Ether lipid / plasmalogen biosynthesis (FAR1/2 -> GNPAT -> AGPS -> PexRAP -> ER assembly -> PEDS1)

Ether phospholipids, and especially the plasmalogens (1-O-alk-1'-enyl-2-acyl glycerophospholipids), are major membrane lipids - abundant in brain, heart and immune cells - that serve in membrane structure, vesicular trafficking, signalling and as endogenous antioxidants. Unlike ester glycerolipids their synthesis begins in the peroxisome. Fatty acyl-CoA reductase (FAR1, the rate-limiting and plasmalogen-feedback- regulated isoform; FAR2 a paralog) reduces long-chain fatty acyl-CoA to the fatty alcohol that will form the ether-linked sn-1 chain. In parallel, glyceronephosphate O-acyltransferase (GNPAT/DHAPAT) acylates dihydroxyacetone phosphate (DHAP) to acyl-DHAP - the first committed step. Alkyldihydroxyacetone-phosphate synthase (AGPS), an FAD enzyme that forms a complex with GNPAT, then exchanges the acyl group of acyl-DHAP for the FAR-derived fatty alcohol, creating the defining O-alkyl ether bond and yielding alkyl-DHAP. After further steps (reduction to alkyl-glycerol-3-phosphate, acylation, and headgroup addition, largely at the ER) the resulting plasmanylethanolamine is converted to the vinyl-ether plasmalogen plasmenylethanolamine by the ER desaturase PEDS1 (plasmanylethanolamine desaturase, formerly TMEM189), which introduces the characteristic 1-O-alk-1'-enyl double bond. Loss-of-function across the peroxisomal steps causes rhizomelic chondrodysplasia punctata (PEX7/RCDP1, GNPAT/RCDP2, AGPS/RCDP3, FAR1/RCDP4) and related plasmalogen- deficiency disorders.

MODULE:ether_lipid_plasmalogen_biosynthesisDRAFTMetabolic Pathwaymodules/ether_lipid_plasmalogen_biosynthesis.yaml
ether lipid biosynthetic processGO:0008611 fatty alcohol biosynthetic processGO:1903175 glycerophospholipid biosynthetic processGO:0046474
GO:0008611
ether lipid biosynthetic process
FAR1/2, GNPAT, AGPS and PEDS1 build ether phospholipids/plasmalogens (GO:0008611).
GO:1903175
fatty alcohol biosynthetic process
FAR1/FAR2 make the fatty alcohol donor for the ether bond (GO:1903175).
file:human/FAR1/FAR1-ai-review.yaml
FAR1 gene review (human)
Fatty acyl-CoA reductase 1 (UniProtKB:Q8WVX9, GO:0102965) matches the completed human FAR1 review.
file:human/FAR2/FAR2-ai-review.yaml
FAR2 gene review (human)
Fatty acyl-CoA reductase 2 (UniProtKB:Q96K12, GO:0102965) matches the completed human FAR2 review.
file:human/GNPAT/GNPAT-ai-review.yaml
GNPAT gene review (human)
Glyceronephosphate O-acyltransferase (UniProtKB:O15228, GO:0016287) matches the completed human GNPAT review.
file:human/AGPS/AGPS-ai-review.yaml
AGPS gene review (human)
Alkylglycerone-phosphate synthase (UniProtKB:O00116, GO:0008609) matches the completed human AGPS review.
file:human/PEDS1/PEDS1-ai-review.yaml
PEDS1 gene review (human)
Plasmanylethanolamine desaturase (UniProtKB:A5PLL7, GO:0050207) matches the completed human PEDS1 review.
7Nodes
6Parts
0Variant Sets
0Variants
6Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:ether_lipid_plasmalogen_biosynthesis 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.

Function consistency and core coverage

6 gene-function check(s) reflected in core functions · 0 conflict(s) · 8 evidence or coverage gap(s) (14 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
far_activity FAR1 (human; rate-limiting)
UniProtKB:Q8WVX9
Family Representative 		alcohol-forming long-chain fatty acyl-CoA reductase activity
GO:0102965 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
far_activity FAR2 (human; paralog)
UniProtKB:Q96K12
Family Representative 		alcohol-forming long-chain fatty acyl-CoA reductase activity
GO:0102965 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gnpat_activity GNPAT (human)
UniProtKB:O15228
Family Representative 		glycerone-phosphate O-acyltransferase activity
GO:0016287 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
agps_activity AGPS (human)
UniProtKB:O00116
Family Representative 		alkylglycerone-phosphate synthase activity
GO:0008609 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pexrap_activity DHRS7B / PexRAP (human)
UniProtKB:Q6IAN0
Family Representative 		acylglycerone-phosphate reductase (NADP+) activity
GO:0000140 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
selenoi_activity SELENOI (human)
UniProtKB:Q9C0D9
Family Representative 		ethanolaminephosphotransferase activity
GO:0004307 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
peds1_activity PEDS1 / TMEM189 (human)
UniProtKB:A5PLL7
Family Representative 		plasmanylethanolamine desaturase activity
GO:0050207 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
peds1_activity CarF (Myxococcus xanthus)
UniProtKB:Q9AE87
Family Representative 		plasmanylethanolamine desaturase activity
GO:0050207 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
far_activity FAR / fatty acyl-CoA reductase family
PANTHER:PTHR11011
Family 		alcohol-forming long-chain fatty acyl-CoA reductase activity
GO:0102965 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11011.
gnpat_activity GNPAT / glycerone-phosphate O-acyltransferase family
PANTHER:PTHR12563
Family 		glycerone-phosphate O-acyltransferase activity
GO:0016287 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0016287.
agps_activity AGPS / alkyl-DHAP synthase (FAD amine oxidase-type) family
PANTHER:PTHR46568
Family 		alkylglycerone-phosphate synthase activity
GO:0008609 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR46568.
pexrap_activity DHRS7B (PexRAP) subfamily
PANTHER:PTHR44196:SF1
Family 		acylglycerone-phosphate reductase (NADP+) activity
GO:0000140 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR44196:SF1.
selenoi_activity EPT1 / SELENOI subfamily
PANTHER:PTHR10414:SF47
Family 		ethanolaminephosphotransferase activity
GO:0004307 		Family Function Unreviewed
Family review leaves GO:0004307 UNRESOLVED. The family spans phosphobase-transfer enzymes with different donor specificity, including CHPT1, SELENOI/EPT1 and dual-specificity CEPT1 branches. Human CEPT1 catalyzes phosphatidylcholine and phosphatidylethanolamine synthesis using CDP-choline or CDP-ethanolamine and diacylglycerol; mixed-micelle assays also resolve acceptor-lipid preferences (PMID:12216837). Thus phosphatidylethanolamine synthesis is supported for characterized ethanolamine-accepting branches, but not for every choline-preferring relative. The fly CG33116 assignment alone does not establish donor specificity or a ceramide rather than diacylglycerol acceptor.
peds1_activity PEDS1 / plasmanylethanolamine desaturase (fatty-acid-desaturase-like) family
PANTHER:PTHR48177
Family 		plasmanylethanolamine desaturase activity
GO:0050207 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR48177.

Gene-review completeness (6/8 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 2 missing review · 6 reviewed but lacking deep research

Gene Review Complete Deep research
AGPS O00116 ✓ 32/33 ✗
FAR1 Q8WVX9 ✓ ✓ ✗
FAR2 Q96K12 ✓ ✓ ✗
GNPAT O15228 ✓ ✓ ✗
PEDS1 A5PLL7 ✓ ✓ ✗
DHRS7B / PexRAP (human) Q6IAN0 ✗ — —
CarF (Myxococcus xanthus) Q9AE87 ✗ — —
SELENOI Q9C0D9 ✓ ✓ ✗

Details

Context
peroxisomal membraneGO:0005778 peroxisomal matrixGO:0005782 endoplasmic reticulum membraneGO:0005789
Ether lipid / plasmalogen biosynthesisMetabolic Pathwayether_lipid_plasmalogen_biosynthesis
ether lipid biosynthetic processGO:0008611 fatty alcohol biosynthetic processGO:1903175 glycerophospholipid biosynthetic processGO:0046474
Context
peroxisomal membraneGO:0005778 peroxisomal matrixGO:0005782 endoplasmic reticulum membraneGO:0005789

Ether lipid / plasmalogen biosynthesis (GO:0008611), grounded mainly in human gene reviews. The peroxisomal ether-bond-forming module plus the ER plasmalogen-defining desaturation: FAR1 (Q8WVX9, rate- limiting, plasmalogen-feedback-regulated) / FAR2 (Q96K12, paralog), both PTHR11011, GO:0102965, reduce acyl-CoA -> fatty alcohol at the peroxisomal membrane; GNPAT/DHAPAT (O15228 PTHR12563, GO:0016287) acylates DHAP -> acyl-DHAP (first committed step); AGPS (O00116 PTHR46568, GO:0008609, FAD) exchanges the acyl for the FAR fatty alcohol -> alkyl-DHAP (committed ether-bond step; GNPAT-AGPS complex, peroxisomal matrix); PexRAP/DHRS7B (Q6IAN0, GO:0000140) reduces alkyl-DHAP; in the ER the shared sn-2 acyltransferases and phosphatases (described, not asserted) and SELENOI/EPT1 (Q9C0D9, GO:0004307) assemble plasmanylethanolamine; then PEDS1/TMEM189 (A5PLL7 PTHR48177, GO:0050207) introduces the vinyl-ether double bond -> plasmenylethanolamine. Curation: FAR1/FAR2 very-long-chain (GO:0080019) MF is a chain-length over-annotation (they prefer C16/C18, hence GO:0102965); GNPAT cytosol TAS = transient PTS1 pre-import cargo (non-core); AGPS mitochondrion HDA = peroxisome co-fractionation contaminant. Diseases: rhizomelic chondrodysplasia punctata - PEX7/RCDP1, GNPAT/RCDP2, AGPS/RCDP3, FAR1/RCDP4. GO term ids/labels verified against the local go.db; module passes structural + term-label validation. The bacterial anaerobic route, which reduces a diacyl phospholipid directly (PlsA/PlsAR), is modelled with this module as its eukaryotic alternative in plasmalogen_biosynthesis. SELENOI (Q9C0D9) also appears in kennedy_pathway_phospholipid_synthesis, for the diacyl phosphatidylethanolamine branch. Here it is the ether-lipid head-group step.

Connections

FAR-made fatty alcohol is the alkyl donor AGPS uses to form the ether bond.
dhap_acylation -> ether_bond_formation Provides Input For
GNPAT-made acyl-DHAP is the AGPS substrate whose acyl group is exchanged for the fatty alcohol.
AGPS-made alkyl-DHAP is reduced by PexRAP.
1-O-alkyl-glycerol 3-phosphate is completed to plasmanylethanolamine in the ER.
Plasmanylethanolamine is the PEDS1 substrate.
Part 1: fatty alcohol synthesis (acyl-CoA -> fatty alcohol)
Fatty acyl-CoA reductase (FAR1 / FAR2)Reactionfatty_alcohol_synthesis

Annotons

FAR1/FAR2: alcohol-forming fatty acyl-CoA reductase
far_activity
Participant: Family: FAR / fatty acyl-CoA reductase family
Family:
FAR / fatty acyl-CoA reductase familyPANTHER:PTHR11011
Representative Members: FAR1 (human; rate-limiting)UniProtKB:Q8WVX9 FAR2 (human; paralog)UniProtKB:Q96K12

Function

alcohol-forming long-chain fatty acyl-CoA reductase activityGO:0102965
Substrates: long-chain fatty acyl-CoA (C16/C18) NADPH
Products: long-chain fatty alcohol CoA

Locations

peroxisomal membraneGO:0005778

Reduce fatty acyl-CoA to the fatty alcohol ether-chain donor.

Part 2: DHAP acylation (DHAP -> acyl-DHAP)
Glyceronephosphate O-acyltransferase (GNPAT/DHAPAT)Reactiondhap_acylation

Annotons

GNPAT: glyceronephosphate O-acyltransferase
gnpat_activity
Participant: Family: GNPAT / glycerone-phosphate O-acyltransferase family
Family:
GNPAT / glycerone-phosphate O-acyltransferase familyPANTHER:PTHR12563
Representative Members: GNPAT (human)UniProtKB:O15228

Function

glycerone-phosphate O-acyltransferase activityGO:0016287
Substrates: dihydroxyacetone phosphate (glycerone phosphate, DHAP) long-chain acyl-CoA
Products: acyl-DHAP (acyldihydroxyacetone phosphate) CoA

Locations

peroxisomal membraneGO:0005778

Acylate DHAP to acyl-DHAP.

Part 3: ether-bond formation (acyl-DHAP -> alkyl-DHAP)
Alkyldihydroxyacetone-phosphate synthase (AGPS)Reactionether_bond_formation

Annotons

AGPS: alkylglycerone-phosphate synthase
agps_activity
Participant: Family: AGPS / alkyl-DHAP synthase (FAD amine oxidase-type) family
Family:
AGPS / alkyl-DHAP synthase (FAD amine oxidase-type) familyPANTHER:PTHR46568
Representative Members: AGPS (human)UniProtKB:O00116

Function

alkylglycerone-phosphate synthase activityGO:0008609
Substrates: acyl-DHAP long-chain fatty alcohol (from FAR; FAD cofactor)
Products: alkyl-DHAP (alkyldihydroxyacetone phosphate; O-alkyl ether bond) fatty acid (released acyl group)

Locations

peroxisomal matrixGO:0005782

Form the O-alkyl ether bond, yielding alkyl-DHAP.

Part 4: alkyl-DHAP reduction
1-O-alkyl-DHAP to 1-O-alkyl-sn-glycerol 3-phosphateReactionalkyl_dhap_reduction_step

Annotons

PexRAP (DHRS7B) acyl/alkyl-DHAP reductase
pexrap_activity
Participant: Family: DHRS7B (PexRAP) subfamily
Family:
DHRS7B (PexRAP) subfamilyPANTHER:PTHR44196:SF1
Representative Members: DHRS7B / PexRAP (human)UniProtKB:Q6IAN0
Required Function:
acyl/alkyl-glycerone-phosphate reductase activityGO:0000140

Function

acylglycerone-phosphate reductase (NADP+) activityGO:0000140 The GO label names the acyl substrate, but the term covers the alkyl reaction used here: GO:0000140 has RHEA:36175 (1-O-alkyl-DHAP reduction) as a narrow-match cross-reference alongside its exact-match acyl-DHAP reaction. GO has no separate alkyl-DHAP reductase term.
Substrates: 1-O-alkylglycerone 3-phosphate NADPH
Products: 1-O-alkyl-sn-glycero-3-phosphate NADP(+)

Locations

peroxisomal membraneGO:0005778

Reduces the C2 ketone of alkyl-DHAP, giving the 1-O-alkyl-glycerol 3-phosphate exported to the ER.

Part 5: plasmanylethanolamine assembly
1-O-alkyl-sn-glycerol 3-phosphate to plasmanylethanolamineMetabolic Pathwayplasmanyl_pe_assembly_step

ER steps: sn-2 acylation (RHEA:36235), dephosphorylation of 1-O-alkyl-2-acyl-glycerol 3-phosphate, and transfer of phosphoethanolamine from CDP-ethanolamine (RHEA:36187). The acyltransferases and phosphatases are shared with diacyl glycerolipid synthesis, so no annoton is asserted for them. The head-group step is asserted because SELENOI (EPT1) is needed for normal plasmenyl-PE levels in human cells.

Annotons

SELENOI ethanolaminephosphotransferase
selenoi_activity
Participant: Family: EPT1 / SELENOI subfamily
Family:
EPT1 / SELENOI subfamilyPANTHER:PTHR10414:SF47
Representative Members: SELENOI (human)UniProtKB:Q9C0D9
Required Function:
ethanolaminephosphotransferase activityGO:0004307

Function

ethanolaminephosphotransferase activityGO:0004307
Substrates: 1-O-alkyl-2-acyl-sn-glycerol CDP-ethanolamine
Products: 1-O-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine CMP

Locations

endoplasmic reticulum membraneGO:0005789

Adds the ethanolamine head group, giving plasmanyl-PE, the desaturase substrate.

Part 6: plasmalogen vinyl-ether desaturation (plasmanyl-PE -> plasmenyl-PE)
Plasmanylethanolamine desaturase (PEDS1/TMEM189)Reactionplasmalogen_desaturation

Annotons

PEDS1: plasmanylethanolamine desaturase
peds1_activity
Participant: Family: PEDS1 / plasmanylethanolamine desaturase (fatty-acid-desaturase-like) family
Family:
PEDS1 / plasmanylethanolamine desaturase (fatty-acid-desaturase-like) familyPANTHER:PTHR48177
Representative Members: PEDS1 / TMEM189 (human)UniProtKB:A5PLL7 CarF (Myxococcus xanthus)UniProtKB:Q9AE87

Function

plasmanylethanolamine desaturase activityGO:0050207
Substrates: plasmanylethanolamine (1-O-alkyl-2-acyl-GPE) O2 + reduced cytochrome b5 (di-iron)
Products: plasmenylethanolamine (ethanolamine plasmalogen; 1-O-alk-1'-enyl)

Locations

endoplasmic reticulum membraneGO:0005789

Introduce the 1-O-alk-1'-enyl (vinyl-ether) bond, making the plasmalogen.