De novo sphingolipid (ceramide) biosynthesis; SPTLC1/SPTLC2/SPTSSA/KDSR/CERS1-3/DEGS1

De novo sphingolipid synthesis builds ceramide, the hydrophobic backbone of all complex sphingolipids, from serine and fatty acyl-CoA on the endoplasmic-reticulum membrane. The committed, rate-limiting first step is catalysed by serine palmitoyltransferase (SPT), a pyridoxal-5'-phosphate-dependent membrane complex whose catalytic core is the SPTLC1-SPTLC2 heterodimer with the small regulatory subunit SPTSSA (which sets C16 acyl-CoA specificity): it condenses L-serine with palmitoyl-CoA to 3-ketodihydrosphingosine. 3-ketodihydrosphingosine reductase (KDSR) then reduces this, using NADPH, to dihydrosphingosine (sphinganine). A family of ceramide synthases (CERS1-6) N-acylates sphinganine with a fatty acyl-CoA to give dihydroceramide, each isoform preferring a different acyl chain length: CERS1 makes C18 ceramide (brain/muscle), CERS2 very-long-chain C22-C24 ceramide (broadly expressed), and CERS3 ultra-long-chain C26+ (acyl)ceramides for the skin barrier. Finally the dihydroceramide desaturase DEGS1 introduces the 4,5-trans double bond, an O2- and iron-dependent oxidation that converts dihydroceramide to ceramide. Inherited defects span the pathway: HSAN1 (SPTLC1/SPTLC2), spastic paraplegia (SPTSSA), erythrokeratodermia/thrombocytopenia (KDSR), progressive myoclonic epilepsy 8 (CERS1), congenital ichthyosis ARCI9 (CERS3) and hypomyelinating leukodystrophy 18 (DEGS1).

MODULE:sphingolipid_de_novo_synthesisDRAFTMetabolic Pathwaymodules/sphingolipid_de_novo_synthesis.yaml
sphingolipid biosynthetic processGO:0030148 ceramide biosynthetic processGO:0046513
GO:0030148
sphingolipid biosynthetic process
The module is grounded in sphingolipid biosynthetic process (GO:0030148); it covers de novo synthesis of ceramide from serine and acyl-CoA.
GO:0046513
ceramide biosynthetic process
The pathway product is ceramide (ceramide biosynthetic process, GO:0046513).
Reactome:R-HSA-1660661
Sphingolipid de novo biosynthesis
Step order and intermediates follow the human Reactome "Sphingolipid de novo biosynthesis" pathway (reactions R-HSA-428127 SPT, R-HSA-428123 KDSR, R-HSA-428185 CerS, R-HSA-428259 DEGS1).
file:human/SPTLC1/SPTLC1-ai-review.yaml
SPTLC1 gene review (human)
The SPT catalytic-subunit step (UniProtKB:O15269, GO:0004758) matches the completed human SPTLC1 review.
file:human/SPTLC2/SPTLC2-ai-review.yaml
SPTLC2 gene review (human)
The SPT PLP-binding catalytic-subunit step (UniProtKB:O15270, GO:0004758) matches the completed human SPTLC2 review.
file:human/SPTSSA/SPTSSA-ai-review.yaml
SPTSSA gene review (human)
The SPT small regulatory subunit (UniProtKB:Q969W0, SPT complex GO:0017059) matches the completed human SPTSSA review.
file:human/KDSR/KDSR-ai-review.yaml
KDSR gene review (human)
The 3-ketodihydrosphingosine reductase step (UniProtKB:Q06136, GO:0047560) matches the completed human KDSR review.
file:human/CERS1/CERS1-ai-review.yaml
CERS1 gene review (human)
The C18-specific ceramide-synthase step (UniProtKB:P27544, GO:0050291) matches the completed human CERS1 review.
file:human/CERS2/CERS2-ai-review.yaml
CERS2 gene review (human)
The very-long-chain ceramide-synthase step (UniProtKB:Q96G23, GO:0050291) matches the completed human CERS2 review.
file:human/CERS3/CERS3-ai-review.yaml
CERS3 gene review (human)
The ultra-long-chain ceramide-synthase step (UniProtKB:Q8IU89, GO:0050291) matches the completed human CERS3 review.
file:human/DEGS1/DEGS1-ai-review.yaml
DEGS1 gene review (human)
The dihydroceramide-desaturase step (UniProtKB:O15121, GO:0042284) matches the completed human DEGS1 review.
5Nodes
4Parts
0Variant Sets
0Variants
6Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:sphingolipid_de_novo_synthesis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (8/8 grounded genes reviewed)

7 complete review(s) · 0 with deep research · 0 missing review · 8 reviewed but lacking deep research

Gene Review Complete Deep research
CERS1 P27544 ✓ ✓ ✗
CERS2 Q96G23 ✓ 42/43 ✗
CERS3 Q8IU89 ✓ ✓ ✗
DEGS1 O15121 ✓ ✓ ✗
KDSR Q06136 ✓ ✓ ✗
SPTLC1 O15269 ✓ ✓ ✗
SPTLC2 O15270 ✓ ✓ ✗
SPTSSA Q969W0 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789
De novo sphingolipid (ceramide) biosynthesisMetabolic Pathwaysphingolipid_de_novo_synthesis
sphingolipid biosynthetic processGO:0030148 ceramide biosynthetic processGO:0046513
Context
endoplasmic reticulum membraneGO:0005789

De novo sphingolipid (ceramide) biosynthesis, grounded to the human enzymes of the SPT complex (SPTLC1 O15269 + SPTLC2 O15270, GO:0004758, EC 2.3.1.50; small subunit SPTSSA Q969W0; complex GO:0017059), KDSR (Q06136, GO:0047560, EC 1.1.1.102), the ceramide synthases CERS1 (P27544), CERS2 (Q96G23) and CERS3 (Q8IU89) (all GO:0050291, EC 2.3.1.24) and DEGS1 (O15121, GO:0042284, EC 1.14.19.17). GO molecular-function/BP/location terms were taken from the completed human gene reviews and verified against the local go.db; Reactome reaction ids/titles were verified against the local reactome cache. Each step uses a PANTHER family selector with the human enzyme(s) as representative; SPT is a PROTEIN_COMPLEX node (SPTLC1 + SPTLC2 catalytic + SPTSSA activator), and the ceramide-synthase node lists CERS1/2/3 as representative members of the CerS family (PTHR12560), which share the sphingosine-N-acyltransferase reaction and differ only in acyl-CoA chain-length preference (CERS1 C18, CERS2 C22-24, CERS3 C26+; CERS4/5/6 are additional family members not in this dismech mapping subset). Substrate palmitoyl-CoA comes from fatty-acid synthesis; the product ceramide is the hub for complex sphingolipids — sphingomyelin (SGMS1/2), glucosylceramide (UGCG) and gangliosides — and for sphingosine-1- phosphate signalling (separate modules). Disorders span the pathway: HSAN1/1C (SPTLC1/SPTLC2), spastic paraplegia (SPTSSA), erythrokeratodermia/thrombocytopenia (KDSR), progressive myoclonic epilepsy 8 (CERS1), congenital ichthyosis ARCI9 (CERS3) and hypomyelinating leukodystrophy 18 (DEGS1).

Connections

spt_step -> kdsr_step Provides Input For
3-ketodihydrosphingosine from SPT is reduced by KDSR to sphinganine.
kdsr_step -> cers_step Provides Input For
Sphinganine from KDSR is N-acylated by the ceramide synthases to dihydroceramide.
cers_step -> degs1_step Provides Input For
Dihydroceramide from the ceramide synthases is desaturated by DEGS1 to ceramide.
Part 1: committed step (serine + palmitoyl-CoA condensation)
L-serine + palmitoyl-CoA to 3-ketodihydrosphingosineProtein Complexspt_step

Annotons

SPTLC1: serine palmitoyltransferase subunit
sptlc1_activity
Participant: Family: Serine palmitoyltransferase / AOS family (SPTLC)
Family:
Serine palmitoyltransferase / AOS family (SPTLC)PANTHER:PTHR13693
Representative Members: SPTLC1 (human)UniProtKB:O15269

Function

serine C-palmitoyltransferase activityGO:0004758
Substrates: L-serine palmitoyl-CoA
Products: 3-ketodihydrosphingosine (3-ketosphinganine) CoA CO2

Locations

endoplasmic reticulum membraneGO:0005789

Catalytic subunit of SPT; deficiency = HSAN1 (toxic 1-deoxysphingolipids).

SPTLC2: PLP-binding catalytic SPT subunit
sptlc2_activity
Participant: Family: Serine palmitoyltransferase / AOS family (SPTLC)
Family:
Serine palmitoyltransferase / AOS family (SPTLC)PANTHER:PTHR13693
Representative Members: SPTLC2 (human)UniProtKB:O15270

Function

serine C-palmitoyltransferase activityGO:0004758
Substrates: L-serine palmitoyl-CoA
Products: 3-ketodihydrosphingosine

Locations

endoplasmic reticulum membraneGO:0005789

PLP-binding catalytic subunit of SPT.

SPTSSA: small regulatory SPT subunit (ssSPTa)
sptssa_activity
Participant: Family: Small subunit of serine palmitoyltransferase family (SPTSS)
Family:
Small subunit of serine palmitoyltransferase family (SPTSS)PANTHER:PTHR47084
Representative Members: SPTSSA (human)UniProtKB:Q969W0

Function

enzyme activator activityGO:0008047
Substrates: SPTLC1-SPTLC2 catalytic core
Products: activated, C16-specific SPT complex

Locations

endoplasmic reticulum membraneGO:0005789

Small accessory subunit that activates SPT and sets C16 acyl-CoA specificity.

Part 2: reduction to sphinganine
3-ketodihydrosphingosine to dihydrosphingosine (sphinganine)Reactionkdsr_step

Annotons

KDSR: 3-ketodihydrosphingosine reductase
kdsr_activity
Participant: Family: 3-ketodihydrosphingosine reductase / SDR family (KDSR)
Family:
3-ketodihydrosphingosine reductase / SDR family (KDSR)PANTHER:PTHR43550
Representative Members: KDSR (human)UniProtKB:Q06136

Function

3-dehydrosphinganine reductase activityGO:0047560
Substrates: 3-ketodihydrosphingosine NADPH
Products: dihydrosphingosine (sphinganine) NADP+

Locations

endoplasmic reticulum membraneGO:0005789

Reduces 3-ketodihydrosphingosine to sphinganine; deficiency = erythrokeratodermia variabilis / thrombocytopenia.

Part 3: N-acylation to dihydroceramide (ceramide synthase family)
sphinganine + acyl-CoA to dihydroceramideReactioncers_step

Annotons

CERS1/2/3: ceramide synthase (N-acyltransferase)
cers_activity
Participant: Family: Ceramide synthase / TRAM-LAG-CLN8 (TLC) family (CERS)
Family:
Ceramide synthase / TRAM-LAG-CLN8 (TLC) family (CERS)PANTHER:PTHR12560
Representative Members: CERS1 (human, C18-specific)UniProtKB:P27544 CERS2 (human, C22-C24)UniProtKB:Q96G23 CERS3 (human, C26+)UniProtKB:Q8IU89

Function

sphingosine N-acyltransferase activityGO:0050291
Substrates: dihydrosphingosine (sphinganine) fatty acyl-CoA (chain length set by CerS isoform)
Products: dihydroceramide CoA

Locations

endoplasmic reticulum membraneGO:0005789

N-acylation step; the six ceramide synthases produce ceramides of distinct chain lengths. Disorders: EPM8 (CERS1), ARCI9 (CERS3).

Part 4: desaturation to ceramide (final step)
dihydroceramide to ceramide (4,5-trans double bond)Reactiondegs1_step

Annotons

DEGS1: dihydroceramide desaturase
degs1_activity
Participant: Family: Sphingolipid delta-4 desaturase / fatty-acid-hydroxylase family (DEGS)
Family:
Sphingolipid delta-4 desaturase / fatty-acid-hydroxylase family (DEGS)PANTHER:PTHR12879
Representative Members: DEGS1 (human)UniProtKB:O15121

Function

sphingolipid delta-4 desaturase activityGO:0042284
Substrates: dihydroceramide O2 NAD(P)H / reduced electron donor
Products: ceramide H2O

Locations

endoplasmic reticulum membraneGO:0005789

Final step; converts dihydroceramide to ceramide. Deficiency = hypomyelinating leukodystrophy 18 (HLD18).