SAMD8 (SMSr) is a multipass membrane enzyme enriched in the endoplasmic reticulum, with a small Golgi pool observed in cultured human cells. It transfers phosphoethanolamine from phosphatidylethanolamine to ceramide, producing ceramide phosphoethanolamine and diacylglycerol. SAM-domain-mediated oligomerization promotes ER retention. Human biochemical studies also demonstrate glycerophospholipid-hydrolyzing activities, whose substrate range and relative importance depend on construct and assay conditions. Acute perturbations in cultured cells disrupt ceramide homeostasis and can trigger mitochondrial apoptosis, whereas stable loss can be tolerated; mouse studies connect PE hydrolysis to hepatic lipid metabolism and conditional regulation of serine palmitoyltransferase (SPT). Human liver and adipose transcriptomes show coexpression with SPT genes, while direct mechanistic SPT experiments have been performed in mice.
Definition: Catalysis of the reaction: ceramide + phosphatidylethanolamine = ceramide phosphoethanolamine + 1,2-diacyl-sn-glycerol. This activity transfers a phosphoethanolamine group from PE to ceramide.
Justification: The live GO:0002950 label resembles this activity, but its definition specifies CDP-ethanolamine and CMP rather than phosphatidylethanolamine and DAG. PMID:19506037 tests this donor distinction directly. Keep the chemically distinct PE-dependent capacity under broad GO:0016780 until an exact term or corrected GO definition exists; no GO:0002950 assertion is added.
Parent term: phosphotransferase activity, for other substituted phosphate groups
Supporting Evidence:
Definition: Catalysis of the reaction: phosphatidylethanolamine + H2O = 1,2-diacyl-sn-glycerol + phosphoethanolamine. This activity specifically hydrolyzes PE to generate DAG and phosphoethanolamine.
Supporting Evidence:
Definition: The ability to detect and respond to ceramide concentration changes in the endoplasmic reticulum, regulating ceramide homeostasis through enzymatic conversion to prevent ceramide-induced cellular stress.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0033188 sphingomyelin synthase activity | IBA GO_REF:0000033 | UNDECIDED | Summary: SAMD8 strongly favors CPE production; the extent of residual sphingomyelin synthase capacity requires reconciliation. Reason: The current PTHR21290 IBD for sphingomyelin synthase activity remains at PTN000480004. PMID:19506037 directly distinguishes SMSr CPE synthesis from conventional SM synthesis, while the updated UniProt account informed by PMID:38388831 describes little or no SMS activity. A substrate preference is not equivalent to demonstrated zero turnover. The 2024 full mechanistic assays, including gain-of-function mutants and wild-type controls, need focused assessment before a categorical loss claim. Withdraw the absolute removal and the erroneous replacement by the CDP-choline reaction. The completed OpenScientist report recommends rejection, but explicitly did not retrieve PMID:38388831; it therefore does not resolve the modern wild-type residual-activity controls. Newly accessed PMID:34332077 directly reports no NBD-SM in its recombinant human assay, strengthening the condition-specific negative evidence. Retain UNDECIDED pending the full 2024 comparison rather than equate little or no activity with a universal exclusion. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000480004 Β· PTN000480004 UNRESOLVED Target substrate preference and negative earlier SM assays are substantive, but residual capacity versus complete loss requires evaluation of the newer wild-type controls. Supporting Evidence: PMID:19506037 Although formation of NBD-CPE was stimulated by addition of PE, addition of either PC or CDP-ethanolamine had no effect file:human/SAMD8/SAMD8-hypotheses/lipid-reaction-spectrum-pathways-and-compartments/openscientist.md Two of the three UniProt-cited PLC papers (PMID 34332077, 38388831) were not retrievable PMID:34332077 Indeed, rSMSr produced NBD-CPE (Fig. 3A) but not NBD-SM (Fig. 3B). |
| GO:0000139 Golgi membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A small Golgi pool of wild-type SMSr is directly observed alongside its predominant ER localization. Reason: PMID:28120887 explicitly reports a minor but significant wild-type GFP-SMSr Golgi pool in HeLa SMSr-knockout cells and quantifies colocalization with Golgi marker GM130 relative to calnexin. SAM deletion and oligomerization mutants increase redistribution, but the Golgi signal is not confined to mutants. These target data support retaining the ancestral PTN000480004 localization as non-core. The completed OpenScientist report incorrectly calls the Golgi pool mutant-only; its recommendation is rejected because the cited primary explicitly observes wild-type GFP-SMSr there. Supporting Evidence: PMID:28120887 GFP-SMSr primarily resides in the ER while a minor but significant pool of the enzyme is localized in the Golgi complex. file:human/SAMD8/SAMD8-report-assessment.md The wild-type Golgi pool is directly documented in PMID:28120887; the report calls it mutant-only. |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SAMD8 correctly localizes to the ER membrane. This is well-supported by experimental evidence showing ER-specific localization mediated by the SAM domain through oligomerization (PMID:19506037, PMID:28120887). Reason: This annotation is correct and supported by multiple lines of experimental evidence. SAMD8 is an ER-resident membrane protein that controls ceramide homeostasis specifically in the ER. Supporting Evidence: PMID:19506037 Note that removal of SAM causes hSMSr-V5 to redistribute from the ER to the Golgi file:human/SAMD8/SAMD8-deep-research-falcon.md Cabukusta et al. (2017, *Scientific Reports*, Jan 2017) show that SMSr is **ER-resident** and that ER retention depends on **homotypic oligomerization mediated by its SAM domain** |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | UNDECIDED | Summary: A secondary plasma-membrane pool remains unresolved; predominant ER residency does not prove complete exclusion. Reason: PTN000480004 retains plasma-membrane localization in the current PAINT snapshot. The direct SMSr studies establish ER enrichment and a small wild-type Golgi pool, showing that ER retention is not absolute. They do not provide a decisive target-specific plasma-membrane exclusion assay. Leave this location unresolved pending assessment of full-length endogenous protein and trafficking conditions, rather than infer a paralog-transfer error solely from its major compartment. The completed report infers absence from predominant ER residence and paralog localization, without new target-specific exclusion evidence; its categorical rejection is not adopted. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000480004 Β· PTN000480004 UNRESOLVED ER enrichment and retention establish a major compartment but do not experimentally exclude every plasma-membrane pool. Supporting Evidence: PMID:28120887 GFP-SMSr primarily resides in the ER while a minor but significant pool of the enzyme is localized in the Golgi complex. file:human/SAMD8/SAMD8-report-assessment.md The report did not establish absence of a secondary plasma-membrane pool. |
| GO:0046513 ceramide biosynthetic process | IBA GO_REF:0000033 | UNDECIDED | Summary: SMSr regulates ER ceramide abundance, while its asserted participation in ceramide formation requires separate assessment. Reason: PMID:19506037 establishes CPE formation and regulation of ceramide levels, but regulation is not identical to a step that forms ceramide. The PAINT PTN000480004 placement includes the target human protein among experimental descendants, which is valid descendant grounding rather than circular support. Forward CPE synthesis consumes ceramide; that alone neither establishes nor excludes a reverse reaction or a distinct contribution to ceramide formation. Leave the biosynthetic claim unresolved pending source/term-scope clarification while retaining GO:2000303 regulation of ceramide biosynthesis. PMID:40998032 adds human liver/adipose coexpression with SPT genes and mouse SPT-activity, PE-rescue and SPTLC2 co-IP experiments. This is substantive pathway-regulatory work, not evidence of a ceramide-forming reaction by SMSr; whether GO:0046513 encompasses this role versus the separate regulation term remains the specific curator question. The report omitted this paper and its blanket no-in-vivo-ceramide-effect inference is limited by the high-fat-diet mouse result. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000480004 Β· PTN000480004 UNRESOLVED IBD includes experimental target evidence. Adjudication concerns biosynthetic participation versus regulation, not target self-inclusion. Supporting Evidence: PMID:19506037 Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER PMID:40998032 the directionality of the relationship cannot easily be assessed with observational human RNA-seq data. PMID:40998032 We found that PE supplementation significantly reduced SPT activity in a dose-dependent fashion (Fig. 5D). |
| GO:0047493 ceramide cholinephosphotransferase activity | IBA GO_REF:0000033 | MODIFY | Summary: The inherited CDP-choline-specific term conflates nucleotide-donor chemistry with SMS-family phospholipid headgroup transfer. Reason: Live GO:0047493 defines CDP-choline + ceramide = CMP + H+ + sphingomyelin. Source-node PTN000480004 is genuinely ancestral to human SAMD8 leaf PTN002501711, but its SMS1/SMS2 source biochemistry transfers phosphocholine from phosphatidylcholine, producing DAG rather than CMP (PMID:14685263; PMID:19506037). The focused OpenScientist report also conflates these reactions. Human SMSr directly transfers phosphoethanolamine from PE to ceramide; generalize to GO:0016780, which preserves established substituted-phosphate transfer without asserting the unsupported nucleotide donor. This source-term correction does not claim that every possible CDP-choline assay is negative. GO:0002950 is not an alternative: it specifies CDP-ethanolamine/CMP, whereas the measured CPE reaction uses PE/DAG. An exact donor-specific ontology term is proposed separately. Propagation Review Root cause: SOURCE BAD Sources checked: PANTHER:PTN000480004 Β· PTN000480004 SOURCE BAD Actual target descent is verified. Source SMS1/SMS2 chemistry uses phosphatidylcholine/DAG, not the CDP-choline/CMP reaction in GO:0047493; the error concerns the ancestral term mapping, not donor count or misplaced target topology. Proposed replacements: phosphotransferase activity, for other substituted phosphate groups Supporting Evidence: PMID:19506037 Although formation of NBD-CPE was stimulated by addition of PE, addition of either PC or CDP-ethanolamine had no effect file:human/SAMD8/SAMD8-report-assessment.md GO:0047493 uses CDP-choline and produces CMP; the SMS1/SMS2 reaction uses phosphatidylcholine and produces DAG. file:human/SAMD8/SAMD8-hypotheses/lipid-reaction-spectrum-pathways-and-compartments/openscientist.md transfer of phosphoethanolamine from PE onto ceramide |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Correct annotation based on UniProt subcellular location mapping. SAMD8 is an ER membrane protein, confirmed by experimental evidence (PMID:19506037, PMID:28120887). Reason: This IEA annotation correctly identifies SAMD8 ER membrane localization based on UniProt curation, which aligns with experimental evidence showing ER-specific localization. Supporting Evidence: PMID:19506037 hSMSr-V5 gave a reticular and nuclear envelope staining pattern and colocalized with the ER marker protein disulfide isomerase (Fig |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: Correct but very general annotation. SAMD8 is involved in lipid metabolism through its PE-PLC activity and ceramide-to-CPE conversion, affecting both sphingolipid and glycerophospholipid metabolism (PMID:37586586, PMID:19506037). Reason: This broad annotation is correct as SAMD8 participates in multiple aspects of lipid metabolism including sphingolipid regulation, PE hydrolysis, and DAG production. However, more specific terms would be more informative. Supporting Evidence: PMID:37586586 Sphingomyelin synthase-related protein SMSr is a phosphatidylethanolamine phospholipase C that promotes nonalcoholic fatty liver disease. file:human/SAMD8/SAMD8-deep-research-falcon.md they can cleave glycerophospholipids to release **diacylglycerol (DAG)** and a phosphorylated headgroup |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: Correct annotation. SAMD8 participates in sphingolipid metabolism by converting ceramide to CPE and regulating ceramide homeostasis in the ER (PMID:19506037). Reason: This annotation accurately reflects SAMD8 involvement in sphingolipid metabolism through its ceramide phosphoethanolamine synthase activity and role in ceramide homeostasis. Supporting Evidence: PMID:19506037 We propose that SMSr is a CPES with dual activity as ceramide sensor to control ceramide homeostasis in the ER and that the latter process is critical for the integrity of the early secretory pathway |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Correct but overly general. SAMD8 has phosphotransferase activity, transferring phosphoethanolamine from PE to ceramide (PMID:19506037). Reason: This broad annotation is technically correct as SAMD8 transfers phosphoethanolamine groups. However, more specific transferase terms would be more informative. Supporting Evidence: PMID:19506037 To test whether SMSr proteins catalyze CPE production, human SMSr (hSMSr) and Drosophila SMSr (dSMSr) were expressed in budding yeast |
| GO:0016780 phosphotransferase activity, for other substituted phosphate groups | IEA GO_REF:0000002 | ACCEPT | Summary: Correct annotation. SAMD8 transfers phosphoethanolamine groups from PE to ceramide, fitting this phosphotransferase category (PMID:19506037). Reason: This annotation correctly captures SAMD8 phosphotransferase activity for substituted phosphate groups (phosphoethanolamine). This is more specific than general transferase activity and appropriate for the enzyme function. Supporting Evidence: PMID:19506037 CPE production also occurs in mammals and is catalyzed by a phosphatidylethanolamine (PE)/ceramide ethanolamine phosphotransferase or CPE synthase (CPES; Malgat et al., 1986, 1987) |
| GO:0046513 ceramide biosynthetic process | IEA GO_REF:0000117 | UNDECIDED | Summary: SMSr regulates ER ceramide abundance, while its asserted participation in ceramide formation requires separate assessment. Reason: PMID:19506037 establishes CPE formation and regulation of ceramide levels, but regulation is not identical to a step that forms ceramide. The PAINT PTN000480004 placement includes the target human protein among experimental descendants, which is valid descendant grounding rather than circular support. Forward CPE synthesis consumes ceramide; that alone neither establishes nor excludes a reverse reaction or a distinct contribution to ceramide formation. Leave the biosynthetic claim unresolved pending source/term-scope clarification while retaining GO:2000303 regulation of ceramide biosynthesis. PMID:40998032 adds human liver/adipose coexpression with SPT genes and mouse SPT-activity, PE-rescue and SPTLC2 co-IP experiments. This is substantive pathway-regulatory work, not evidence of a ceramide-forming reaction by SMSr; whether GO:0046513 encompasses this role versus the separate regulation term remains the specific curator question. The report omitted this paper and its blanket no-in-vivo-ceramide-effect inference is limited by the high-fat-diet mouse result. Supporting Evidence: PMID:19506037 Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER PMID:40998032 the directionality of the relationship cannot easily be assessed with observational human RNA-seq data. PMID:40998032 We found that PE supplementation significantly reduced SPT activity in a dose-dependent fashion (Fig. 5D). |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Correct annotation based on immunofluorescence data. SAMD8 localizes to the ER, confirmed by multiple studies (PMID:19506037). Reason: This IDA annotation correctly identifies SAMD8 ER localization based on direct experimental evidence from immunofluorescence studies. Supporting Evidence: PMID:19506037 hSMSr-V5 gave a reticular and nuclear envelope staining pattern and colocalized with the ER marker protein disulfide isomerase (Fig |
| GO:0005829 cytosol | IDA GO_REF:0000052 | UNDECIDED | Summary: The curated HPA cytosolic signal needs reagent- and product-specific reconciliation with ER membrane localization. Reason: Multipass membrane topology and a predominant ER pool do not justify dismissing the curated immunofluorescence result without inspecting its images and antibody specificity. PMID:28659495 also demonstrates caspase-dependent release of the N-terminal SAM region, although it does not show that this fragment explains the HPA observation. Leave the experimental annotation unresolved instead of treating membrane topology as proof that every detected product is confined to membranes. Supporting Evidence: PMID:28659495 Both staurosporine and FasL trigger a caspase-mediated release of the N-terminal SAM domain of human SMSr in HeLa cells. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8959462 | ACCEPT | Summary: Correct annotation from Reactome pathway curation. SAMD8 is an ER membrane protein that catalyzes CPE synthesis in the ER (PMID:19506037). Reason: This TAS annotation from Reactome correctly identifies SAMD8 ER membrane localization, consistent with experimental evidence. Supporting Evidence: PMID:19506037 SMSr displays CPES activity and, contrary to SMS1 and 2, localizes to the ER. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:19506037 Sphingomyelin synthase-related protein SMSr controls ceramid... | ACCEPT | Summary: Correct annotation based on direct experimental evidence showing ER membrane localization via immunofluorescence microscopy (PMID:19506037). Reason: This IDA annotation is fully supported by the cited experimental evidence showing SAMD8 colocalization with ER markers and its reticular distribution pattern. Supporting Evidence: PMID:19506037 hSMSr-V5 gave a reticular and nuclear envelope staining pattern and colocalized with the ER marker protein disulfide isomerase (Fig |
| GO:0046513 ceramide biosynthetic process | IDA PMID:19506037 Sphingomyelin synthase-related protein SMSr controls ceramid... | UNDECIDED | Summary: SMSr regulates ER ceramide abundance, while its asserted participation in ceramide formation requires separate assessment. Reason: PMID:19506037 establishes CPE formation and regulation of ceramide levels, but regulation is not identical to a step that forms ceramide. The PAINT PTN000480004 placement includes the target human protein among experimental descendants, which is valid descendant grounding rather than circular support. Forward CPE synthesis consumes ceramide; that alone neither establishes nor excludes a reverse reaction or a distinct contribution to ceramide formation. Leave the biosynthetic claim unresolved pending source/term-scope clarification while retaining GO:2000303 regulation of ceramide biosynthesis. PMID:40998032 adds human liver/adipose coexpression with SPT genes and mouse SPT-activity, PE-rescue and SPTLC2 co-IP experiments. This is substantive pathway-regulatory work, not evidence of a ceramide-forming reaction by SMSr; whether GO:0046513 encompasses this role versus the separate regulation term remains the specific curator question. The report omitted this paper and its blanket no-in-vivo-ceramide-effect inference is limited by the high-fat-diet mouse result. Supporting Evidence: PMID:19506037 Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER PMID:40998032 the directionality of the relationship cannot easily be assessed with observational human RNA-seq data. PMID:40998032 We found that PE supplementation significantly reduced SPT activity in a dose-dependent fashion (Fig. 5D). |
| GO:2000303 regulation of ceramide biosynthetic process | IDA PMID:19506037 Sphingomyelin synthase-related protein SMSr controls ceramid... | ACCEPT | Summary: SMSr contributes to ceramide-homeostasis regulation in human cultured cells, with complementary mouse evidence linking PE metabolism to SPT regulation. Reason: This annotation accurately reflects SAMD8 role as a key regulator of ceramide homeostasis. The cited paper demonstrates that blocking SAMD8 causes ceramide accumulation and that it operates as a ceramide sensor. PMID:40998032 provides a plausible mechanistic connection: mouse overexpression and high-fat-diet loss change SPT activity, PE supplementation reverses SPTLC2 elevation and reduces microsomal SPT activity, and SPTLC2 co-immunoprecipitates with tagged SMSr. Human evidence in that study is coexpression, and the exact PE-to-SPT mechanism remains open; do not describe a demonstrated direct binary switch in human cells. Supporting Evidence: PMID:19506037 We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER. PMID:40998032 We found that SPTLC2 co-immunoprecipitated with SMSr-Flag (Fig. 5E) |
| GO:0006686 sphingomyelin biosynthetic process | NAS PMID:14685263 Identification of a family of animal sphingomyelin synthases... | UNDECIDED | Summary: The early NAS sphingomyelin-biosynthesis assertion requires the same capacity and physiological-context assessment as the catalytic claim. Reason: PMID:14685263 identifies the SMS family but the specific human SMSr role was clarified later as CPE synthesis. PMID:19506037 supplies important contrary substrate evidence; newer structural work distinguishes strong CPE preference from little or no SMS activity. Whether residual wild-type chemistry contributes to SM biosynthesis remains unresolved. Keep the NAS assertion uncertain pending focused adjudication rather than infer the process solely from family name or reject it solely from preference. The completed OpenScientist report recommends rejection, but explicitly did not retrieve PMID:38388831; it therefore does not resolve the modern wild-type residual-activity controls. Newly accessed PMID:34332077 directly reports no NBD-SM in its recombinant human assay, strengthening the condition-specific negative evidence. Retain UNDECIDED pending the full 2024 comparison rather than equate little or no activity with a universal exclusion. Supporting Evidence: file:human/SAMD8/SAMD8-hypotheses/lipid-reaction-spectrum-pathways-and-compartments/openscientist.md Two of the three UniProt-cited PLC papers (PMID 34332077, 38388831) were not retrievable PMID:34332077 Indeed, rSMSr produced NBD-CPE (Fig. 3A) but not NBD-SM (Fig. 3B). |
| GO:0016020 membrane | NAS PMID:14685263 Identification of a family of animal sphingomyelin synthases... | ACCEPT | Summary: Correct but overly general annotation. SAMD8 is a membrane protein with 6 transmembrane helices, but more specifically localizes to the ER membrane (PMID:19506037). Reason: This general membrane annotation is correct as SAMD8 is an integral membrane protein. However, more specific annotations (ER membrane) are available and more informative. Supporting Evidence: PMID:14685263 Using a functional cloning strategy in yeast, we identified a novel family of integral membrane proteins exhibiting all enzymatic features previously attributed to animal SM synthase. |
| GO:0004629 C-type glycerophospholipase activity | IDA PMID:37586586 Sphingomyelin synthase-related protein SMSr is a phosphatidy... | NEW | Summary: Retain the existing proposal for C-type glycerophospholipase activity, with substrate and construct scope made explicit. Reason: PMID:33621517 measures hydrolysis of several glycerophospholipids by purified human SMSr lacking its SAM domain and confirms PAP and PI-PLC activities for full-length human SMSr immunoprecipitated from COS-7 cells, with catalytic-mutant controls. PMID:37586586 provides complementary mouse PE-PLC physiology. These data support the broad PLC reaction but not a universal claim that PE is the only substrate or the predominant activity in every human tissue. This pre-existing NEW molecular-function assertion is retained without adding further redundant activities. PMID:34332077 independently confirms PE-PLC activity of recombinant human SMSr but finds no PC/PA hydrolysis and an inconclusive fluorescent-PI comparison with substrate background hydrolysis. The two 2021 studies disagree over broader specificity; this supports retaining the broad PLC class while leaving the physiological substrate spectrum conditional. Supporting Evidence: PMID:33621517 The SMSr expressed in the COS-7Β cells exhibited PAP and PI-PLC activities PMID:33621517 a CPE synthase-inactive mutant of SMSr (D348E) (20) failed to show PAP and PI-PLC activities PMID:34332077 The cDNA for human SMSr was cloned into an expression vector modified from pFastBac Dual |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:24259670 Sphingomyelin synthase-related protein SMSr is a suppressor ... | NEW | Summary: Retain the existing anti-apoptotic regulation proposal with its direct primary source and cell-context limit. Reason: PMID:24259670 directly establishes that SMSr catalytic activity and its SAM domain suppress ceramide-mediated mitochondrial apoptosis in cultured cells, with ceramide synthesis/export and mitochondrial ceramidase rescue experiments. The enzyme performs a regulatory role rather than merely being a caspase substrate. PMID:28120887 reports survival of stable SMSr-knockout HeLa cells, so this is not a universal requirement for cell survival. The old reviewer-authored NEW proposal now cites the apoptosis-specific primary PMID:24259670 rather than the earlier ceramide paper; no GOA source row was changed. Supporting Evidence: PMID:24259670 Disruption of SMSr catalytic activity causes a rise in ER ceramides and their mislocalization to mitochondria, triggering a mitochondrial pathway of apoptosis. |
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Download this section (compressed HTML)Q: How does SAMD8 sense ceramide levels in the ER - is it through direct binding, allosteric regulation, or changes in oligomerization state?
Suggested experts: Joost Holthuis (Utrecht University) - corresponding author on key SAMD8 papers, Ceramide/sphingolipid metabolism experts
Q: What determines whether SAMD8 acts primarily as a CPE synthase versus PE-PLC in different tissues or metabolic states?
Suggested experts: Hepatic lipid metabolism specialists, NAFLD researchers
Q: What is the fate of the trace amounts of CPE produced by SAMD8 - is it rapidly degraded or does it have signaling functions?
Suggested experts: Lipidomics experts, Sphingolipid catabolism researchers
Q: How should GO represent SMSr-dependent ceramide biosynthetic participation versus regulation of the pathway? PMID:40998032 establishes mouse PE-sensitive SPT regulation and co-IP, while human evidence is coexpression; a direct human mechanism and reverse CPE reaction remain unresolved.
Experiment: Use the existing human SMSr structures from PMID:38388831 to design matched full-length assays for PE/DAG-dependent CPE synthesis, residual PC-dependent SM synthesis and reverse reactions; reconstitute SPT with controlled PE and SMSr to distinguish lipid-mediated regulation from physical coupling.
Hypothesis: Relative headgroup-transfer and hydrolysis activities depend on membrane/substrate conditions, while PE-mediated SPT regulation need not imply a direct catalytic interaction.
Type: Biochemical mechanism and structure
Experiment: Track real-time ER ceramide levels using fluorescent sensors while manipulating SAMD8 activity or expression
Hypothesis: SAMD8 activity increases proportionally with ER ceramide levels until a threshold is reached, acting as a homeostatic sensor
Type: Live cell ceramide imaging
Experiment: Generate conditional SAMD8 knockouts in brain, liver, and pancreatic beta cells to assess tissue-specific functions
Hypothesis: SAMD8 deficiency in neurons leads to age-dependent neurodegeneration due to ceramide accumulation, while liver-specific knockout protects against NAFLD
Type: Tissue-specific knockout studies
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