Dolichol / dolichyl-phosphate biosynthesis (cis-PT -> DHRSX -> SRD5A3 -> DHRSX -> DOLK)

Dolichyl phosphate (Dol-P) is the essential polyprenol lipid carrier on which the eukaryotic glycosylation machinery assembles and delivers glycans: it anchors the lipid-linked oligosaccharide for N-linked glycosylation, the mannose/glucose donors (Dol-P-Man, Dol-P-Glc) for N-glycan, O-mannose, GPI-anchor and C/O-mannosylation, and it is regenerated after each transfer cycle. Its biosynthesis begins where the isoprenoid-diphosphate trunk ends: the ER-membrane cis-prenyltransferase (cis-PT) complex — catalytic subunit DHDDS plus the non-catalytic partner NUS1 (NgBR) — elongates (2E,6E)-farnesyl diphosphate (FPP) by many cis (Z)-condensations of isopentenyl diphosphate (IPP) to the long-chain dehydrodolichyl diphosphate (dehydro-Dol-PP). This polyprenyl diphosphate is dephosphorylated to polyprenol by a phosphatase that has not been identified in humans. Polyprenol is then converted to dolichol by a three-step detour rather than by a single reduction. DHRSX oxidizes polyprenol to polyprenal (NAD+), SRD5A3 reduces the alpha-isoprene double bond of polyprenal to give dolichal (NADPH), and DHRSX reduces dolichal to dolichol (NADPH). Dolichol kinase DOLK then phosphorylates dolichol (CTP-dependent) to Dol-P, completing the carrier pool. The dolichyl-diphosphate phosphatase DOLPP1 regenerates Dol-P from the Dol-PP released after oligosaccharyltransferase moves the glycan onto protein. The cis-PT subunits, SRD5A3, DOLK and DOLPP1 are endoplasmic reticulum membrane proteins, whereas DHRSX has been localized to lipid droplets. Defects across this module cause congenital disorders of glycosylation (DHDDS-CDG/RP59, NUS1-CDG/epileptic encephalopathy, DHRSX-CDG, SRD5A3-CDG, DOLK-CDG) and inherited retinal dystrophy.

MODULE:dolichyl_phosphate_biosynthesisDRAFTMetabolic Pathwaymodules/dolichyl_phosphate_biosynthesis.yaml
dolichyl monophosphate biosynthetic processGO:0043048 polyprenol biosynthetic processGO:0016094 dolichol-linked oligosaccharide biosynthetic processGO:0006488
GO:0043048
dolichyl monophosphate biosynthetic process
The pathway culminates in dolichyl phosphate (Dol-P) synthesis (GO:0043048).
GO:0016094
polyprenol biosynthetic process
cis-PT + reductase build the long-chain polyprenol/dolichol backbone (GO:0016094).
GO:0006488
dolichol-linked oligosaccharide biosynthetic process
Dol-P is the carrier for the lipid-linked oligosaccharide used in N-glycosylation (GO:0006488).
file:human/DHDDS/DHDDS-ai-review.yaml
DHDDS gene review (human)
cis-PT catalytic subunit (UniProtKB:Q86SQ9, GO:0045547) matches the completed human DHDDS review.
file:human/NUS1/NUS1-ai-review.yaml
NUS1 gene review (human)
cis-PT non-catalytic subunit / NgBR (UniProtKB:Q96E22, contributes_to GO:0045547) matches the completed human NUS1 review.
file:human/DOLPP1/DOLPP1-ai-review.yaml
DOLPP1 gene review (human)
Dolichyl-diphosphate phosphatase (UniProtKB:Q86YN1, GO:0047874) matches the completed human DOLPP1 review.
file:human/SRD5A3/SRD5A3-ai-review.yaml
SRD5A3 gene review (human)
Polyprenol reductase (UniProtKB:Q9H8P0, GO:0160198) matches the completed human SRD5A3 review.
file:human/DOLK/DOLK-ai-review.yaml
DOLK gene review (human)
Dolichol kinase (UniProtKB:Q9UPQ8, GO:0004168) matches the completed human DOLK review.
PMID:42360632
From Isoprene Units to Polyprenols and Dolichols: 70 Years of Polyisoprenoid Biosynthesis Research.
2026 review used to audit the module. It describes the 2024 revision of polyprenol-to-dolichol conversion from one SRD5A3 reduction to a three-step DHRSX/SRD5A3/DHRSX detour through polyprenal and dolichal. It also notes that polyprenols come from polyprenyl diphosphate dephosphorylation by a generic polyprenyl diphosphate phosphatase. The earlier module version modeled that step with DOLPP1 and omitted DHRSX.
In the first step, DHRSX functions as a dehydrogenase, oxidizing polyprenol alcohol to an aldehyde intermediate known as polyprenal. Subsequently, SRD5A3 acts as a polyprenal reductase, utilizing NADPH to reduce the double bond and form dolichal. In the third and final step, DHRSX acts again, this time as a NADPH-dependent reductase, converting the terminal aldehyde group of dolichal back into an alcohol to produce dolichol [23].
PMID:38821050
A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis.
Primary evidence for the three-step detour. DHRSX (UniProtKB:Q8N5I4) performs the first (NAD+-dependent polyprenol dehydrogenase, GO:0160196) and third (NADPH-dependent dolichal reductase, GO:0160197) steps, and SRD5A3 performs only the second. DHRSX deficiency causes DHRSX-CDG.
Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps.
gomodel:66c7d41500000080
Dolichol biosynthetic process (Human).
A cached production human GO-CAM (curated from PMID:38821050) models the same route: DHDDS cis-prenyltransferase, DHRSX polyprenol dehydrogenase (NAD+) and dolichal reductase (NADPH) activities in the lipid droplet, SRD5A3 polyprenal reductase and DOLK in the ER membrane. The polyprenyl diphosphate to polyprenol step is modeled as a generic catalytic activity (GO:0003824) enabled by an unspecified protein (CHEBI:36080), matching the unassigned phosphatase recorded here as a knowledge gap.
PMID:42201967
The revised three-step detour pathway in dolichol biosynthesis is evolutionarily conserved in budding yeast.
Yeast TDA5 is a functional DHRSX ortholog: human DHRSX, but not DFG10 or SRD5A3, rescues the tda5 deletion. The detour is therefore conserved beyond mammals. Whether Env9 also takes part in yeast is still debated (PMID:42360632).
These findings show that Tda5 serves the same function as DHRSX in yeast, thereby demonstrating conservation of the three-step detour pathway in yeast and supporting a broader eukaryotic framework for dolichol biosynthesis.
7Nodes
6Parts
0Variant Sets
0Variants
7Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:dolichyl_phosphate_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

4 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
dhdds_activity DHDDS (human; catalytic subunit)
UniProtKB:Q86SQ9
Family Representative 		dehydrodolichyl diphosphate synthase activity (cis-prenyltransferase)
GO:0045547 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nus1_partner NUS1 (human; NgBR)
UniProtKB:Q96E22
Family Representative 		dehydrodolichyl diphosphate synthase activity (contributing subunit)
GO:0045547 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
polyprenol_oxidation_activity DHRSX (human)
UniProtKB:Q8N5I4
Family Representative 		polyprenol dehydrogenase (NAD+) activity
GO:0160196 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
srd5a3_activity SRD5A3 (human)
UniProtKB:Q9H8P0
Family Representative 		polyprenal reductase activity
GO:0160198 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dolichal_reduction_activity DHRSX (human)
UniProtKB:Q8N5I4
Family Representative 		dolichal reductase (NADPH) activity
GO:0160197 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dolk_activity DOLK (human)
UniProtKB:Q9UPQ8
Family Representative 		dolichol kinase activity
GO:0004168 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dolpp1_activity DOLPP1 (human)
UniProtKB:Q86YN1
Family Representative 		dolichyldiphosphatase activity
GO:0047874 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dhdds_activity DHDDS / cis-prenyltransferase (UPP synthase) family
PANTHER:PTHR10291
Family 		dehydrodolichyl diphosphate synthase activity (cis-prenyltransferase)
GO:0045547 		Family Supported
Family review supports GO:0045547 FAMILY_WIDE. Shared cis-prenyl elongation chemistry of the whole family (with primer exceptions noted).
nus1_partner NUS1 / NgBR (Nogo-B receptor) family
PANTHER:PTHR21528
Family 		dehydrodolichyl diphosphate synthase activity (contributing subunit)
GO:0045547 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR21528.
polyprenol_oxidation_activity DHRSX / SDR-family polyprenol dehydrogenase-dolichal reductase
PANTHER:PTHR24320:SF264
Family 		polyprenol dehydrogenase (NAD+) activity
GO:0160196 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24320:SF264.
srd5a3_activity SRD5A3 / steroid 5-alpha-reductase (polyprenol reductase) family
PANTHER:PTHR14624
Family 		polyprenal reductase activity
GO:0160198 		Family Supported
Family review supports GO:0160198 FAMILY_WIDE. Shown for human SRD5A3 and S. cerevisiae Dfg10, which span the family; the family has no divergent paralog group. This is the activity the modules attach to the family.
dolichal_reduction_activity DHRSX / SDR-family polyprenol dehydrogenase-dolichal reductase
PANTHER:PTHR24320:SF264
Family 		dolichal reductase (NADPH) activity
GO:0160197 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24320:SF264.
dolk_activity DOLK / dolichol kinase family
PANTHER:PTHR13205
Family 		dolichol kinase activity
GO:0004168 		Family Function Unreviewed
Family review leaves GO:0004168 UNRESOLVED. Direct yeast and human experiments establish dolichol kinase activity, and curated pombe orthology supports its transfer to Sec59. Other polyprenol kinase branches and substrates must be distinguished rather than inferred from a broad membrane-kinase fold. The complete set of substrate-specific branches is not asserted.
dolpp1_activity DOLPP1 / PAP2 lipid-phosphatase (dolichyldiphosphatase) family
PANTHER:PTHR11247
Family 		dolichyldiphosphatase activity
GO:0047874 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11247.

Gene-review completeness (5/6 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 1 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
DHDDS Q86SQ9 ✓ ✓ ✗
DOLK Q9UPQ8 ✓ ✓ ✗
DOLPP1 Q86YN1 ✓ ✓ ✗
NUS1 Q96E22 ✓ ✓ ✗
DHRSX (human) Q8N5I4 ✗ — —
SRD5A3 Q9H8P0 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789 lipid dropletGO:0005811
Dolichol / dolichyl-phosphate biosynthesisMetabolic Pathwaydolichyl_phosphate_biosynthesis
dolichyl monophosphate biosynthetic processGO:0043048 polyprenol biosynthetic processGO:0016094 dolichol-linked oligosaccharide biosynthetic processGO:0006488
Context
endoplasmic reticulum membraneGO:0005789 lipid dropletGO:0005811

Dolichol / dolichyl-phosphate biosynthesis (GO:0043048 + GO:0016094), grounded to five completed human gene reviews; it consumes FPP/IPP from the isoprenoid_diphosphate_biosynthesis module and supplies the Dol-P glycan carrier to N-glycosylation (dolichol-linked oligosaccharide, GO:0006488) and to the downstream DPM1/DPM2/DPM3 + MPDU1 utilization steps (separate, already reviewed). Steps: (1) ER cis-PT complex = DHDDS (Q86SQ9 PTHR10291, catalytic, GO:0045547) + NUS1/NgBR (Q96E22 PTHR21528, obligate non-catalytic partner, contributes_to GO:0045547 via its C-terminal -RXG motif; in_complex GO:1904423) elongates FPP with many cis-IPP units -> dehydrodolichyl-PP; this is dephosphorylated to polyprenol by an unassigned polyprenyl diphosphate phosphatase (knowledge gap); (2) DHRSX (Q8N5I4 PTHR24320:SF264, GO:0160196) oxidizes polyprenol -> polyprenal; (3) SRD5A3 (Q9H8P0 PTHR14624, GO:0160198 polyprenal reductase) saturates the alpha-isoprene unit -> dolichal; (4) DHRSX (GO:0160197) reduces dolichal -> dolichol; (5) DOLK (Q9UPQ8 PTHR13205, GO:0004168 dolichol kinase, CTP-dependent) -> Dol-P; (6) DOLPP1 (Q86YN1 PTHR11247, GO:0047874) dephosphorylates Dol-PP -> Dol-P + Pi in the recycling arm after OST glycan transfer. Revision (2026-10): an earlier version placed DOLPP1 on the de novo chain and had SRD5A3 convert polyprenol directly to dolichol. The 2024 identification of the DHRSX detour (PMID:38821050), its conservation in yeast (TDA5, PMID:42201967) and the 2026 review (PMID:42360632) replace that model. DHRSX has no gene review in this repository yet; its grounding is UniProtKB:Q8N5I4 and GOA EXP/IDA annotations to GO:0160196/GO:0160197 from PMID:38821050. Defects: DHDDS-CDG/RP59, NUS1-CDG/epileptic encephalopathy, DHRSX-CDG, SRD5A3-CDG, DOLK-CDG. GO term ids/labels verified with QuickGO.

Connections

Polyprenyl (dehydrodolichyl) diphosphate is dephosphorylated to polyprenol, which DHRSX oxidizes. The phosphatase that removes both phosphates in this de novo step has not been identified in humans.
Polyprenal from DHRSX is reduced by SRD5A3 to dolichal.
Dolichal from SRD5A3 is reduced by DHRSX to dolichol.
dolichal_reduction -> dolichol_kinase Provides Input For
Dolichol from DHRSX is phosphorylated by DOLK to Dol-P.
Part 1: cis-prenyltransferase (FPP + nIPP -> dehydrodolichyl-PP)
cis-Prenyltransferase complex (DHDDS catalytic + NUS1 partner)Reactioncis_prenyltransferase

Annotons

DHDDS (+NUS1): dehydrodolichyl diphosphate synthase (cis-PT)
dhdds_activity
Participant: Family: DHDDS / cis-prenyltransferase (UPP synthase) family
Family:
DHDDS / cis-prenyltransferase (UPP synthase) familyPANTHER:PTHR10291
Representative Members: DHDDS (human; catalytic subunit)UniProtKB:Q86SQ9

Function

dehydrodolichyl diphosphate synthase activity (cis-prenyltransferase)GO:0045547
Substrates: (2E,6E)-farnesyl diphosphate (FPP) isopentenyl diphosphate (IPP; multiple, Mg2+)
Products: dehydrodolichyl diphosphate (polyprenyl-PP) diphosphate

Locations

endoplasmic reticulum membraneGO:0005789

Elongate FPP with many cis-IPP units to dehydrodolichyl diphosphate.

NUS1/NgBR: cis-PT non-catalytic subunit
nus1_partner
Participant: Family: NUS1 / NgBR (Nogo-B receptor) family
Family:
NUS1 / NgBR (Nogo-B receptor) familyPANTHER:PTHR21528
Representative Members: NUS1 (human; NgBR)UniProtKB:Q96E22

Function

dehydrodolichyl diphosphate synthase activity (contributing subunit)GO:0045547
Substrates: (2E,6E)-farnesyl diphosphate (FPP) isopentenyl diphosphate (IPP)
Products: dehydrodolichyl diphosphate (polyprenyl-PP)

Locations

endoplasmic reticulum membraneGO:0005789

Stabilize DHDDS and complete the cis-PT active site (RXG motif).

Part 2: polyprenol -> polyprenal oxidation
Polyprenol dehydrogenase (DHRSX)Reactionpolyprenol_oxidation

Annotons

DHRSX: polyprenol dehydrogenase (NAD+) activity
polyprenol_oxidation_activity
Participant: Family: DHRSX / SDR-family polyprenol dehydrogenase-dolichal reductase
Family:
DHRSX / SDR-family polyprenol dehydrogenase-dolichal reductasePANTHER:PTHR24320:SF264
Representative Members: DHRSX (human)UniProtKB:Q8N5I4

Function

polyprenol dehydrogenase (NAD+) activityGO:0160196
Substrates: polyprenol NAD+
Products: polyprenal NADH

Locations

lipid dropletGO:0005811

First step of the polyprenol-to-dolichol detour. DHRSX is reported on lipid droplets (IDA, PMID:38821050), not in the ER membrane with the other enzymes. Deficiency causes DHRSX-CDG.

Part 3: polyprenal -> dolichal reduction
Polyprenal reductase (SRD5A3)Reactionpolyprenal_reduction

Annotons

SRD5A3: polyprenal reductase
srd5a3_activity
Participant: Family: SRD5A3 / steroid 5-alpha-reductase (polyprenol reductase) family
Family:
SRD5A3 / steroid 5-alpha-reductase (polyprenol reductase) familyPANTHER:PTHR14624
Representative Members: SRD5A3 (human)UniProtKB:Q9H8P0

Function

polyprenal reductase activityGO:0160198
Substrates: polyprenal (alpha-unsaturated aldehyde) NADPH
Products: dolichal

Locations

endoplasmic reticulum membraneGO:0005789

Saturate the alpha-isoprene unit of polyprenal, yielding dolichal.

Part 4: dolichal -> dolichol reduction
Dolichal reductase (DHRSX)Reactiondolichal_reduction

Annotons

DHRSX: dolichal reductase (NADPH) activity
dolichal_reduction_activity
Participant: Family: DHRSX / SDR-family polyprenol dehydrogenase-dolichal reductase
Family:
DHRSX / SDR-family polyprenol dehydrogenase-dolichal reductasePANTHER:PTHR24320:SF264
Representative Members: DHRSX (human)UniProtKB:Q8N5I4

Function

dolichal reductase (NADPH) activityGO:0160197
Substrates: dolichal NADPH
Products: dolichol NADP+

Locations

lipid dropletGO:0005811

Third step of the polyprenol-to-dolichol detour. The same DHRSX protein acts as an NAD+-dependent polyprenol dehydrogenase (the first reaction of the detour) and as an NADPH-dependent dolichal reductase here (the third reaction), in two steps that are not consecutive.

Part 5: dolichol phosphorylation -> Dol-P
Dolichol kinase (DOLK)Reactiondolichol_kinase

Annotons

DOLK: dolichol kinase
dolk_activity
Participant: Family: DOLK / dolichol kinase family
Family:
DOLK / dolichol kinase familyPANTHER:PTHR13205
Representative Members: DOLK (human)UniProtKB:Q9UPQ8

Function

dolichol kinase activityGO:0004168
Substrates: dolichol CTP
Products: dolichyl phosphate (Dol-P) CDP

Locations

endoplasmic reticulum membraneGO:0005789

Phosphorylate dolichol (CTP donor) to dolichyl phosphate (Dol-P).

Part 6: dolichyl-diphosphate dephosphorylation (Dol-PP recycling arm)
Dolichyl-diphosphate phosphatase (DOLPP1)Reactiondolpp_dephosphorylation

Annotons

DOLPP1: dolichyldiphosphatase
dolpp1_activity
Participant: Family: DOLPP1 / PAP2 lipid-phosphatase (dolichyldiphosphatase) family
Family:
DOLPP1 / PAP2 lipid-phosphatase (dolichyldiphosphatase) familyPANTHER:PTHR11247
Representative Members: DOLPP1 (human)UniProtKB:Q86YN1

Function

dolichyldiphosphatase activityGO:0047874
Substrates: dolichyl diphosphate (Dol-PP) H2O
Products: dolichyl phosphate (Dol-P) phosphate

Locations

endoplasmic reticulum membraneGO:0005789

Hydrolyze dolichyl diphosphate to dolichyl phosphate + Pi. This regenerates Dol-P from the Dol-PP released after oligosaccharyltransferase transfers the glycan to protein. It is a recycling arm that feeds the same Dol-P pool as DOLK. DOLPP1 is not assigned to the de novo dephosphorylation of polyprenyl diphosphate to polyprenol.