SMPD2 (neutral sphingomyelinase 1 / nSMase1) — review notes

UniProt: O60906 (NSMA_HUMAN), gene SMPD2, HGNC:11121, 423 aa, EC 3.1.4.12.

Identity and family

Catalytic activity — the SMase vs lysophospholipase nuance

The gene was originally cloned as a putative neutral sphingomyelinase
(Tomiuk et al. 1998, PMID:9520418), but the functional characterization that
followed showed its cellular role is more that of a lyso-PAF phospholipase C
than a bulk cellular SMase:

UniProt records EC 3.1.4.12 with multiple catalytic-activity reactions:
sphingomyelin → ceramide + phosphocholine; sphingosylphosphocholine → sphingoid
base + phosphocholine; and hydrolysis of 1-O-octadecyl-/1-O-hexadecyl-/
1-hexadecanoyl-glycero-3-phosphocholine (lyso-PAF / lyso-PC) → the corresponding
(alkyl/acyl)-glycerol + phosphocholine
[file:human/SMPD2/SMPD2-uniprot.txt "Also hydrolyzes"].
All the lyso-PAF / lyso-PC reactions release phosphocholine by cleaving the
phosphodiester bond — i.e. a phospholipase C-type cleavage, not a
lysophospholipase (EC 3.1.1.5) acyl-ester hydrolysis. So the appropriate MF for
the lyso-PAF activity is GO:0004629 (current ontology label
"C-type glycerophospholipase activity", formerly "phospholipase C activity";
def: "cleaves the first phosphodiester bond between the phosphate and glycerol,
producing a mono- or a diacylglycerol, depending on whether the substrate is a
lysoglycerophospholipid or a glycerophospholipid"), a sibling of sphingomyelin
phosphodiesterase activity (both are under phosphoric diester hydrolase activity
GO:0008081).

Cofactor: Mg(2+) [file:human/SMPD2/SMPD2-uniprot.txt "Name=Mg(2+)"].
Kinetics: KM 26.2 uM for sphingomyelin; comparable KM (~27 uM) for lyso-PAF
substrates; the enzyme handles SM, SPC, and lyso-PAF/lyso-PC with similar
efficiency [file:human/SMPD2/SMPD2-uniprot.txt "KM=26.2 uM for sphingomyelin"].

Pathway / process

Localization

Interactions

Numerous IntAct binary interactions (ARFIP1, CCN1, COQ8A, GAD2, MTHFR, NDRG4,
PBX3, PGRMC2, PITPNC1, SH3GLB1, SLC10A1, SLC7A8, STAR, TMEM14B, TMEM167B)
[file:human/SMPD2/SMPD2-uniprot.txt "O60906; P53367: ARFIP1"]. These are
high-throughput binary/AP-MS screens (HuRI, BioPlex, neurodegeneration
interactome) and do not by themselves define a specific molecular function
beyond generic protein binding.

Reference assessment

Core function synthesis

  1. MF: sphingomyelin phosphodiesterase activity (GO:0004767), Mg2+-dependent,
    in vitro (IDA). Represents the classical/cloned activity.
  2. MF: C-type glycerophospholipase activity (GO:0004629, formerly "phospholipase
    C activity") — captures the physiologically preferred lyso-PAF / lyso-PC / SPC
    phospholipase-C activity (IDA to the general phosphoric diester hydrolase
    activity GO:0008081 supports this).
  3. BP: sphingomyelin catabolic process (GO:0006685) / sphingolipid metabolic
    process — the UniProt-stated pathway.
  4. Location: integral membrane protein (ER/Golgi and plasma/cell membrane).

2026-09-20 IBA re-review: reaction chemistry and localization

Restore conditional human ceramide/signaling, core ER/catabolism and four non-core interaction rows. Preserve broad phosphodiester-hydrolase chemistry; glycerophospholipase core excludes the sphingoid substrate. Caveola and mechanical-response rows unresolved after full primary antigen tracing; independent ceramide evidence retained.

All 30 source assertions were preserved. See the primary evidence checks and audit. The outstanding question is caveola-mechanosignaling-antigen-identity.

Recovery PR review: generic binding policy (2026-09-22)

Applied the repository policy to the re-reviewed GO:0005515 rows. Removal concerns
the uninformative function label and does not refute the source interaction.
Rows whose target-specific assays remain inaccessible are UNDECIDED. Source
assertions and supporting evidence are preserved.

2026-11-06 ORGANELLES ER batch 4 (endoplasmic reticulum rows)