive regulation of ATP-dependent activity	IDA PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitoc...	ACCEPT	Summary: Evidence shows increased Ca2+-ATPase activity in heart mitochondria when purified regucalcin is added to the enzyme assay, and in heart mitochondria of regucalcin transgenic rats. The biological_process term positive regulation of ATP-dependent activity is a faithful reading of this IDA, with the correct sign. Reason: Changed from MODIFY (to the molecular_function term GO:0060590 ATPase regulator activity) at review follow-up; a BP annotation should not be replaced by an MF term. Whether regucalcin is a direct ATPase regulator is also unresolved, since the effect is lost with ruthenium red or lanthanum (Ca2+ uniporter inhibitors) and after digitonin solubilization, so the MF is raised as a suggested question instead. Supporting Evidence: PMID:16786169 This study demonstrates that regucalcin has an activating effect on Ca2+-ATPase in rat heart mitochondria PMID:16786169 The effect of regucalcin in increasing mitochondrial Ca2+-ATPase activity was not observed in the presence of ruthenium red
GO:0050848 regulation of calcium-mediated signaling	IDA PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitoc...	ACCEPT	Summary: Regulation of calcium signaling through Ca2+-ATPase modulation and calcium binding. Core regulatory function. Supporting Evidence: PMID:16786169 This study demonstrates that regucalcin has an activating effect on Ca2+-ATPase in rat heart mitochondria, suggesting its role in the regulation of heart mitochondrial function.
GO:0005634 nucleus	ISO GO_REF:0000096	ACCEPT	Summary: Duplicate nuclear localization based on orthology. Consistent with functional evidence. Reason: GOA no longer carries this row. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus
GO:0005737 cytoplasm	ISO GO_REF:0000096	ACCEPT	Summary: Another duplicate cytoplasmic localization based on orthology. Consistent with other evidence. Reason: GOA no longer carries this row. Supporting Evidence: UniProtKB:Q03336 SUBCELLULAR LOCATION: Cytoplasm.
GO:0004341 gluconolactonase activity	ISO GO_REF:0000121	ACCEPT	Summary: Gluconolactonase activity transferred by orthology from mouse Rgn (MGI:MGI:108024); the core enzymatic activity of SMP30/regucalcin. Reason: Rat SMP30 has directly measured aldonolactonase activity (IDA, PMID:16585534), and the mouse donor is a one-to-one ortholog; replaces the retired GO_REF:0000096 ISO row from the same donor. Supporting Evidence: UniProtKB:Q03336 Reaction=D-glucono-1,5-lactone + H2O = D-gluconate + H(+)
GO:0004341 gluconolactonase activity	ISO GO_REF:0000121	ACCEPT	Summary: Gluconolactonase activity transferred by orthology from human RGN (UniProtKB:Q15493). Reason: Donor-split duplicate of the mouse-sourced ISO row; here the donor is human regucalcin (Q15493), a one-to-one ortholog. The activity is established for the rat enzyme itself (PMID:16585534). Supporting Evidence: UniProtKB:Q03336 Reaction=D-glucono-1,5-lactone + H2O = D-gluconate + H(+)
GO:0004341 gluconolactonase activity	ISS GO_REF:0000024	ACCEPT	Summary: Gluconolactonase activity by sequence similarity to mouse Rgn (UniProtKB:Q64374). Reason: Mouse SMP30 is a characterized gluconolactonase; the rat enzyme has the same activity by direct assay (PMID:16585534). Consistent with the existing ISS row. Supporting Evidence: UniProtKB:Q03336 Reaction=D-glucono-1,5-lactone + H2O = D-gluconate + H(+)
GO:0005509 calcium ion binding	ISO GO_REF:0000121	ACCEPT	Summary: Calcium ion binding transferred by orthology from human RGN (UniProtKB:Q15493). Reason: Regucalcin was isolated as a Ca2+-binding protein from rat liver (PMID:699201), and a divalent cation, probably Ca2+ or Mg2+ physiologically, is bound at the lactonase active site. Donor-split row with human regucalcin as donor; consistent with the rat IDA row. Supporting Evidence: UniProtKB:Q03336 The physiological cofactor for gluconolactonase activity is most likely Ca(2+) or Mg(2+).
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Nucleus (is_active_in) from the PAINT node PTN004208435 of the SMP-30/gluconolactonase family. Regucalcin is found in both cytoplasm and nucleus of rat hepatocytes and hepatoma cells, where it suppresses nuclear DNA and RNA synthesis. Reason: No target-specific divergence argues against the inherited location, and rat studies report nuclear regucalcin acting on nuclear DNA synthesis (PMID:11500948). Consistent with the accepted nucleus ISS row. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus
GO:0005634 nucleus	ISO GO_REF:0000121	ACCEPT	Summary: Nucleus transferred by orthology from mouse Rgn (MGI:MGI:108024). Reason: Replaces the retired GO_REF:0000096 ISO row from the same donor; consistent with the nucleus IBA and ISS rows and with rat data on nuclear regucalcin. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cytoplasm (is_active_in) from the PAINT node PTN004208435. Regucalcin is a soluble cytosolic protein, originally purified from rat liver cytosol. Reason: The inherited location matches UniProt and the rat purification studies; the gluconolactonase step of ascorbate synthesis takes place in the cytosol. Supporting Evidence: UniProtKB:Q03336 SUBCELLULAR LOCATION: Cytoplasm.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasm from the UniProt subcellular-location mapping. Reason: Matches the UniProt subcellular location and the cytosolic origin of purified rat regucalcin; replaces the retired GO_REF:0000120 IEA row. Supporting Evidence: UniProtKB:Q03336 SUBCELLULAR LOCATION: Cytoplasm.
GO:0005737 cytoplasm	ISO GO_REF:0000121	ACCEPT	Summary: Cytoplasm transferred by orthology from mouse Rgn (MGI:MGI:108024). Reason: Replaces the retired GO_REF:0000096 ISO row from the same donor; consistent with UniProt and rat data. Supporting Evidence: UniProtKB:Q03336 SUBCELLULAR LOCATION: Cytoplasm.
GO:0008270 zinc ion binding	ISO GO_REF:0000121	ACCEPT	Summary: Zinc ion binding transferred by orthology from human RGN (UniProtKB:Q15493). Reason: The lactonase binds one divalent metal ion per subunit and is most active with Zn2+ in vitro, though the physiological metal is probably Ca2+ or Mg2+. Donor-split row reviewed consistently with the existing zinc ion binding ISS row. Supporting Evidence: UniProtKB:Q03336 Note=Binds 1 divalent metal cation per subunit. Most active with Zn(2+) and Mn(2+) ions.
GO:0017148 negative regulation of translation	IDA PMID:2280766 Effect of calcium-binding protein regucalcin on hepatic prot...	ACCEPT	Summary: Negative regulation of translation (IDA). Addition of purified regucalcin to rat liver supernatant decreased in vitro protein synthesis and leucyl-tRNA synthetase activity. This GOA row replaces the retired IDA row for negative regulation of macromolecule biosynthetic process from the same paper, and absorbs the evidence of a former NEW row for this term. Reason: The curator's IDA is consistent with the cached abstract. Accepted, with the caveat that the effect was shown by adding micromolar purified protein to liver extracts in one laboratory, and whether regucalcin inhibits the synthetase directly or via Ca2+ handling is not resolved. Supporting Evidence: PMID:2280766 the protein caused a remarkable decrease in hepatic protein synthesis PMID:2280766 the protein (1.0-2.0 microM) caused a remarkable decrease in the enzyme activity.
GO:0019853 L-ascorbic acid biosynthetic process	ISO GO_REF:0000121	ACCEPT	Summary: L-ascorbic acid biosynthetic process transferred by orthology from mouse Rgn (MGI:MGI:108024). Reason: SMP30 catalyzes the lactonization step of ascorbate synthesis in non-primate mammals; the rat enzyme has the activity (PMID:16585534). Replaces the retired GO_REF:0000096 ISO row from the same donor. Supporting Evidence: UniProtKB:Q03336 Catalyzes a key step in ascorbic acid (vitamin C) biosynthesis.
GO:0045732 positive regulation of protein catabolic process	IDA PMID:1513338 Calcium-binding protein regucalcin increases calcium-indepen...	KEEP AS NON CORE	Summary: Positive regulation of protein catabolic process (IDA). Regucalcin added to rat liver cytosol increased neutral, largely Ca2+-independent, cysteinyl proteinase activity. This is the GOA replacement for the retired obsolete term GO:1903052 from the same paper, which the earlier review had proposed. Reason: The effect is an in vitro increase in cytosolic proteinase activity from a single laboratory; it is consistent with the term but peripheral to regucalcin's core lactonase and Ca2+-binding roles. Supporting Evidence: PMID:1513338 The present findings suggest that regucalcin increases proteolytic activity in rat liver cytosol, and that regucalcin may activate Ca(2+)-independent neutral cysteinyl-proteinase.
GO:0050848 regulation of calcium-mediated signaling	IBA GO_REF:0000033	ACCEPT	Summary: Regulation of calcium-mediated signaling from the PAINT node PTN004208435, with rat Rgn (RGD:3560) among the experimental sources. Reason: Consistent with the accepted IDA row for this term (PMID:16786169); rat regucalcin is the experimental grounding for the node, which is expected rather than circular. Supporting Evidence: UniProtKB:Q03336 Modulates Ca(2+) signaling, and Ca(2+)-dependent cellular processes and enzyme activities.

Gene Description

Existing Annotations Review

Core Functions

Catalyzes lactonization of L-gulonic acid to L-gulono-gamma-lactone in the penultimate step of L-ascorbic acid biosynthesis

Binds calcium ions to regulate intracellular calcium homeostasis and calcium-dependent processes

Protects cells from apoptosis by inhibiting Ca2+-activated DNA fragmentation

References

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Notes

Bioreason Rl Predictions

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Curation Summary

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