Cholesterol biosynthesis II — lanosterol to cholesterol (post-lanosterol); SLOS, CDPX2, CHILD, lathosterolosis

The post-lanosterol segment of cholesterol biosynthesis converts lanosterol into cholesterol through a ~19-reaction sequence of demethylations, isomerisation, desaturations and reductions carried out by endoplasmic-reticulum-membrane enzymes. The three lanosterol methyl groups are removed first: CYP51A1 (a cytochrome P450) removes the 14-alpha-methyl group; then the two C4 methyls are removed in two rounds by the C4- demethylation machinery in which MSMO1 (a non-heme di-iron methylsterol oxidase) oxidises the C4 methyl to a carboxylate and NSDHL (a 3-beta-hydroxysteroid dehydrogenase/ C4-decarboxylase) decarboxylates it (a 3-ketoreductase then restores the 3-beta-ol). EBP (sterol Delta(8)-Delta(7) isomerase) shifts the ring double bond from Delta8 to Delta7; SC5D (lathosterol oxidase / sterol-C5-desaturase) introduces the C5-6 double bond; and DHCR7 (7-dehydrocholesterol reductase) reduces the C7-8 double bond to give cholesterol. The pathway runs as two interconvertible arms — the Bloch arm (retaining the side-chain Delta24 double bond until the end) and the Kandutsch-Russell arm (in which DHCR24 reduces the Delta24 bond early) — that differ only in the timing of the DHCR24 step. Inherited enzyme defects cause distinctive malformation/skeletal/skin disorders: DHCR7 -> Smith-Lemli-Opitz syndrome; SC5D -> lathosterolosis; EBP -> X-linked chondrodysplasia punctata 2 (Conradi-Hunermann-Happle); NSDHL -> CHILD syndrome; MSMO1 -> SC4MOL deficiency; and DHCR24 -> desmosterolosis.

MODULE:cholesterol_synthesis_post_lanosterolDRAFTMetabolic Pathwaymodules/cholesterol_synthesis_post_lanosterol.yaml
cholesterol biosynthetic processGO:0006695
GO:0006695
cholesterol biosynthetic process
The module is grounded in cholesterol biosynthetic process (GO:0006695); it covers the post-lanosterol lanosterol -> cholesterol segment.
Reactome:R-HSA-191273
Cholesterol biosynthesis
Reactions follow the human Reactome cholesterol-biosynthesis pathway: R-HSA-194678 (CYP51A1), R-HSA-194641 (MSMO1), R-HSA-194642 (NSDHL), R-HSA-6807052 (EBP), R-HSA-195664 (SC5D) and R-HSA-196402 (DHCR7).
file:human/CYP51A1/CYP51A1-ai-review.yaml
CYP51A1 gene review (human)
The lanosterol 14-demethylation step (UniProtKB:Q16850, GO:0008398) matches the completed human CYP51A1 review.
file:human/MSMO1/MSMO1-ai-review.yaml
MSMO1 gene review (human)
The C4-methyl-oxidation step (UniProtKB:Q15800, GO:0000254) matches the completed human MSMO1 review.
file:human/NSDHL/NSDHL-ai-review.yaml
NSDHL gene review (human)
The C4-decarboxylation step (UniProtKB:Q15738, GO:0000252) matches the completed human NSDHL review.
file:human/EBP/EBP-ai-review.yaml
EBP gene review (human)
The Delta8-Delta7 isomerisation step (UniProtKB:Q15125, GO:0000247) matches the completed human EBP review.
file:human/SC5D/SC5D-ai-review.yaml
SC5D gene review (human)
The C5-desaturation step (UniProtKB:O75845, GO:0050046) matches the completed human SC5D review.
file:human/DHCR7/DHCR7-ai-review.yaml
DHCR7 gene review (human)
The 7-dehydrocholesterol-reduction (final) step (UniProtKB:Q9UBM7, GO:0047598) matches the completed human DHCR7 review.
file:human/DHCR24/DHCR24-ai-review.yaml
DHCR24 gene review (human)
The Delta24 side-chain reduction (UniProtKB:Q15392, GO:0000246) that distinguishes the Bloch and Kandutsch-Russell arms is the previously completed human DHCR24 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:cholesterol_synthesis_post_lanosterol 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 (6/6 grounded genes reviewed)

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

Gene Review Complete Deep research
CYP51A1 Q16850 ✓ ✓ ✗
DHCR7 Q9UBM7 ✓ ✓ ✗
EBP Q15125 ✓ ✓ ✗
MSMO1 Q15800 ✓ ✓ ✗
NSDHL Q15738 ✓ ✓ ✗
SC5D O75845 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789
Cholesterol biosynthesis (lanosterol -> cholesterol)Metabolic Pathwaycholesterol_synthesis_post_lanosterol
cholesterol biosynthetic processGO:0006695
Context
endoplasmic reticulum membraneGO:0005789

The post-lanosterol segment of cholesterol biosynthesis grounded to the human enzymes CYP51A1 (UniProtKB:Q16850, GO:0008398, EC 1.14.14.154), MSMO1 (Q15800, GO:0000254, EC 1.14.18.9), NSDHL (Q15738, GO:0000252), EBP (Q15125, GO:0000247, EC 5.3.3.5), SC5D (O75845, GO:0050046, EC 1.14.19.20) and DHCR7 (Q9UBM7, GO:0047598, EC 1.3.1.21). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector with the human enzyme as representative (MSMO1 and SC5D share the fatty-acid- hydroxylase/sterol-desaturase family PTHR11863). This is a SIMPLIFIED ordered view of a ~19-reaction, branched segment: it runs as two interconvertible arms — the Bloch arm (the side-chain Delta24 bond is kept until the end) and the Kandutsch-Russell arm (DHCR24 reduces Delta24 early) — differing only in when DHCR24 (UniProtKB:Q15392, GO:0000246 Delta24-sterol reductase; reviewed previously, on main, deficiency = desmosterolosis) acts; intervening C14- and 3-keto-reductase steps (e.g. by LBR/TM7SF2 and HSD17B7) are abbreviated. Upstream, lanosterol comes from the sterol_commitment_squalene_to_lanosterol module (FDFT1/SQLE/LSS); the immediate substrate lanosterol is made by the mevalonate -> squalene route. Disorders map to individual steps: CYP51A1 (no common disease), MSMO1 (SC4MOL deficiency), NSDHL (CHILD/CK syndrome), EBP (CDPX2 / Conradi-Hunermann-Happle), SC5D (lathosterolosis), DHCR7 (Smith-Lemli-Opitz syndrome), DHCR24 (desmosterolosis).

Connections

cyp51a1_step -> msmo1_step Provides Input For
The 14-demethylated sterol from CYP51A1 undergoes C4-demethylation (MSMO1/NSDHL).
msmo1_step -> nsdhl_step Provides Input For
The 4-carboxy sterol from MSMO1 is decarboxylated by NSDHL.
nsdhl_step -> ebp_step Provides Input For
After C4-demethylation, the Delta8-sterol is isomerised by EBP.
ebp_step -> sc5d_step Provides Input For
The Delta7-sterol (lathosterol) from EBP is desaturated by SC5D.
sc5d_step -> dhcr7_step Provides Input For
7-dehydrocholesterol from SC5D is reduced by DHCR7 to cholesterol.
Part 1: 14-alpha-demethylation
lanosterol to 14-demethyl-lanosterol (FF-MAS)Reactioncyp51a1_step

Annotons

CYP51A1: sterol 14-alpha-demethylase
cyp51a1_activity
Participant: Family: Sterol 14-alpha-demethylase family (CYP51A1)
Family:
Sterol 14-alpha-demethylase family (CYP51A1)PANTHER:PTHR24304
Representative Members: CYP51A1 (human)UniProtKB:Q16850

Function

sterol 14-demethylase activityGO:0008398
Substrates: lanosterol (or 24,25-dihydrolanosterol)
Products: 14-demethyl sterol (FF-MAS) + formate

Locations

endoplasmic reticulum membraneGO:0005789

P450 that removes lanosterol's 14-alpha-methyl group (three oxidative steps), the first post-lanosterol demethylation.

Part 2: C4-methyl oxidation
4,4-dimethyl/4-methyl sterol to 4-carboxy sterol (C4-methyl oxidation)Reactionmsmo1_step

Annotons

MSMO1: C4-methylsterol oxidase
msmo1_activity
Participant: Family: Fatty acid hydroxylase / methylsterol oxidase family (MSMO1/SC5D)
Family:
Fatty acid hydroxylase / methylsterol oxidase family (MSMO1/SC5D)PANTHER:PTHR11863
Representative Members: MSMO1 (human)UniProtKB:Q15800

Function

C-4 methylsterol oxidase activityGO:0000254
Substrates: 4-alpha-methyl sterol O2 / NAD(P)H
Products: 4-alpha-carboxy sterol

Locations

endoplasmic reticulum membraneGO:0005789

Non-heme di-iron oxidase oxidising the sterol C4-methyl group to a carboxylate (repeated for both C4 methyls); the oxidative part of C4-demethylation. MSMO1 deficiency = SC4MOL deficiency.

Part 3: C4-decarboxylation / 3-oxidation
4-carboxy sterol to 3-keto sterol + CO2 (then reduced to 3-beta-ol)Reactionnsdhl_step

Annotons

NSDHL: sterol-4-carboxylate 3-dehydrogenase (decarboxylating)
nsdhl_activity
Participant: Family: NSDHL / 3-beta-HSD-like C4-decarboxylase family (NSDHL)
Family:
NSDHL / 3-beta-HSD-like C4-decarboxylase family (NSDHL)PANTHER:PTHR43245
Representative Members: NSDHL (human)UniProtKB:Q15738

Function

3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activityGO:0000252
Substrates: 3-beta-hydroxy-4-alpha-carboxy sterol NAD(P)+
Products: 3-keto sterol + CO2

Locations

endoplasmic reticulum membraneGO:0005789

NAD(P)+-dependent 3-dehydrogenation/decarboxylation of the 4-carboxysterol; the decarboxylating half of C4-demethylation. NSDHL deficiency = CHILD / CK syndrome.

Part 4: Delta8 -> Delta7 isomerisation
Delta(8)-sterol to Delta(7)-sterolReactionebp_step

Annotons

EBP: sterol Delta(8),Delta(7)-isomerase
ebp_activity
Participant: Family: Emopamil-binding protein / sterol isomerase family (EBP)
Family:
Emopamil-binding protein / sterol isomerase family (EBP)PANTHER:PTHR14207
Representative Members: EBP (human)UniProtKB:Q15125

Function

C-8 sterol isomerase activityGO:0000247
Substrates: Delta(8)-sterol (e.g. zymostenol)
Products: Delta(7)-sterol (e.g. lathosterol)

Locations

endoplasmic reticulum membraneGO:0005789

Shifts the ring double bond from Delta8 to Delta7. Deficiency = X-linked chondrodysplasia punctata 2 (Conradi-Hunermann-Happle).

Part 5: C5-desaturation
Delta(7)-sterol (lathosterol) to Delta(5,7)-sterol (7-dehydrocholesterol)Reactionsc5d_step

Annotons

SC5D: lathosterol oxidase (sterol-C5-desaturase)
sc5d_activity
Participant: Family: Fatty acid hydroxylase / sterol desaturase family (SC5D/MSMO1)
Family:
Fatty acid hydroxylase / sterol desaturase family (SC5D/MSMO1)PANTHER:PTHR11863
Representative Members: SC5D (human)UniProtKB:O75845

Function

delta7-sterol 5(6)-desaturase activityGO:0050046
Substrates: lathosterol (Delta7-sterol) O2 / NAD(P)H
Products: 7-dehydrocholesterol (Delta5,7-sterol)

Locations

endoplasmic reticulum membraneGO:0005789

Introduces the C5-6 double bond (lathosterol -> 7-dehydrocholesterol). Deficiency = lathosterolosis.

Part 6: 7-dehydrocholesterol reduction (final)
7-dehydrocholesterol to cholesterolReactiondhcr7_step

Annotons

DHCR7: 7-dehydrocholesterol reductase
dhcr7_activity
Participant: Family: 7-dehydrocholesterol reductase family (DHCR7)
Family:
7-dehydrocholesterol reductase family (DHCR7)PANTHER:PTHR21257
Representative Members: DHCR7 (human)UniProtKB:Q9UBM7

Function

7-dehydrocholesterol reductase activityGO:0047598
Substrates: 7-dehydrocholesterol NADPH
Products: cholesterol

Locations

endoplasmic reticulum membraneGO:0005789

Reduces the C7-8 double bond of 7-dehydrocholesterol to give cholesterol (and, in the Bloch arm, 7-dehydrodesmosterol -> desmosterol); 7-DHC is also the vitamin-D3 precursor. Deficiency = Smith-Lemli-Opitz syndrome.