SGPL1 is sphingosine-1-phosphate lyase 1, a pyridoxal 5'-phosphate (PLP)-dependent enzyme (EC 4.1.2.27) anchored in the endoplasmic reticulum membrane that catalyzes the final, irreversible degradative step of sphingolipid metabolism. It cleaves phosphorylated sphingoid bases, chiefly sphingosine-1-phosphate (S1P; also sphinganine 1-phosphate), into a long-chain fatty aldehyde ((2E)-hexadecenal or hexadecanal) plus phosphoethanolamine. This reaction has no reverse counterpart and is the only exit from the sphingolipid pathway, channeling sphingoid-derived carbon into glycerolipid and ethanolamine-phosphate metabolism. The catalytic domain faces the cytosol; the enzyme is a homodimer that binds PLP covalently through a Schiff base to Lys-353. By irreversibly degrading S1P, SGPL1 terminates S1P signaling and helps establish the tissue-to-blood/lymph S1P gradient that governs lymphocyte egress and immune function, and it acts as a modulator of the ceramide/S1P "rheostat" controlling cell survival. Biallelic loss-of-function variants cause an autosomal-recessive syndrome (SPLIS / RENI, MIM:617575) featuring steroid-resistant nephrotic syndrome, primary adrenal insufficiency, ichthyosis, immunodeficiency, and neurological defects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO/IBA) placement of SGPL1 activity in the ER. Consistent with experimental localization; the more precise term is ER membrane (GO:0005789), but the ER assignment is correct. |
| GO:0008117 sphinganine-1-phosphate aldolase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. GO:0008117 is the canonical GO term for the S1P/sphinganine 1-phosphate lyase reaction (EC 4.1.2.27, RHEA:18593); no separate "sphingosine-1-phosphate lyase activity" term exists. IBA recovers the conserved function across orthologs and agrees with direct human experimental data. |
| GO:0030149 sphingolipid catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. SGPL1 performs the terminal, irreversible step of sphingolipid catabolism. IBA correctly recovers this conserved role. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SubCell keyword mapping to ER membrane. This is the precise, correct location: SGPL1 is a single-pass type III ER membrane protein with its catalytic domain on the cytoplasmic side. Corroborated by experimental annotations below. |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to the very general grandparent term "lipid metabolic process". Correct but uninformative; the specific sphingolipid catabolic process (GO:0030149) captures the function. |
| GO:0008117 sphinganine-1-phosphate aldolase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (RHEA:18593 / EC 4.1.2.27) mapping to the core lyase activity. Consistent with the experimental IDA/IMP annotations. |
| GO:0016830 carbon-carbon lyase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping to the general parent MF "carbon-carbon lyase activity". Correct (the enzyme cleaves a C-C bond) but the specific child GO:0008117 is the informative term. |
| GO:0030170 pyridoxal phosphate binding | IEA GO_REF:0000002 | ACCEPT | Summary: Core molecular function feature. SGPL1 is a PLP-dependent enzyme; PLP is bound covalently via a Schiff base to Lys-353 (essential for catalysis) and is confirmed in the crystal structure. Although IEA, this is strongly supported by direct structural and cofactor evidence. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a large-scale innate-immunity interactome screen (HI5); IntAct records SGPL1-STING1 (Q86WV6). Uninformative as a molecular function and no specific physiological complex is established. Retained (experimental IPI) but flagged as over-annotation; not promoted to a core function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from the HuRI high-throughput binary interactome (many ER/membrane partners, e.g. aquaporins, ERG28, FA2H, IFITM3). Systematic-screen hits with no specific molecular function; retained but flagged as over-annotation. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Automated ER localization (from mouse ortholog). Correct; ER membrane (GO:0005789) is the more precise term. |
| GO:0030149 sphingolipid catabolic process | TAS Reactome:R-HSA-9845614 | ACCEPT | Summary: Reactome traceable assertion placing SGPL1 in sphingolipid catabolism. Correct core biological process. |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway mapping (UPA00222, sphingolipid metabolism). Correct but a parent of the more specific catabolic process (GO:0030149); consistent with the UniProt PATHWAY annotation. |
| GO:0008117 sphinganine-1-phosphate aldolase activity | TAS Reactome:R-HSA-428681 | ACCEPT | Summary: Reactome traceable assertion for the S1P/sphinganine 1-phosphate lyase reaction. Core molecular function, consistent with experimental data. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence localization to the ER. Consistent with all other localization evidence; ER membrane is the precise term. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:14570870 Sphingosine-phosphate lyase enhances stress-induced ceramide... | ACCEPT | Summary: Experimental localization of recombinant human SGPL1 to the ER. Core location: SGPL1 is an integral ER membrane protein. Supporting Evidence: PMID:14570870 The recombinant enzyme was active, localized to the endoplasmic reticulum, and reduced baseline sphingosine and sphingosine 1-phosphate levels. |
| GO:0008117 sphinganine-1-phosphate aldolase activity | EXP PMID:22784711 First evidence of sphingosine 1-phosphate lyase protein expr... | ACCEPT | Summary: Direct measurement of SPL enzymatic activity in human tissue/cell lines. Supports the core lyase molecular function. Supporting Evidence: PMID:22784711 This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P) |
| GO:0008117 sphinganine-1-phosphate aldolase activity | IMP PMID:28165339 Mutations in sphingosine-1-phosphate lyase cause nephrosis w... | ACCEPT | Summary: Disease-variant / mutational evidence: SGPL1 patient mutations reduce or abolish enzyme activity, and WT human SGPL1 (but not variants) rescues the S1P-lyase-deficient dpl1-delta yeast strain, directly demonstrating the lyase activity for the human protein. Supports the core molecular function. Supporting Evidence: PMID:28165339 expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Ξ yeast strains, whereas expression of disease-associated variants did not. |
| GO:0030149 sphingolipid catabolic process | IMP PMID:28165339 Mutations in sphingosine-1-phosphate lyase cause nephrosis w... | ACCEPT | Summary: Loss of SGPL1 (patient mutations) impairs sphingolipid catabolism, and the human enzyme complements sphingolipid-catabolism-deficient yeast. Supports the core biological process. Supporting Evidence: PMID:28165339 All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. |
| GO:0097190 apoptotic signaling pathway | IDA PMID:14570870 Sphingosine-phosphate lyase enhances stress-induced ceramide... | KEEP AS NON CORE | Summary: SGPL1 overexpression potentiates stress-induced apoptosis, and lyase activity is required for the effect. This is a real but downstream/indirect consequence of altering the S1P/ceramide rheostat rather than a distinct molecular function of SGPL1; the reaction products themselves have no apoptotic effect. Kept as a genuine but non-core process. Supporting Evidence: PMID:14570870 Lyase enzymatic activity was required to potentiate apoptosis, because cells expressing a catalytically inactive enzyme behaved like controls. |
| GO:0006631 fatty acid metabolic process | IDA PMID:24809814 Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-meth... | KEEP AS NON CORE | Summary: The lyase reaction produces a long-chain fatty aldehyde ((2E)-hexadecenal), which feeds into fatty-acid/glycerolipid metabolism. This is a peripheral downstream role of the catabolic activity rather than a core function; retained as non-core. |
| GO:0008117 sphinganine-1-phosphate aldolase activity | IDA PMID:24809814 Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-meth... | ACCEPT | Summary: Biochemical assay and co-crystal structure of the homodimeric human S1P lyase with PLP and an active-site inhibitor directly demonstrate the lyase activity. Core molecular function. Supporting Evidence: PMID:24809814 as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. |
| GO:0030149 sphingolipid catabolic process | IDA PMID:24809814 Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-meth... | ACCEPT | Summary: Direct demonstration of S1P-degrading (sphingolipid catabolic) activity via the biochemical inhibitor assay. Core biological process. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-428681 | ACCEPT | Summary: Reactome traceable assertion for ER membrane association. Core location, consistent with experimental evidence. |
| GO:0005783 endoplasmic reticulum | IDA PMID:14570870 Sphingosine-phosphate lyase enhances stress-induced ceramide... | ACCEPT | Summary: Direct experimental ER localization of recombinant human SGPL1. Correct; ER membrane is the precise term. Supporting Evidence: PMID:14570870 The recombinant enzyme was active, localized to the endoplasmic reticulum, and reduced baseline sphingosine and sphingosine 1-phosphate levels. |
| GO:0008117 sphinganine-1-phosphate aldolase activity | IDA PMID:14570870 Sphingosine-phosphate lyase enhances stress-induced ceramide... | ACCEPT | Summary: Recombinant human SGPL1 was enzymatically active and reduced sphingosine/S1P levels, directly demonstrating the lyase activity. Core molecular function. Supporting Evidence: PMID:14570870 The recombinant enzyme was active, localized to the endoplasmic reticulum, and reduced baseline sphingosine and sphingosine 1-phosphate levels. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:11018465 Human sphingosine-1-phosphate lyase: cDNA cloning, functiona... | ACCEPT | Summary: Author statement (cDNA cloning paper) of a single N-terminal membrane span, consistent with the integral ER membrane localization established by later experimental work. Correct core location. Supporting Evidence: PMID:11018465 Hydropathy plots revealed the presence of one membrane span near the amino-terminal |
| GO:0006672 ceramide metabolic process | IDA PMID:14570870 Sphingosine-phosphate lyase enhances stress-induced ceramide... | KEEP AS NON CORE | Summary: SGPL1 does not act on ceramide directly; overexpression raises stress-induced ceramide indirectly by shifting the S1P/ceramide balance. A genuine but indirect metabolic effect, retained as non-core rather than a direct molecular function. Supporting Evidence: PMID:14570870 Stress increased the amounts of long- and very long-chain ceramides in HEK293 cells, and this was enhanced in cells overexpressing wild type but not catalytically inactive lyase. |
| GO:0008117 sphinganine-1-phosphate aldolase activity | NAS PMID:11018465 Human sphingosine-1-phosphate lyase: cDNA cloning, functiona... | ACCEPT | Summary: Author statement from the original human cDNA cloning / functional expression study assigning the S1P-lyase activity to SGPL1. Core molecular function (corroborated by later IDA/IMP evidence). Supporting Evidence: PMID:11018465 Sphingosine-1-phosphate lyase catalyzes the last step in sphingolipid breakdown, the cleavage of phosphorylated sphingoid bases such as sphingenine-1-phosphate. |
| GO:0030149 sphingolipid catabolic process | NAS PMID:11018465 Human sphingosine-1-phosphate lyase: cDNA cloning, functiona... | ACCEPT | Summary: Author statement that SGPL1 catalyzes the last step in sphingolipid breakdown. Core biological process; corroborated by experimental and phylogenetic annotations. Supporting Evidence: PMID:11018465 Sphingosine-1-phosphate lyase catalyzes the last step in sphingolipid breakdown, the cleavage of phosphorylated sphingoid bases such as sphingenine-1-phosphate. |
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Download this section (compressed HTML)Q: Beyond homodimerization, does SGPL1 have any physiologically meaningful, specific protein partner (e.g. a channeling or regulatory complex), or are the reported binary interactome hits largely incidental ER co-localization?
Experiment: Structure-guided in-vitro kinetics on purified WT vs SPLIS/RENI disease variants (e.g. R222Q, S346I) to quantify how each mutation affects PLP binding, substrate turnover, protein stability, and dimerization, mapping enzymatic loss to clinical severity.
Hypothesis: SPLIS/RENI disease severity correlates with the degree of residual S1P-lyase catalytic activity and protein stability of the mutant enzyme.
Type: enzyme kinetics / protein biochemistry
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