Dolichol phosphate and lipid-linked sugar-donor supply for glycosylation; SRD5A3/DOLK/DPM1/DPM2/DPM3/ALG5/MPDU1

Assembly of the dolichol-linked oligosaccharide (and of GPI anchors, O- and C-mannosylation) depends on a dolichyl-phosphate lipid carrier and on two lipid-linked monosaccharide donors, dolichyl-phosphate-mannose (Dol-P-Man) and dolichyl-phosphate-glucose (Dol-P-Glc). This module curates their supply at the endoplasmic-reticulum membrane. The polyprenol reductase SRD5A3 catalyses the last step of de novo dolichol synthesis, reducing the alpha-isoprene unit of polyprenol to dolichol; dolichol kinase DOLK then phosphorylates dolichol (using CTP) to dolichyl phosphate (Dol-P), the essential carrier. Dol-P is charged with sugars by two systems: the dolichol-phosphate-mannose (DPM) synthase, a three-subunit complex in which DPM1 is the GDP-mannose-utilising catalytic subunit and DPM2 (regulatory/stabilising) and DPM3 (membrane anchor for the TM-less DPM1) are non-catalytic, produces Dol-P-Man from GDP-mannose and Dol-P; and ALG5 (dolichyl-phosphate beta-glucosyltransferase) produces Dol-P-Glc from UDP-glucose and Dol-P. The utilisation factor MPDU1 (Lec35) is then required for these lipid-linked donors to be used by the lumenal glycosyltransferases. Because they feed the whole glycosylation system, defects in every gene here cause a congenital disorder of glycosylation: SRD5A3-CDG (CDG-Iq), DOLK-CDG (CDG-Im, dilated cardiomyopathy), DPM1-CDG (CDG-Ie), DPM2-CDG (CDG-Iu) and DPM3-CDG (CDG-Io) — the latter two dystroglycanopathies — MPDU1-CDG (CDG-If) and ALG5-CDG.

MODULE:dolichol_phosphate_sugar_donor_supplyDRAFTMetabolic Pathwaymodules/dolichol_phosphate_sugar_donor_supply.yaml

dolichol-linked oligosaccharide biosynthetic processGO:0006488 dolichyl monophosphate biosynthetic processGO:0043048

GO:0006488

dolichol-linked oligosaccharide biosynthetic process

The module supplies the dolichyl-phosphate carrier and the Dol-P-Man/Dol-P-Glc donors consumed by dolichol-linked oligosaccharide biosynthesis (GO:0006488).

GO:0043048

dolichyl monophosphate biosynthetic process

SRD5A3 and DOLK produce the dolichyl phosphate (Dol-P) carrier (dolichyl monophosphate biosynthetic process, GO:0043048).

Reactome:R-HSA-446199

Synthesis of dolichyl-phosphate

The dolichol -> Dol-P segment (SRD5A3 polyprenol reduction, DOLK phosphorylation) follows the human Reactome "Synthesis of dolichyl-phosphate" sub-pathway.

Reactome:R-HSA-162699

Synthesis of dolichyl-phosphate mannose

The Dol-P-Man branch (DPM1/DPM2/DPM3 complex) follows the human Reactome "Synthesis of dolichyl-phosphate mannose" sub-pathway (reaction R-HSA-162721).

file:human/SRD5A3/SRD5A3-ai-review.yaml

SRD5A3 gene review (human)

The polyprenol -> dolichol step (UniProtKB:Q9H8P0, GO:0160198) matches the completed human SRD5A3 review.

file:human/DOLK/DOLK-ai-review.yaml

DOLK gene review (human)

The dolichol -> Dol-P step (UniProtKB:Q9UPQ8, GO:0004168) matches the completed human DOLK review.

file:human/DPM1/DPM1-ai-review.yaml

DPM1 gene review (human)

The catalytic Dol-P-Man synthase step (UniProtKB:O60762, GO:0004582) matches the completed human DPM1 review.

file:human/DPM2/DPM2-ai-review.yaml

DPM2 gene review (human)

The regulatory DPM-synthase subunit (UniProtKB:O94777, GO:0008047) matches the completed human DPM2 review.

file:human/DPM3/DPM3-ai-review.yaml

DPM3 gene review (human)

The membrane-anchoring DPM-synthase subunit (UniProtKB:Q9P2X0, GO:0043495) matches the completed human DPM3 review.

file:human/ALG5/ALG5-ai-review.yaml

ALG5 gene review (human)

The Dol-P-Glc synthase step (UniProtKB:Q9Y673, GO:0004581) matches the completed human ALG5 review.

file:human/MPDU1/MPDU1-ai-review.yaml

MPDU1 gene review (human)

The Dol-P-Man/Dol-P-Glc utilisation factor (UniProtKB:O75352, GO:0006488) matches the completed human MPDU1 review.

6Nodes

5Parts

0Variant Sets

0Variants

7Annotons

5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:dolichol_phosphate_sugar_donor_supply 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 (7/7 grounded genes reviewed)

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

Gene	Review	Complete	Deep research
ALG5 Q9Y673	✓	✓	✗
DOLK Q9UPQ8	✓	✓	✗
DPM1 O60762	✓	✓	✗
DPM2 O94777	✓	✓	✗
DPM3 Q9P2X0	✓	✓	✗
MPDU1 O75352	✓	✓	✗
SRD5A3 Q9H8P0	✓	✓	✗

Tree

Dolichol-P and lipid-linked sugar-donor supplyMetabolic Pathwaydolichol_phosphate_sugar_donor_supply

Parts
1. 1. dolichol synthesis (polyprenol reduction)
2. polyprenol to dolicholReactionsrd5a3_step
  
  Annotons
  - SRD5A3: polyprenol reductase Family: Steroid 5-alpha reductase family (SRD5A3 polyprenol reductase)
3. 2. dolichyl phosphate synthesis (phosphorylation)
4. dolichol to dolichyl phosphate (Dol-P)Reactiondolk_step
  
  Annotons
  - DOLK: dolichol kinase Family: Dolichol kinase family (DOLK)
5. 3. Dol-P-Man synthesis (three-subunit synthase complex)
6. GDP-mannose + Dol-P to dolichyl-phosphate-mannose (Dol-P-Man)Protein Complexdpm_complex_step
  
  Annotons
  - DPM1: Dol-P-Man synthase catalytic subunit Family: Dolichyl-phosphate mannosyltransferase family (DPM1)
  - DPM2: DPM synthase regulatory subunit Family: DPM2 family (regulatory subunit)
  - DPM3: DPM synthase membrane anchor Family: DPM3 family (anchoring subunit)
7. 4. Dol-P-Glc synthesis
8. UDP-glucose + Dol-P to dolichyl-phosphate-glucose (Dol-P-Glc)Reactionalg5_step
  
  Annotons
  - ALG5: dolichyl-phosphate beta-glucosyltransferase Family: Dolichyl-phosphate glucosyltransferase family (ALG5)
9. 5. utilisation of the lipid-linked donors
10. presentation/utilisation of Dol-P-Man and Dol-P-GlcReactionmpdu1_step
  
  Annotons
  - MPDU1 (Lec35): Dol-P-Man/Dol-P-Glc utilisation factor Family: MPDU1/Lec35 family

Details

Context

endoplasmic reticulum membraneGO:0005789

Dolichol-P and lipid-linked sugar-donor supplyMetabolic Pathwaydolichol_phosphate_sugar_donor_supply

dolichol-linked oligosaccharide biosynthetic processGO:0006488 dolichyl monophosphate biosynthetic processGO:0043048

Context

endoplasmic reticulum membraneGO:0005789

Dolichyl-phosphate and lipid-linked sugar-donor supply, grounded to the human enzymes SRD5A3 (UniProtKB:Q9H8P0, GO:0160198, EC 1.3.1.94), DOLK (Q9UPQ8, GO:0004168, EC 2.7.1.108), the DPM synthase complex (DPM1 O60762 GO:0004582 catalytic EC 2.4.1.83, DPM2 O94777 GO:0008047 regulatory, DPM3 Q9P2X0 GO:0043495 anchor; complex GO:0033185), ALG5 (Q9Y673, GO:0004581, EC 2.4.1.117) and MPDU1 (O75352, non-catalytic utilisation factor). 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 protein as representative so the module generalises across orthologs/paralogs; the DPM synthase is modelled as a PROTEIN_COMPLEX node (one catalytic + two non-catalytic subunits). Note SRD5A3 is a polyprenol reductase, not a physiological steroid 5alpha-reductase despite its name; MPDU1 (Lec35) has no informative molecular-function term and is represented by its BP role. This module supplies the Dol-P carrier (used by DPAGT1 and the cytoplasmic LLO module) and the Dol-P-Man / Dol-P-Glc donors (used by the lumenal LLO module ALG3/ALG9/ALG12 and ALG6/ALG8/ ALG10), and also feeds GPI-anchor and O-/C-mannosylation. Disorders: every gene is a CDG type I (SRD5A3-, DOLK-, DPM1-, DPM2-, DPM3-, MPDU1-, ALG5-CDG), with DPM2-/DPM3-CDG presenting as muscular dystrophy-dystroglycanopathies and DOLK-CDG as dilated cardiomyopathy.

Connections

srd5a3_step -> dolk_step Provides Input For

Dolichol from SRD5A3 is phosphorylated by DOLK to dolichyl phosphate.

dolk_step -> dpm_complex_step Provides Input For

Dol-P from DOLK is mannosylated by the DPM synthase complex to Dol-P-Man.

dolk_step -> alg5_step Provides Input For

Dol-P from DOLK is glucosylated by ALG5 to Dol-P-Glc.

dpm_complex_step -> mpdu1_step Provides Input For

Dol-P-Man made by the DPM synthase is presented by MPDU1 for lumenal glycosyltransferases.

alg5_step -> mpdu1_step Provides Input For

Dol-P-Glc made by ALG5 is presented by MPDU1 for lumenal glycosyltransferases.

Part 1: dolichol synthesis (polyprenol reduction)

polyprenol to dolicholReactionsrd5a3_step

Annotons

SRD5A3: polyprenol reductase

srd5a3_activity

Participant: Family: Steroid 5-alpha reductase family (SRD5A3 polyprenol reductase)

Family:

Steroid 5-alpha reductase family (SRD5A3 polyprenol reductase)PANTHER:PTHR14624

Representative Members: SRD5A3 (human)UniProtKB:Q9H8P0

Function

polyprenal reductase activityGO:0160198

Substrates: polyprenol NADPH

Products: dolichol

Locations

endoplasmic reticulum membraneGO:0005789

Final step of de novo dolichol synthesis. Deficiency = SRD5A3-CDG (CDG-Iq; ocular coloboma, cerebellar involvement).

Part 2: dolichyl phosphate synthesis (phosphorylation)

dolichol to dolichyl phosphate (Dol-P)Reactiondolk_step

Annotons

DOLK: dolichol kinase

dolk_activity

Participant: Family: Dolichol kinase family (DOLK)

Family:

Dolichol kinase family (DOLK)PANTHER: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

Produces the Dol-P carrier used by DPM synthase, ALG5, DPAGT1 and GPI/O-mannosylation. Deficiency = DOLK-CDG (CDG-Im; dilated cardiomyopathy).

Part 3: Dol-P-Man synthesis (three-subunit synthase complex)

GDP-mannose + Dol-P to dolichyl-phosphate-mannose (Dol-P-Man)Protein Complexdpm_complex_step

Annotons

DPM1: Dol-P-Man synthase catalytic subunit

dpm1_activity

Participant: Family: Dolichyl-phosphate mannosyltransferase family (DPM1)

Family:

Dolichyl-phosphate mannosyltransferase family (DPM1)PANTHER:PTHR43398

Representative Members: DPM1 (human)UniProtKB:O60762

Function

dolichyl-phosphate beta-D-mannosyltransferase activityGO:0004582

Substrates: GDP-mannose dolichyl phosphate

Products: dolichyl-phosphate-mannose (Dol-P-Man) GDP

Locations

endoplasmic reticulum membraneGO:0005789

Catalytic subunit; deficiency = DPM1-CDG (CDG-Ie).

DPM2: DPM synthase regulatory subunit

dpm2_activity

Participant: Family: DPM2 family (regulatory subunit)

Family:

DPM2 family (regulatory subunit)PANTHER:PTHR15039

Representative Members: DPM2 (human)UniProtKB:O94777

Function

enzyme activator activityGO:0008047

Substrates: DPM synthase complex (DPM1/DPM3)

Products: activated/stabilised Dol-P-Man synthase

Locations

endoplasmic reticulum membraneGO:0005789

Regulatory/stabilising subunit; deficiency = DPM2-CDG (dystroglycanopathy).

DPM3: DPM synthase membrane anchor

dpm3_activity

Participant: Family: DPM3 family (anchoring subunit)

Family:

DPM3 family (anchoring subunit)PANTHER:PTHR16433

Representative Members: DPM3 (human)UniProtKB:Q9P2X0

Function

protein-membrane adaptor activityGO:0043495

Substrates: DPM1 (catalytic subunit)

Products: ER-membrane-anchored DPM synthase

Locations

endoplasmic reticulum membraneGO:0005789

Membrane-anchoring subunit; deficiency = DPM3-CDG (dystroglycanopathy).

Part 4: Dol-P-Glc synthesis

UDP-glucose + Dol-P to dolichyl-phosphate-glucose (Dol-P-Glc)Reactionalg5_step

Annotons

ALG5: dolichyl-phosphate beta-glucosyltransferase

alg5_activity

Participant: Family: Dolichyl-phosphate glucosyltransferase family (ALG5)

Family:

Dolichyl-phosphate glucosyltransferase family (ALG5)PANTHER:PTHR10859

Representative Members: ALG5 (human)UniProtKB:Q9Y673

Function

dolichyl-phosphate beta-glucosyltransferase activityGO:0004581

Substrates: UDP-glucose dolichyl phosphate

Products: dolichyl-phosphate-glucose (Dol-P-Glc) UDP

Locations

endoplasmic reticulum membraneGO:0005789

Makes the Dol-P-Glc glucose donor for the lumenal LLO glucosylation steps. Deficiency = ALG5-CDG.

Part 5: utilisation of the lipid-linked donors

presentation/utilisation of Dol-P-Man and Dol-P-GlcReactionmpdu1_step

Annotons

MPDU1 (Lec35): Dol-P-Man/Dol-P-Glc utilisation factor

mpdu1_activity

Participant: Family: MPDU1/Lec35 family

Family:

MPDU1/Lec35 familyPANTHER:PTHR12226

Representative Members: MPDU1 (human)UniProtKB:O75352

Processes

dolichol-linked oligosaccharide biosynthetic processGO:0006488

Locations

endoplasmic reticulum membraneGO:0005789

Non-catalytic utilisation/presentation factor enabling lumenal use of Dol-P-Man and Dol-P-Glc. MPDU1 has no informative molecular-function term (no F-aspect GOA annotation); represented here by its biological-process role.

file:human/MPDU1/MPDU1-ai-review.yaml

non-catalytic ER-membrane factor required for utilisation/presentation of Dol-P-Man and Dol-P-Glc (the lipid-linked donors) to lumenal glycosyltransferases; deficiency = MPDU1-CDG (CDG-If)