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, and the resulting Delta14 bond is reduced by TM7SF2 or LBR; 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 (the 3-ketoreductase HSD17B7 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. Isotope tracing shows that tissues mostly combine the Bloch arm with a modified Kandutsch-Russell arm, in which DHCR24 reduces zymosterol, rather than using the canonical Kandutsch-Russell route, in tissue-specific proportions. 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:0047750) 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:0050614 Delta24-sterol reductase activity, the core function in the completed DHCR24 review) distinguishes the Bloch and Kandutsch-Russell arms. An earlier version of this statement cited GO:0000246, which is the ergosterol Delta24(24-1) reductase term.

PMID:42532476

Sterol flux rewiring: Cholesterol biosynthesis as a dynamic signaling network.

2026 review used to audit the module. It treats the post-lanosterol segment as partially overlapping Bloch and Kandutsch-Russell branches whose use varies by tissue, and DHCR24 as a node of that switch. The earlier module version named DHCR24 but did not model it as a part.

Beyond lanosterol, biosynthesis follows the partially overlapping Bloch and Kandutsch–Russell pathways, whose relative contributions vary among tissues and physiological conditions (3, 11, 16).

PMID:26114596

Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways.

Primary isotope-tracing evidence that tissues use the Bloch pathway and a hybrid modified Kandutsch-Russell (MK-R) pathway, in which DHCR24 acts on zymosterol, rather than the canonical Kandutsch-Russell pathway.

Surprisingly, no tissue used the canonical K-R pathway. Rather, a hybrid pathway was identified that we call the modified K-R (MK-R) pathway.

10Nodes

9Parts

0Variant Sets

0Variants

10Annotons

10Connections

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.

Function consistency and core coverage

8 gene-function check(s) reflected in core functions · 0 conflict(s) · 10 evidence or coverage gap(s) (20 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.

Annoton	Participant	Function	Assessment
cyp51a1_activity	CYP51A1 (human) UniProtKB:Q16850 Family Representative	sterol 14-demethylase activity GO:0008398	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tm7sf2_activity	TM7SF2 (human) UniProtKB:O76062 Family Representative	Delta14-sterol reductase activity GO:0050613	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
lbr_activity	LBR (human) UniProtKB:Q14739 Family Representative	Delta14-sterol reductase activity GO:0050613	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
msmo1_activity	MSMO1 (human) UniProtKB:Q15800 Family Representative	C-4 methylsterol oxidase activity GO:0000254	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nsdhl_activity	NSDHL (human) UniProtKB:Q15738 Family Representative	3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity GO:0000252	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsd17b7_activity	HSD17B7 (human) UniProtKB:P56937 Family Representative	3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activity GO:0000253	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
ebp_activity	EBP (human) UniProtKB:Q15125 Family Representative	cholestenol delta-isomerase activity GO:0047750	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sc5d_activity	SC5D (human) UniProtKB:O75845 Family Representative	delta7-sterol 5(6)-desaturase activity GO:0050046	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dhcr7_activity	DHCR7 (human) UniProtKB:Q9UBM7 Family Representative	7-dehydrocholesterol reductase activity GO:0047598	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dhcr24_activity	DHCR24 (human) UniProtKB:Q15392 Family Representative	Delta24-sterol reductase activity GO:0050614	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyp51a1_activity	Sterol 14-alpha-demethylase family (CYP51A1) Family	sterol 14-demethylase activity GO:0008398	Family Id Missing The family has no identifier linking it to a curated family review.
tm7sf2_activity	TM7SF2 Delta14-sterol reductase subfamily PANTHER:PTHR21257:SF52 Family	Delta14-sterol reductase activity GO:0050613	Family Supported Family review supports GO:0050613 for PANTHER:PTHR21257:SF52. ERG24/TM7SF2 (SF52, selected by ergosterol_biosynthesis) and LBR (SF55).
lbr_activity	LBR Delta14-sterol reductase subfamily PANTHER:PTHR21257:SF55 Family	Delta14-sterol reductase activity GO:0050613	Family Supported Family review supports GO:0050613 for PANTHER:PTHR21257:SF55. ERG24/TM7SF2 (SF52, selected by ergosterol_biosynthesis) and LBR (SF55).
msmo1_activity	Fatty acid hydroxylase / methylsterol oxidase family (MSMO1/SC5D) PANTHER:PTHR11863 Family	C-4 methylsterol oxidase activity GO:0000254	Family Function Unreviewed Family review leaves GO:0000254 UNRESOLVED. Mouse and human CH25H cDNAs encode cholesterol 25-hydroxylases with experimentally required histidine clusters (PMID:9852097). This side-chain hydroxylation differs from C4 methylsterol oxidation and C5 desaturation in other branches of the sterol-enzyme grouping. C4 methylsterol oxidase activity is therefore not a family-wide grant and is not supported for CH25H; the exact positively supported sterol-oxidase subfamily set remains unresolved.
nsdhl_activity	NSDHL / 3-beta-HSD-like C4-decarboxylase family (NSDHL) Family	3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity GO:0000252	Family Id Missing The family has no identifier linking it to a curated family review.
hsd17b7_activity	3-keto-steroid reductase / HSD17B7 subfamily PANTHER:PTHR44442:SF1 Family	3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activity GO:0000253	Family Review Missing No supported structured family review is available for PANTHER:PTHR44442:SF1.
ebp_activity	Emopamil-binding protein / sterol isomerase family (EBP) PANTHER:PTHR14207 Family	cholestenol delta-isomerase activity GO:0047750	Family Review Missing No supported structured family review is available for PANTHER:PTHR14207.
sc5d_activity	Fatty acid hydroxylase / sterol desaturase family (SC5D/MSMO1) PANTHER:PTHR11863 Family	delta7-sterol 5(6)-desaturase activity GO:0050046	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0050046.
dhcr7_activity	7-dehydrocholesterol reductase family (DHCR7) PANTHER:PTHR21257 Family	7-dehydrocholesterol reductase activity GO:0047598	Family Scope Restricted GO:0047598 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. DHCR7 (SF38); cholesterol_synthesis_post_lanosterol selects the base family.
dhcr24_activity	DHCR24 / 24-dehydrocholesterol reductase subfamily PANTHER:PTHR10801:SF0 Family	Delta24-sterol reductase activity GO:0050614	Family Review Missing No supported structured family review is available for PANTHER:PTHR10801:SF0.

Gene-review completeness (8/10 grounded genes reviewed)

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

Gene	Review	Complete	Deep research
CYP51A1 Q16850	✓	✓	✗
DHCR24 Q15392	✓	44/50	✓
DHCR7 Q9UBM7	✓	30/31	✗
EBP Q15125	✓	✓	✗
LBR Q14739	✓	✓	✓
MSMO1 Q15800	✓	✓	✗
NSDHL Q15738	✓	✓	✗
TM7SF2 (human) O76062	✗	—	—
HSD17B7 (human) P56937	✗	—	—
SC5D O75845	✓	✓	✗

Tree

Cholesterol biosynthesis (lanosterol -> cholesterol)Metabolic Pathwaycholesterol_synthesis_post_lanosterol

Parts
1. 1. 14-alpha-demethylation
2. lanosterol to 14-demethyl-lanosterol (FF-MAS)Reactioncyp51a1_step
  
  Annotons
  - CYP51A1: sterol 14-alpha-demethylase Family: Sterol 14-alpha-demethylase family (CYP51A1)
3. 2. Delta14 reduction
4. 14-demethyl sterol (FF-MAS) to Delta14-reduced sterol (T-MAS)Reactiondelta14_reduction_step
  
  Annotons
  - TM7SF2: Delta14-sterol reductase Family: TM7SF2 Delta14-sterol reductase subfamily
  - LBR: Delta14-sterol reductase Family: LBR Delta14-sterol reductase subfamily
5. 3. C4-methyl oxidation
6. 4,4-dimethyl/4-methyl sterol to 4-carboxy sterol (C4-methyl oxidation)Reactionmsmo1_step
  
  Annotons
  - MSMO1: C4-methylsterol oxidase Family: Fatty acid hydroxylase / methylsterol oxidase family (MSMO1/SC5D)
7. 4. C4-decarboxylation / 3-oxidation
8. 4-carboxy sterol to 3-keto sterol + CO2 (then reduced to 3-beta-ol)Reactionnsdhl_step
  
  Annotons
  - NSDHL: sterol-4-carboxylate 3-dehydrogenase (decarboxylating) Family: NSDHL / 3-beta-HSD-like C4-decarboxylase family (NSDHL)
9. 5. 3-keto reduction
10. 3-keto sterol to 3-beta-hydroxy sterolReactionhsd17b7_step
  
  Annotons
  - HSD17B7: 3-keto-steroid reductase Family: 3-keto-steroid reductase / HSD17B7 subfamily
11. 6. Delta8 -> Delta7 isomerisation
12. Delta(8)-sterol to Delta(7)-sterolReactionebp_step
  
  Annotons
  - EBP: sterol Delta(8),Delta(7)-isomerase Family: Emopamil-binding protein / sterol isomerase family (EBP)
13. 7. C5-desaturation
14. Delta(7)-sterol (lathosterol) to Delta(5,7)-sterol (7-dehydrocholesterol)Reactionsc5d_step
  
  Annotons
  - SC5D: lathosterol oxidase (sterol-C5-desaturase) Family: Fatty acid hydroxylase / sterol desaturase family (SC5D/MSMO1)
15. 8. 7-dehydrocholesterol reduction (final)
16. 7-dehydrocholesterol to cholesterolReactiondhcr7_step
  
  Annotons
  - DHCR7: 7-dehydrocholesterol reductase Family: 7-dehydrocholesterol reductase family (DHCR7)
17. 9. Delta24 side-chain reduction (Bloch / modified Kandutsch-Russell switch)
18. Delta24-sterol to 24,25-dihydro sterol (desmosterol to cholesterol; zymosterol to zymostenol)Reactiondhcr24_step
  
  Annotons
  - DHCR24: Delta24-sterol reductase Family: DHCR24 / 24-dehydrocholesterol reductase subfamily

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:0047750, 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 were checked against the local reactome/ cache; R-HSA-194698 (TM7SF2), R-HSA-194674 (LBR) and R-HSA-194689 (HSD17B7) were cached in the 2026-10 revision and their reaction summaries confirmed to describe the Delta14 reduction and the C4-demethylation 3-keto reduction. 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:0050614 Delta24-sterol reductase; deficiency = desmosterolosis) acts. Revision (2026-10, after the review PMID:42532476): DHCR24 is now an explicit part, connected both from HSD17B7 (zymosterol, the modified K-R entry; PMID:26114596) and from DHCR7 (desmosterol, the Bloch end). The Delta14-reduction step (TM7SF2 O76062 / LBR Q14739, GO:0050613) and the 3-keto reduction of C4 demethylation (HSD17B7 P56937, GO:0000253) were added because the earlier chain skipped them. None of these three has a gene review in this repository; they are grounded to reviewed UniProt entries, GOA experimental annotations and Reactome reactions. The parts list still shows one C4-demethylation pass (MSMO1 -> NSDHL -> HSD17B7), which runs twice in the pathway. 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 -> delta14_reduction_step Provides Input For

The Delta14 bond left by CYP51A1 demethylation (FF-MAS) is reduced by TM7SF2 or LBR.

delta14_reduction_step -> msmo1_step Provides Input For

The Delta14-reduced 4,4-dimethyl sterol (T-MAS) undergoes C4-demethylation (MSMO1/NSDHL/HSD17B7).

msmo1_step -> nsdhl_step Provides Input For

The 4-carboxy sterol from MSMO1 is decarboxylated by NSDHL.

nsdhl_step -> hsd17b7_step Provides Input For

The 3-keto sterol from NSDHL is reduced back to the 3-beta-ol by HSD17B7.

hsd17b7_step -> ebp_step Provides Input For

In the Bloch arm, zymosterol (the Delta8-sterol left after two C4-demethylation rounds) is isomerised by EBP.

hsd17b7_step -> dhcr24_step Provides Input For

In the modified Kandutsch-Russell arm, zymosterol is reduced by DHCR24 to zymostenol.

dhcr7_step -> dhcr24_step Provides Input For

In the Bloch arm, desmosterol made by DHCR7 is reduced by DHCR24 to cholesterol.

dhcr24_step -> ebp_step Provides Input For

In the modified Kandutsch-Russell arm, zymostenol made by DHCR24 is isomerised by EBP to lathosterol and continues through SC5D and DHCR7 to cholesterol (PMID:26114596).

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)

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: Delta14 reduction

14-demethyl sterol (FF-MAS) to Delta14-reduced sterol (T-MAS)Reactiondelta14_reduction_step

Two paralogous Delta14-sterol reductases can each perform this step. TM7SF2 is an ER enzyme, and the lamin B receptor LBR carries the same sterol-reductase activity.

Annotons

TM7SF2: Delta14-sterol reductase

tm7sf2_activity

Participant: Family: TM7SF2 Delta14-sterol reductase subfamily

Family:

TM7SF2 Delta14-sterol reductase subfamilyPANTHER:PTHR21257:SF52

Representative Members: TM7SF2 (human)UniProtKB:O76062

Function

Delta14-sterol reductase activityGO:0050613

Substrates: 4,4-dimethylcholesta-8,14,24-trien-3beta-ol (FF-MAS) NADPH

Products: 4,4-dimethylcholesta-8,24-dien-3beta-ol (T-MAS)

Locations

endoplasmic reticulum membraneGO:0005789

Reduces the C14-15 double bond left by CYP51A1 demethylation; redundant with LBR.

LBR: Delta14-sterol reductase

lbr_activity

Participant: Family: LBR Delta14-sterol reductase subfamily

Family:

LBR Delta14-sterol reductase subfamilyPANTHER:PTHR21257:SF55

Representative Members: LBR (human)UniProtKB:Q14739

Function

Delta14-sterol reductase activityGO:0050613

Substrates: 4,4-dimethylcholesta-8,14,24-trien-3beta-ol (FF-MAS) NADPH

Products: 4,4-dimethylcholesta-8,24-dien-3beta-ol (T-MAS)

Locations

endoplasmic reticulum membraneGO:0005789

Lamin B receptor with sterol Delta14-reductase activity; paralog that overlaps TM7SF2 at this step. Its sterol-reductase activity is located in the nuclear envelope and ER membrane.

Part 3: 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 4: 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)

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 5: 3-keto reduction

3-keto sterol to 3-beta-hydroxy sterolReactionhsd17b7_step

Annotons

HSD17B7: 3-keto-steroid reductase

hsd17b7_activity

Participant: Family: 3-keto-steroid reductase / HSD17B7 subfamily

Family:

3-keto-steroid reductase / HSD17B7 subfamilyPANTHER:PTHR44442:SF1

Representative Members: HSD17B7 (human)UniProtKB:P56937

Function

3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activityGO:0000253

Substrates: 3-keto C4-demethylated sterol (from NSDHL) NADPH

Products: 3-beta-hydroxy sterol (4-methylzymosterol, then zymosterol after the second round)

Locations

endoplasmic reticulum membraneGO:0005789

Restores the 3-beta-hydroxyl after NSDHL oxidative decarboxylation, completing each of the two C4-demethylation rounds.

Part 6: 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

cholestenol delta-isomerase activityGO:0047750

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 7: 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 8: 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.

Part 9: Delta24 side-chain reduction (Bloch / modified Kandutsch-Russell switch)

Delta24-sterol to 24,25-dihydro sterol (desmosterol to cholesterol; zymosterol to zymostenol)Reactiondhcr24_step

DHCR24 reduces the side-chain Delta24 bond. When it acts decides the branch. In the Bloch pathway it acts last, on desmosterol. In the modified Kandutsch-Russell (MK-R) pathway it acts on zymosterol, giving zymostenol, which then passes through EBP, SC5D and DHCR7. Isotope tracing in mice found no tissue using the canonical Kandutsch-Russell route from lanosterol, and the Bloch:MK-R ratio varies with tissue and flux (PMID:26114596).

Annotons

DHCR24: Delta24-sterol reductase

dhcr24_activity

Participant: Family: DHCR24 / 24-dehydrocholesterol reductase subfamily

Family:

DHCR24 / 24-dehydrocholesterol reductase subfamilyPANTHER:PTHR10801:SF0

Representative Members: DHCR24 (human)UniProtKB:Q15392

Function

Delta24-sterol reductase activityGO:0050614

Substrates: Delta24 sterol (desmosterol in the Bloch arm; zymosterol in the MK-R arm) NADPH

Products: 24,25-dihydro sterol (cholesterol; zymostenol)

Locations

endoplasmic reticulum membraneGO:0005789

Reduces the side-chain Delta24 bond; its timing distinguishes the Bloch and modified Kandutsch-Russell arms. Deficiency = desmosterolosis.