Retinoid visual cycle (11-cis-retinal regeneration across RPE and photoreceptors)

Vision depends on continuous regeneration of the 11-cis-retinal chromophore that photobleaches to all-trans-retinal each time a photon isomerizes a visual pigment. The classical (RPE) visual cycle recycles it across the photoreceptor and retinal-pigment-epithelium (RPE) cells. In photoreceptors, light isomerizes 11-cis-retinal bound to opsin to all-trans-retinal, which is released and reduced to all-trans-retinol by NADPH-dependent retinol dehydrogenases (RDH8 in the outer segment, RDH12 in the inner segment; this also detoxifies the reactive aldehyde). All-trans-retinol travels to the RPE, where lecithin:retinol acyltransferase (LRAT) esterifies it to all-trans-retinyl ester (the pathway's storage/committed form). The central RPE enzyme RPE65 then carries out the coupled ester-hydrolysis and trans-to-cis isomerization, producing 11-cis-retinol, which the NAD+-dependent 11-cis-retinol dehydrogenase RDH5 oxidizes to 11-cis-retinal for return to photoreceptors and recombination with opsin. The cellular retinaldehyde-binding protein RLBP1 (CRALBP) chaperones the hydrophobic 11-cis-retinoids through these steps, and RGR, an opsin-family photoisomerase in RPE/Muller cells, provides a light-driven route regenerating 11-cis-retinal from all-trans-retinal. RDH11 contributes broad retinaldehyde-reductase activity, and DHRS3 buffers retinaldehyde/retinoic-acid levels. Defects across the cycle cause inherited retinal dystrophies: RPE65 and LRAT (Leber congenital amaurosis, the RPE65 form treated by voretigene neparvovec gene therapy), RDH12 (LCA13), RDH5 (fundus albipunctatus), RLBP1 (retinitis punctata albescens / Bothnia dystrophy) and RGR (retinitis pigmentosa).

MODULE:retinoid_visual_cycleDRAFTMetabolic Pathwaymodules/retinoid_visual_cycle.yaml
visual perceptionGO:0007601 retinol metabolic processGO:0042572
GO:0007601
visual perception
The visual cycle regenerates the 11-cis-retinal chromophore required for visual perception (GO:0007601).
GO:0042572
retinol metabolic process
LRAT/RPE65/RDH5/RDH8/RDH11/RDH12/DHRS3 interconvert retinol/retinal/retinyl-ester (GO:0042572).
file:human/LRAT/LRAT-ai-review.yaml
LRAT gene review (human)
The retinol->retinyl-ester step (UniProtKB:O95237, GO:0047173) matches the completed human LRAT review.
file:human/RPE65/RPE65-ai-review.yaml
RPE65 gene review (human)
The retinyl-ester->11-cis-retinol isomerohydrolase step (UniProtKB:Q16518, GO:0052885) matches the completed human RPE65 review.
file:human/RDH5/RDH5-ai-review.yaml
RDH5 gene review (human)
The 11-cis-retinol->11-cis-retinal step (UniProtKB:Q92781, GO:0106429) matches the completed human RDH5 review.
file:human/RDH8/RDH8-ai-review.yaml
RDH8 gene review (human)
The photoreceptor all-trans-retinal->retinol reduction step (UniProtKB:Q9NYR8, GO:0052650) matches the completed human RDH8 review.
file:human/RDH11/RDH11-ai-review.yaml
RDH11 gene review (human)
The broad retinaldehyde reductase step (UniProtKB:Q8TC12, GO:0052650) matches the completed human RDH11 review.
file:human/RDH12/RDH12-ai-review.yaml
RDH12 gene review (human)
The photoreceptor all-trans-retinal reductase step (UniProtKB:Q96NR8, GO:0052650) matches the completed human RDH12 review.
file:human/RLBP1/RLBP1-ai-review.yaml
RLBP1 gene review (human)
The 11-cis-retinoid carrier role (UniProtKB:P12271, GO:0005502) matches the completed human RLBP1 review.
file:human/RGR/RGR-ai-review.yaml
RGR gene review (human)
The light-driven all-trans->11-cis-retinal photoisomerase role (UniProtKB:P47804, GO:0016859) matches the completed human RGR review.
file:human/DHRS3/DHRS3-ai-review.yaml
DHRS3 gene review (human)
The all-trans-retinaldehyde reductase / retinoid-buffer step (UniProtKB:O75911, GO:0052650) matches the completed human DHRS3 review.
9Nodes
8Parts
0Variant Sets
0Variants
8Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:retinoid_visual_cycle 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 (9/9 grounded genes reviewed)

9 complete review(s) · 0 with deep research · 0 missing review · 9 reviewed but lacking deep research

Gene Review Complete Deep research
DHRS3 O75911 ✓ ✓ ✗
LRAT O95237 ✓ ✓ ✗
RDH11 Q8TC12 ✓ ✓ ✗
RDH12 Q96NR8 ✓ ✓ ✗
RDH5 Q92781 ✓ ✓ ✗
RDH8 Q9NYR8 ✓ ✓ ✗
RGR P47804 ✓ ✓ ✗
RLBP1 P12271 ✓ ✓ ✗
RPE65 Q16518 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789 photoreceptor outer segmentGO:0001750
Retinoid visual cycleMetabolic Pathwayretinoid_visual_cycle
visual perceptionGO:0007601 retinol metabolic processGO:0042572
Context
endoplasmic reticulum membraneGO:0005789 photoreceptor outer segmentGO:0001750

Retinoid visual cycle (GO:0007601 + GO:0042572), grounded to nine completed human gene reviews. PHOTORECEPTOR arm: RDH8 (Q9NYR8 outer segment) + RDH12 (Q96NR8 inner segment; LCA13) share PTHR43157, GO:0052650 NADPH all-trans-retinal reductase (post-bleach clearance/detox). RPE arm: all-trans-retinol -> LRAT (O95237 PTHR46678, GO:0047173 retinyl-ester synthesis; LCA14) -> RPE65 (Q16518 PTHR10543, GO:0052885 Fe-dependent isomerohydrolase, the committed all-trans->11-cis step; LCA2 = Luxturna target) -> RDH5 (Q92781 PTHR43313, GO:0106429 NAD+ 11-cis-retinol DH -> 11-cis-retinal; fundus albipunctatus). CARRIERS/ ALT: RLBP1/CRALBP (P12271 PTHR10174, non-catalytic GO:0005502/GO:0019841 11-cis-retinoid carrier, `processes`; retinitis punctata albescens) and RGR (P47804 PTHR24240, opsin-family light-driven photoisomerase GO:0016859 + GO:0005503 all-trans-retinal binding; RP44 — GPCR-signalling annotations are family over-propagations, no consistent G-protein coupling). SUPPORT: RDH11 (Q8TC12, same PTHR43157, broad NADPH retinaldehyde reductase) and DHRS3 (O75911 PTHR24322, GO:0052650, RA-feedback buffer with RDH10). Recurrent curation catch: the SDR reviews corrected many all-trans-retinol-DH (NAD+, GO:0004745) IEAs to the cofactor-accurate NADP+ term GO:0052650 (or NAD+ GO:0106429 for RDH5); steroid-DH side activities kept non-core. GO term ids/labels verified against the local go.db. The retinyl esters link to retinoid storage; retinaldehyde also feeds retinoic-acid synthesis (ALDH1A, separate). Disorders: RPE65/ LRAT/RDH12 LCA; RDH5 fundus albipunctatus; RLBP1 Bothnia dystrophy; RGR RP44.

Connections

The all-trans-retinol made in photoreceptors travels to the RPE and is esterified by LRAT.
The all-trans-retinyl ester is the substrate for the RPE65 isomerohydrolase.
The 11-cis-retinol made by RPE65 is oxidized by RDH5 to 11-cis-retinal.
cralbp_carrier -> cis_retinol_oxidation Positively Regulates
CRALBP (RLBP1) presents 11-cis-retinol to RDH5 and carries 11-cis-retinoids, enhancing cycle flux.
photoisomerase -> cis_retinol_oxidation Provides Input For
RGR photoisomerizes all-trans- to 11-cis-retinal, an alternative light-driven source of the chromophore.
Part 1: photoreceptor all-trans-retinal reduction (post-bleach clearance)
Photoreceptor retinol dehydrogenases (RDH8/RDH12)Reactionphotoreceptor_atral_reduction

Annotons

RDH8/RDH12: all-trans-retinal reductase (NADPH)
rdh8_12_activity
Participant: Family: photoreceptor retinol dehydrogenase (SDR) family
Family:
photoreceptor retinol dehydrogenase (SDR) familyPANTHER:PTHR43157
Representative Members: RDH8 (human; outer segment)UniProtKB:Q9NYR8 RDH12 (human; inner segment)UniProtKB:Q96NR8

Function

all-trans-retinol dehydrogenase (NADP+) activityGO:0052650
Substrates: all-trans-retinal (from photobleached opsin) NADPH
Products: all-trans-retinol NADP+

Locations

photoreceptor outer segmentGO:0001750

Reduce photobleached all-trans-retinal to all-trans-retinol (NADPH).

Part 2: retinol esterification (storage/commitment)
Lecithin:retinol acyltransferase (LRAT)Reactionretinol_esterification

Annotons

LRAT: lecithin:retinol acyltransferase
lrat_activity
Participant: Family: LRAT / NlpC-P60 acyltransferase family
Family:
LRAT / NlpC-P60 acyltransferase familyPANTHER:PTHR46678
Representative Members: LRAT (human)UniProtKB:O95237

Function

phosphatidylcholine-retinol O-acyltransferase activityGO:0047173
Substrates: all-trans-retinol phosphatidylcholine (lecithin)
Products: all-trans-retinyl ester 2-acyl-sn-glycero-3-phosphocholine

Locations

endoplasmic reticulum membraneGO:0005789

Esterify all-trans-retinol to all-trans-retinyl ester (RPE).

Part 3: isomerohydrolysis (the committed RPE isomerization)
Retinoid isomerohydrolase (RPE65)Reactionisomerohydrolysis

Annotons

RPE65: retinyl-ester 11-cis isomerohydrolase
rpe65_activity
Participant: Family: RPE65 / carotenoid-oxygenase family
Family:
RPE65 / carotenoid-oxygenase familyPANTHER:PTHR10543
Representative Members: RPE65 (human)UniProtKB:Q16518

Function

all-trans-retinyl-ester hydrolase, 11-cis retinol forming activityGO:0052885
Substrates: all-trans-retinyl ester (Fe2+ cofactor)
Products: 11-cis-retinol fatty acid

Locations

endoplasmic reticulum membraneGO:0005789

Hydrolyse + isomerize all-trans-retinyl ester to 11-cis-retinol (committed step).

Part 4: 11-cis-retinol oxidation to chromophore
11-cis retinol dehydrogenase (RDH5)Reactioncis_retinol_oxidation

Annotons

RDH5: 11-cis retinol dehydrogenase (NAD+)
rdh5_activity
Participant: Family: RDH5 / 11-cis retinol dehydrogenase (SDR) family
Family:
RDH5 / 11-cis retinol dehydrogenase (SDR) familyPANTHER:PTHR43313
Representative Members: RDH5 (human)UniProtKB:Q92781

Function

11-cis-retinol dehydrogenase (NAD+) activityGO:0106429
Substrates: 11-cis-retinol NAD+
Products: 11-cis-retinal (chromophore) NADH

Locations

endoplasmic reticulum membraneGO:0005789

Oxidize 11-cis-retinol to 11-cis-retinal (final chromophore).

Part 5: 11-cis retinoid chaperone (carrier)
Cellular retinaldehyde-binding protein (RLBP1)Reactioncralbp_carrier

Annotons

RLBP1 (CRALBP): 11-cis-retinoid carrier
rlbp1_activity
Participant: Family: RLBP1 / CRAL-TRIO (Sec14-like) retinoid-carrier family
Family:
RLBP1 / CRAL-TRIO (Sec14-like) retinoid-carrier familyPANTHER:PTHR10174
Representative Members: RLBP1 (human)UniProtKB:P12271

Processes

visual perceptionGO:0007601

Locations

endoplasmic reticulum membraneGO:0005789

Non-catalytic 11-cis-retinal/retinol carrier (GO:0005502/GO:0019841 binding) that chaperones the hydrophobic 11-cis-retinoids between RPE65, RDH5 and the photoreceptors, enhancing visual-cycle flux; loss = retinitis punctata albescens / Bothnia dystrophy.

Part 6: light-driven photoisomerase (alternative regeneration)
RPE-retinal photoisomerase (RGR)Reactionphotoisomerase

Annotons

RGR: retinal photoisomerase (opsin family)
rgr_activity
Participant: Family: RGR / opsin (retinal G protein-coupled receptor) family
Family:
RGR / opsin (retinal G protein-coupled receptor) familyPANTHER:PTHR24240
Representative Members: RGR (human)UniProtKB:P47804

Function

cis-trans isomerase (retinal photoisomerase) activityGO:0016859
Substrates: all-trans-retinal (bound chromophore; light)
Products: 11-cis-retinal

Locations

endoplasmic reticulum membraneGO:0005789

Light-driven photoisomerization of all-trans- to 11-cis-retinal (RPE/Muller).

Part 7: broad retinaldehyde reductase (visual cycle support)
Retinol dehydrogenase 11 (RDH11)Reactionretinaldehyde_reductase

Annotons

RDH11: retinaldehyde reductase (NADPH)
rdh11_activity
Participant: Family: RDH11 / retinaldehyde reductase (SDR) family
Family:
RDH11 / retinaldehyde reductase (SDR) familyPANTHER:PTHR43157
Representative Members: RDH11 (human)UniProtKB:Q8TC12

Function

all-trans-retinol dehydrogenase (NADP+) activityGO:0052650
Substrates: all-trans- and cis-retinaldehydes NADPH
Products: the corresponding retinols NADP+

Locations

endoplasmic reticulum membraneGO:0005789

Reduce all-trans/cis retinaldehydes to retinols (NADPH; cycle support).

Part 8: retinaldehyde/retinoic-acid buffering
Retinaldehyde reductase (DHRS3)Reactionretinoid_buffering

Annotons

DHRS3: all-trans-retinaldehyde reductase (NADPH)
dhrs3_activity
Participant: Family: DHRS3 / retinaldehyde reductase (SDR) family
Family:
DHRS3 / retinaldehyde reductase (SDR) familyPANTHER:PTHR24322
Representative Members: DHRS3 (human)UniProtKB:O75911

Function

all-trans-retinol dehydrogenase (NADP+) activityGO:0052650
Substrates: all-trans-retinaldehyde NADPH
Products: all-trans-retinol NADP+

Locations

endoplasmic reticulum membraneGO:0005789

Reduce all-trans-retinaldehyde to retinol (buffers RA supply).