Regucalcin/SMP30 is the lactone-hydrolyzing enzyme gluconolactonase (GNL) in the liver responsible for L-ascorbic acid (vitamin C) biosynthesis PMID:16585534. The lactonase reaction with l-gulono-γ-lactone is the penultimate step in vitamin C biosynthesis PMID:16585534. SMP30 knockout mice developed scurvy when fed vitamin C-deficient diet, confirming its essential role in vitamin C synthesis PMID:16585534.
Regucalcin was originally discovered as a calcium-binding protein in 1978 PMID:699201, though it lacks the typical EF-hand Ca2+-binding motif. It increases Ca2+-ATPase activity in heart mitochondria PMID:16786169. This regulation of Ca2+-ATPase activity is important for maintaining calcium homeostasis PMID:16786169.
Regucalcin expression is coordinately upregulated with tissue maturation and gradually downregulated with aging PMID:8794449. In liver, peak expression occurs in 5-day-old neonates with a second increase from day 7-10, then decreases in adults to about 1/3 of neonatal levels [PMID:8794449 from UniProt]. In kidney, expression increases from day 21, peaks at day 35, and remains high until 3 months.
Regucalcin is found in:
- Cytoplasm (confirmed by multiple sources)
- Nucleus (ISS evidence)
- Mitochondria (especially in heart, where it regulates Ca2+-ATPase) PMID:16786169
The protein is also known as Senescence Marker Protein 30 (SMP30) because its expression decreases with aging. Given its role in vitamin C synthesis and multiple regulatory functions, reduced expression with age may contribute to age-related dysfunction in calcium homeostasis, oxidative stress management, and metabolic regulation.
GOA refresh changes (large turnover):
- 14 new rows seeded: gluconolactonase activity ISO (mouse MGI:108024; human Q15493) and ISS (mouse Q64374); calcium ion binding ISO (human); nucleus IBA and ISO (mouse); cytoplasm IBA, IEA (GO_REF:0000044) and ISO (mouse); zinc ion binding ISO (human); L-ascorbic acid biosynthetic process ISO (mouse); regulation of calcium-mediated signaling IBA (PTN004208435); GO:0017148 negative regulation of translation IDA (PMID:2280766); GO:0045732 positive regulation of protein catabolic process IDA (PMID:1513338).
- 14 rows retired, mostly older ISO (GO_REF:0000096), IEA (GO_REF:0000043/0000120) and two IBA rows, plus the IDA rows for GO:0010558 (now GO:0017148) and obsolete GO:1903052 (now GO:0045732). Retired rows kept with a note.
Decisions:
- Validator error "action=NEW exists in GOA: GO:0017148": the NEW row was folded into the seeded IDA row (ACCEPT) and deleted PMID:2280766. Caveat recorded: single-lab in vitro addition of purified protein; direct versus Ca2+-mediated mechanism unresolved.
- NEW GO:0005739 mitochondrion withdrawn: the only support was activation of mitochondrial Ca2+-ATPase by added regucalcin PMID:16786169, which does not show localization. Moved to suggested_questions; mitochondrion removed from the Ca2+-ATPase core function's locations.
- NEW GO:0004857 enzyme inhibitor activity withdrawn: it is a descendant of GO:0030234 enzyme regulator activity, which the gene already carries, and the mechanism is unresolved. Moved to suggested_questions.
- GO:0030234 enzyme regulator activity (IEA): MARK_AS_OVER_ANNOTATED -> KEEP_AS_NON_CORE (generic, not overreaching; regucalcin is reported to activate Ca2+-ATPases and suppress other enzymes).
- GO:0045732 (IDA, PMID:1513338): KEEP_AS_NON_CORE (in vitro proteinase activation).
- All other PENDING rows ACCEPT, consistent with existing rows for the same terms.
- Added supported_by (UniProt CC lines or deep-research text) to 7 live rows and the retired rows that lacked it.
- core_functions: six entries became five. The two entries that used the withdrawn enzyme inhibitor activity (translation suppression; DNA/RNA synthesis suppression) were merged into one entry with no molecular_function and with verbatim quotes in place of the previous paraphrases.
Open questions:
- Is regucalcin mitochondrial? Does it inhibit enzymes directly?
- Many regulatory annotations (translation, DNA/RNA synthesis, apoptosis, NO synthesis) rest on one laboratory's in vitro and cell-line work; independent confirmation would strengthen them.
Review follow-up 2026-10-17: In response to PR #4622 review: (1) GO:0007283 and GO:1901318 (PMID:23615721) no longer quote the author list; they now quote PMID:23615721 and "suggest a role for RGN in sperm maturation". (2) The calcium ion binding core function now cites the UniProt cofactor line instead of the PMID:699201 title. (3) Title-only quotes on 13 rows were replaced by evidential abstract sentences (PMID:16786169, 2280766, 12239582, 16817230, 8794449, 16167335, 7759556, 9546611); PMID:699201 (no abstract) and the PMID:11129957 row (where the title documents the mismatch) keep their titles. (4) GO:0032781 positive regulation of ATP-dependent activity moved MODIFY (to the MF GO:0060590, cross-aspect) -> ACCEPT, and the Ca2+-ATPase core function no longer asserts GO:0060590; the effect is abolished by ruthenium red, lanthanum and digitonin PMID:16786169, so direct ATPase regulator activity is unproven and is raised as a suggested question. This makes the KEEP_AS_NON_CORE call on the generic GO:0030234 consistent with the core functions.