PMVK (phosphomevalonate kinase, UniProtKB:Q15126) — review notes

Deep research status

Falcon deep research is OUT OF CREDITS (HTTP 402); no -deep-research-falcon.md was
generated. This review is grounded in the UniProt record (PMVK-uniprot.txt), the seeded
GOA (PMVK-goa.tsv), and the cached publications in publications/PMID_*.md (all 12 GOA
PMIDs are present).

Core biology

PMVK is phosphomevalonate kinase (EC 2.7.4.2), a 192-aa cytosolic enzyme of the
nucleoside-monophosphate (NMP) kinase family (P-loop fold). It catalyses the reversible,
ATP- and cation-dependent phosphorylation of (R)-mevalonate 5-phosphate to (R)-mevalonate
5-diphosphate (+ADP) — the step between mevalonate kinase (MVK) and diphosphomevalonate
decarboxylase (MVD) in the mevalonate/isoprenoid pathway.

• UniProt CATALYTIC ACTIVITY: "Reaction=(R)-5-phosphomevalonate + ATP = (R)-5-diphosphomevalonate + ADP; ... EC=2.7.4.2" [Rhea:16341].
• UniProt PATHWAY: "Isoprenoid biosynthesis; isopentenyl diphosphate biosynthesis via mevalonate pathway; isopentenyl diphosphate from (R)-mevalonate: step 2/3."
• PMID:16519518 — recombinant human enzyme; monomer; kinetics both directions.
• PMID:17902708 — Walker-A / basic-residue mutagenesis (K48, R73, R110, R111, R84, R141).
• PMID:8663599 cloning of human liver PMKase; PMKase activity expressed in bacteria; sterol-regulated transcription; identified a C-terminal PTS-1 (Ser-Arg-Leu) but this is now known NOT to drive peroxisomal targeting.
• PMID:9392419 PMKase (with MKase, MDDase) expressed in E. coli and assayed; only MKase (not PMKase) was feedback-inhibited by isoprene intermediates.

Localization: cytosolic (peroxisomal claim retracted)

Early reports (rat, and PTS-1 motif reasoning) proposed peroxisomal localization
PMID:10191291. This was overturned:
- PMID:14729858 — GOA uses this as NOT|peroxisome (IDA) and as cytosol (IDA).
- [PMID:27052676 "The wild-type PMVK exhibited dispersed cytoplasmic localization and showed little co-localization with the peroxisomal marker PEX14"; "PMVK and MVK were predominantly cytosolically localized"] — confirms cytosol.
- UniProt CAUTION: "Was originally thought to be located in the peroxisome (PubMed:10191291). However, was later shown to be cytosolic (PubMed:14729858, PubMed:27052676)."
- PMID:14680974 shows cholesterol biosynthesis is normal in peroxisome-biogenesis-deficient fibroblasts (presqualene enzymes including PMK retain activity), arguing against obligate peroxisomal function.

The conflicting IDA peroxisome annotation from PMID:17180682 (Kovacs/Krisans) is the
minority view that the field and UniProt have since rejected. Per curation policy (do not
REMOVE an experimental IDA whose full text I cannot read), this is kept but marked
over-annotated with the contradicting evidence noted.

Disease

Heterozygous loss-of-function PMVK variants cause autosomal-dominant porokeratosis
(POROK1) — a keratinization disorder — PMID:27052676, PMID:26202976. This is a
downstream phenotype of impaired mevalonate-pathway flux in skin, not the molecular
function; not treated as a core function.

Annotation decisions summary

• MF phosphomevalonate kinase activity (GO:0004631): multiple EXP/IDA + IBA + IEA/TAS — ACCEPT (core). IEA/TAS/IBA duplicates KEEP_AS_NON_CORE.
• ATP binding (GO:0005524) IDA PMID:16519518: ACCEPT (supports mechanism; ATP is the phosphate donor; Walker-A motif).
• BP isopentenyl diphosphate biosynthetic process, mevalonate pathway (GO:0019287): the most precise pathway BP — ACCEPT (core, matches UniProt PATHWAY step 2/3).
• BP cholesterol biosynthetic process (GO:0006695) / sterol biosynthetic process (GO:0016126): correct but downstream/broad — KEEP_AS_NON_CORE (cholesterol is one branch downstream of IPP).
• CC cytosol (GO:0005829) IDA/TAS: ACCEPT (core location). cytoplasm (GO:0005737) IEA: KEEP_AS_NON_CORE (broader parent).
• CC peroxisome (GO:0005777) IDA PMID:17180682: MARK_AS_OVER_ANNOTATED (contradicted by field/UniProt CAUTION; do not REMOVE experimental IDA).
• CC NOT|peroxisome (GO:0005777) IDA PMID:14729858: ACCEPT (correct negation).
• CC membrane (GO:0016020) HDA / extracellular exosome (GO:0070062) HDA: MARK_AS_OVER_ANNOTATED (large-scale proteomics; not a functional location for a cytosolic kinase).
• MF protein binding (GO:0005515) IPI PMID:32296183: MARK_AS_OVER_ANNOTATED (bare, uninformative HuRI Y2H hits; per curation policy, not REMOVE).
• BP response to cholesterol (GO:0070723) IEP PMID:10191291: KEEP_AS_NON_CORE (sterol-regulated transcription of the gene; regulatory response, not core enzymatic function).