Cholesterol biosynthesis I — sterol commitment (squalene -> lanosterol); FDFT1/SQLE/LSS

The sterol-commitment segment of cholesterol biosynthesis converts the isoprenoid intermediate farnesyl diphosphate into the first cyclic sterol, lanosterol, committing carbon away from the branched isoprenoid pool (dolichol, ubiquinone, prenylation) and irreversibly toward sterols. Squalene synthase (FDFT1) performs the first committed step: a reductive head-to-head condensation of two farnesyl-diphosphate molecules (via presqualene diphosphate) to the C30 hydrocarbon squalene. Squalene monooxygenase / epoxidase (SQLE), an FAD flavoprotein and the second rate-limiting, cholesterol-feedback- regulated enzyme of the pathway, oxidises squalene to (S)-2,3-epoxysqualene using O2 and NADPH. Lanosterol synthase (LSS, oxidosqualene cyclase) then carries out the remarkable polycyclization of 2,3-epoxysqualene to lanosterol, the tetracyclic sterol scaffold from which cholesterol (and, in other tissues, downstream sterols) is made by the post-lanosterol demethylation/reduction steps. All three enzymes are endoplasmic-reticulum-membrane proteins. Inherited defects: FDFT1 deficiency (squalene synthase deficiency, a congenital cholesterol-biosynthesis disorder with dysmorphism/developmental delay) and LSS mutations (hypotrichosis with juvenile cataract / congenital cataract, and a palmoplantar keratoderma); SQLE is a validated antifungal/anticancer drug target rather than a Mendelian-disease gene.

MODULE:sterol_commitment_squalene_to_lanosterolDRAFTMetabolic Pathwaymodules/sterol_commitment_squalene_to_lanosterol.yaml
cholesterol biosynthetic processGO:0006695
GO:0006695
cholesterol biosynthetic process
The module is grounded in cholesterol biosynthetic process (GO:0006695); it covers the committed squalene -> lanosterol segment.
Reactome:R-HSA-9969896
Lanosterol biosynthesis
Step order and reaction stoichiometries follow the human Reactome "Lanosterol biosynthesis" reactions R-HSA-191402 (FDFT1), R-HSA-191299 (SQLE) and R-HSA-191366 (LSS).
file:human/FDFT1/FDFT1-ai-review.yaml
FDFT1 gene review (human)
The squalene-synthase step (UniProtKB:P37268, GO:0051996) matches the completed human FDFT1 review.
file:human/SQLE/SQLE-ai-review.yaml
SQLE gene review (human)
The squalene-epoxidase step (UniProtKB:Q14534, GO:0004506) matches the completed human SQLE review.
file:human/LSS/LSS-ai-review.yaml
LSS gene review (human)
The lanosterol-synthase step (UniProtKB:P48449, GO:0000250) matches the completed human LSS review.
4Nodes
3Parts
0Variant Sets
0Variants
3Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:sterol_commitment_squalene_to_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

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (6 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
fdft1_activity FDFT1 (human)
UniProtKB:P37268
Family Representative 		squalene synthase [NAD(P)H] activity
GO:0051996 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sqle_activity SQLE (human)
UniProtKB:Q14534
Family Representative 		squalene monooxygenase activity
GO:0004506 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lss_activity LSS (human)
UniProtKB:P48449
Family Representative 		lanosterol synthase activity
GO:0000250 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fdft1_activity Squalene/phytoene synthase family (FDFT1)
PANTHER:PTHR11626
Family 		squalene synthase [NAD(P)H] activity
GO:0051996 		Family Scope Restricted
GO:0051996 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. The modules (ergosterol_biosynthesis and sterol_commitment_squalene_to_lanosterol) select the base family for this activity. Not safe family-wide, because SF3 (Arabidopsis SQS2) is inactive. Within SF2 it holds for the canonical single-copy fungal, animal and plant enzymes. The Botryococcus SSL-1, SSL-2 and SSL-3 each carry out only part of the reaction or make a different product, so they are listed as member exceptions.
sqle_activity Squalene monooxygenase family (SQLE)
PANTHER:PTHR10835
Family 		squalene monooxygenase activity
GO:0004506 		Family Scope Restricted
GO:0004506 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. SF0, as ergosterol_biosynthesis selects; accepted by ERG1, erg1, SQLE and rat Sqle. sterol_commitment_squalene_to_lanosterol uses the base family, which also takes in the unassessed plant paralogs.
lss_activity Oxidosqualene cyclase family (LSS)
PANTHER:PTHR11764
Family 		lanosterol synthase activity
GO:0000250 		Family Scope Restricted
GO:0000250 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. SF20, as ergosterol_biosynthesis selects; sterol_commitment_squalene_to_lanosterol uses the base family. S. japonicus shc1 in SF20 is a squalene-hopene cyclase and is listed as an exception.

Gene-review completeness (3/3 grounded genes reviewed)

3 complete review(s) · 0 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
FDFT1 P37268 ✓ ✓ ✗
LSS P48449 ✓ ✓ ✗
SQLE Q14534 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789
Sterol commitment (squalene -> lanosterol)Metabolic Pathwaysterol_commitment_squalene_to_lanosterol
cholesterol biosynthetic processGO:0006695
Context
endoplasmic reticulum membraneGO:0005789

The sterol-commitment (squalene -> lanosterol) segment of cholesterol biosynthesis grounded to the human enzymes FDFT1 (UniProtKB:P37268, GO:0051996, EC 2.5.1.21), SQLE (Q14534, GO:0004506, EC 1.14.14.17) and LSS (P48449, GO:0000250, EC 5.4.99.7). 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; all three enzymes reside in the ER membrane. Upstream, farnesyl diphosphate comes from the mevalonate pathway (HMGCS1/HMGCR/ MVK/PMVK/MVD -> IPP -> FDPS); downstream, lanosterol is converted to cholesterol by the post-lanosterol demethylation/reduction enzymes (CYP51A1, TM7SF2/LBR, MSMO1, NSDHL, HSD17B7, EBP, SC5D, DHCR7/DHCR24) via the Bloch and Kandutsch-Russell arms (a separate module, to follow). FDFT1 is the committed branch point diverting the shared isoprenoid pool to sterols; SQLE is the second cholesterol-feedback-regulated rate-limiting control point. Disorders: FDFT1 -> squalene synthase deficiency; LSS -> hypotrichosis with juvenile cataract / congenital cataract (and a palmoplantar keratoderma); SQLE is a drug target (terbinafine-class antifungals; anticancer) rather than a classic disease gene.

Connections

fdft1_step -> sqle_step Provides Input For
Squalene from FDFT1 is epoxidised by SQLE.
sqle_step -> lss_step Provides Input For
2,3-epoxysqualene from SQLE is cyclised by LSS to lanosterol.
Part 1: squalene synthesis (committed step)
2 farnesyl diphosphate + NADPH to squaleneReactionfdft1_step

Annotons

FDFT1: squalene synthase
fdft1_activity
Participant: Family: Squalene/phytoene synthase family (FDFT1)
Family:
Squalene/phytoene synthase family (FDFT1)PANTHER:PTHR11626
Representative Members: FDFT1 (human)UniProtKB:P37268

Function

squalene synthase [NAD(P)H] activityGO:0051996
Substrates: farnesyl diphosphate (x2) NADPH
Products: squalene diphosphate

Locations

endoplasmic reticulum membraneGO:0005789

First committed step of sterol biosynthesis; diverts the isoprenoid pool specifically to sterols. Deficiency = squalene synthase deficiency.

Part 2: epoxidation (second rate-limiting, sterol-regulated)
squalene + O2 + NADPH to (S)-2,3-epoxysqualeneReactionsqle_step

Annotons

SQLE: squalene monooxygenase (epoxidase)
sqle_activity
Participant: Family: Squalene monooxygenase family (SQLE)
Family:
Squalene monooxygenase family (SQLE)PANTHER:PTHR10835
Representative Members: SQLE (human)UniProtKB:Q14534

Function

squalene monooxygenase activityGO:0004506
Substrates: squalene O2 NADPH (via P450 reductase)
Products: (S)-2,3-epoxysqualene (2,3-oxidosqualene)

Locations

endoplasmic reticulum membraneGO:0005789

FAD-dependent epoxidation of squalene; second rate-limiting step, subject to cholesterol-accelerated degradation. Antifungal/anticancer drug target.

Part 3: cyclization to the first cyclic sterol
(S)-2,3-epoxysqualene to lanosterolReactionlss_step

Annotons

LSS: lanosterol synthase (oxidosqualene cyclase)
lss_activity
Participant: Family: Oxidosqualene cyclase family (LSS)
Family:
Oxidosqualene cyclase family (LSS)PANTHER:PTHR11764
Representative Members: LSS (human)UniProtKB:P48449

Function

lanosterol synthase activityGO:0000250
Substrates: (S)-2,3-epoxysqualene
Products: lanosterol

Locations

endoplasmic reticulum membraneGO:0005789

Cyclises 2,3-epoxysqualene to lanosterol, the tetracyclic sterol scaffold and committed precursor of cholesterol. Mutations -> congenital cataract / hypotrichosis.