Ergosterol biosynthesis (squalene -> lanosterol -> ergosterol)

Fungal sterol synthesis converts farnesyl diphosphate from the isoprenoid trunk into ergosterol, the principal sterol of fungal membranes, through about twenty reactions on the endoplasmic-reticulum membrane. The first half is shared with animal cholesterol synthesis. Squalene synthase reductively joins two farnesyl diphosphates into squalene, squalene epoxidase oxidises it to 2,3-oxidosqualene, and lanosterol synthase cyclises that to lanosterol. The cytochrome P450 sterol 14alpha-demethylase (CYP51) then removes the C-14 methyl, a Delta14-reductase saturates the resulting double bond, and a C-4 demethylation complex removes both C-4 methyls in two rounds: a C-4 methylsterol oxidase oxidises the methyl to a carboxylate, a 3beta-hydroxysteroid dehydrogenase/C-4 decarboxylase releases it as CO2, and a 3-ketosteroid reductase restores the 3beta-hydroxyl. A membrane scaffold (Erg28) tethers the three C-4 demethylation enzymes, yielding zymosterol. The ergosterol-specific tail follows. A sterol C-24 methyltransferase adds the C-28 methyl group that animals lack. A C-8 sterol isomerase that is unrelated to the animal EBP isomerase moves the Delta8 bond to Delta7. A C-5 desaturase homologous to animal SC5D adds the Delta5 bond, a cytochrome P450 C-22 desaturase (CYP61) adds the side-chain Delta22 bond, and a C-24(28) reductase completes ergosterol. The P450 steps take electrons from NADPH-cytochrome P450 reductase, and the C-4 oxidase and C-5 desaturase use cytochrome b5, which can also support CYP51. The pathway is the target of the main antifungal drug classes: azoles (CYP51), allylamines such as terbinafine (squalene epoxidase) and morpholines (Delta14-reductase and C-8 isomerase).

MODULE:ergosterol_biosynthesisDRAFTCONCRETEMetabolic Pathwaymodules/ergosterol_biosynthesis.yaml

ergosterol biosynthetic processGO:0006696

GO:0006696

ergosterol biosynthetic process

The module is grounded in the GO biological-process term for ergosterol biosynthesis; the shared squalene -> lanosterol segment is also covered by the template sterol_commitment_squalene_to_lanosterol.

YeastPathways:PWY3O-31704

ergosterol biosynthesis (S. cerevisiae, SGD YeastPathways)

Main YeastCyc frame (FPP -> ergosterol) with ERG20, ERG9, ERG1, ERG7, ERG11, ERG24, ERG25, ERG26, ERG27, ERG6, ERG2, ERG3, ERG5 and ERG4. All catalyst assignments were retained. The FPP-forming ERG20 reactions belong to isoprenoid_diphosphate_biosynthesis. ERG28 (C-4 demethylation scaffold), NCP1 (P450 reductase) and CYB5 (cytochrome b5) are not listed by YeastCyc and were added. The cytochrome b5 and P450-reductase electron carriers appear only as generic reactants in its ERG25, ERG3, ERG1, ERG11 and ERG5 equations.

YeastPathways:ERGOSTEROL-SYN-PWY-1

superpathway of ergosterol biosynthesis I (S. cerevisiae, SGD YeastPathways)

Superpathway frame combining the mevalonate pathway, FPP synthesis and the ergosterol pathway; its upstream segments are the mevalonate_pathway and isoprenoid_diphosphate_biosynthesis modules.

YeastPathways:PWY-5670-1

epoxysqualene biosynthesis (S. cerevisiae, SGD YeastPathways)

ERG9 (two half-reactions via presqualene diphosphate) and ERG1; the first two steps of the commitment segment.

YeastPathways:PWY-6132

lanosterol biosynthesis (S. cerevisiae, SGD YeastPathways)

Single-reaction frame for ERG7 lanosterol synthase, folded into the commitment segment.

YeastPathways:PWY-6074-1

zymosterol biosynthesis (S. cerevisiae, SGD YeastPathways)

Lanosterol -> zymosterol with ERG11, ERG24 and the C-4 demethylation enzymes ERG25, ERG26 and ERG27; the first five tiers of the post-lanosterol segment here.

YeastPathways:PWY-6075-1

ergosterol biosynthesis I (S. cerevisiae, SGD YeastPathways)

Zymosterol -> ergosterol with ERG6, ERG2, ERG3, ERG5 and ERG4; the fungal-specific tail.

PMID:8561481

Physiological implications of sterol biosynthesis in yeast.

Ergosterol is the fungal counterpart of cholesterol, with distinct structural features; most antifungals act on its synthesis or function.

Most of the antifungal compounds in medical and agricultural use affect some aspect of sterol synthesis or function.

PMID:8277826

Sterol synthesis and viability of erg11 (cytochrome P450 lanosterol demethylase) mutations in Saccharomyces cerevisiae and Candida albicans.

In S. cerevisiae the tail steps C-24 methylation (ERG6), C-5 desaturation (ERG3) and Delta8-Delta7 isomerization (ERG2) are dispensable, whereas C-14 demethylation (ERG11) and C-14 reduction (ERG24) are required for aerobic viability.

C-24 methylation (ERG6), C-5 desaturation (ERG3) and delta 8-delta 7 isomerization (ERG2) are not required, while C-14 demethylation (ERG11) and C-14 reduction (ERG24) are each required for aerobic viability.

PMID:18310029

Multiple functions of ergosterol in the fission yeast Schizosaccharomyces pombe.

The S. pombe late-pathway genes erg6, erg2, erg31/erg32, erg5 and sts1/erg4 are required for ergosterol synthesis; erg31 and erg32 are redundant C-5 desaturases.

Disruption of erg31(+) or erg32(+) did not cause ergosterol deficiency or tolerance to polyene drugs, indicating that the two C-5 sterol desaturases have overlapping functions.

PMID:32679672

Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae.

Review of the S. cerevisiae ergosterol pathway, its enzymes and its regulation by sterols, oxygen and iron.

PMID:12119386

Protein-protein interactions among C-4 demethylation enzymes involved in yeast sterol biosynthesis.

Erg25, Erg26, Erg27 and Erg28 form an ER-membrane C-4 demethylation complex with Erg28 as scaffold.

we suggest that Erg28p works as a transmembrane scaffold to tether Erg27p and possibly other C-4 demethylation proteins (Erg25p, Erg26p), forming a demethylation complex in the endoplasmic reticulum.

PMID:15995173

Erg28p is a key protein in the yeast sterol biosynthetic enzyme complex.

Erg28 also interacts with Erg11, Erg1 and Erg6, suggesting a larger tethered enzyme assembly.

Erg28p not only interacted with the C-4 demethylation enzymes and Erg6p but also with Erg11p and Erg1p.

PMID:12842197

In yeast sterol biosynthesis the 3-keto reductase protein (Erg27p) is required for oxidosqualene cyclase (Erg7p) activity.

Erg27 binds and stabilises lanosterol synthase Erg7 and is required for its activity in lipid particles.

We demonstrate that Erg27p is required for oxidosqualene cyclase (Erg7p) activity in LPs

PMID:6163470

Involvement of cytochrome b5 and a cyanide-sensitive monooxygenase in the 4-demethylation of 4,4-dimethylzymosterol by yeast microsomes.

Cytochrome b5 supplies electrons to C-4 demethylation but not to 14alpha-demethylation in yeast microsomes.

cytochrome b5 and a cyanide-sensitive enzyme are involved in the 4-demethylation of 4,4-dimethylzymosterol, but not the 14 alpha-demethylation of lanosterol

PMID:2543395

Disruption of the Saccharomyces cerevisiae gene for NADPH-cytochrome P450 reductase causes increased sensitivity to ketoconazole.

NCP1 deletion is viable but sensitises cells to the CYP51 inhibitor ketoconazole, implying an alternative electron supply.

suggesting that an alternate pathway may provide for the functions of this reductase in S. cerevisiae.

PMID:8181746

Cloning and characterization of a yeast cytochrome b5-encoding gene which suppresses ketoconazole hypersensitivity in a NADPH-P-450 reductase-deficient strain.

CYB5 overexpression suppresses ketoconazole hypersensitivity of a P450-reductase-deficient strain.

yeast cytochrome b5-encoding gene (CYB5), which encodes a 120-amino-acid (aa) protein, is required and sufficient for the suppressor effect.

17Nodes

16Parts

0Variant Sets

0Variants

16Annotons

18Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:ergosterol_biosynthesis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

7 conformance issue(s):

squalene_to_lanosterol → sterol_commitment_squalene_to_lanosterol [info]
connection topology does not match the template motif
lanosterol_to_ergosterol → cholesterol_synthesis_post_lanosterol [info]
tier count 10 does not match template 9 (cholesterol_synthesis_post_lanosterol)
lanosterol_to_ergosterol → cholesterol_synthesis_post_lanosterol [info]
tier 6 function GO:0003838 does not match template GO:0047750
lanosterol_to_ergosterol → cholesterol_synthesis_post_lanosterol [info]
tier 7 function GO:0000247 does not match template GO:0050046
lanosterol_to_ergosterol → cholesterol_synthesis_post_lanosterol [info]
tier 8 function GO:0050046 does not match template GO:0047598
lanosterol_to_ergosterol → cholesterol_synthesis_post_lanosterol [info]
tier 9 function GO:0000249 does not match template GO:0050614
lanosterol_to_ergosterol → cholesterol_synthesis_post_lanosterol [info]
connection topology does not match the template motif

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

squalene_to_lanosterol → lanosterol_to_ergosterol [NOT_CHECKED]

Function consistency and core coverage

34 gene-function check(s) reflected in core functions · 0 conflict(s) · 6 evidence or coverage gap(s) (50 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
erg9_activity	ERG9 (Saccharomyces cerevisiae) UniProtKB:P29704 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).
erg9_activity	erg9 (Schizosaccharomyces pombe) UniProtKB:P36596 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).
erg1_activity	ERG1 (Saccharomyces cerevisiae) UniProtKB:P32476 Family Representative	squalene monooxygenase activity GO:0004506	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg1_activity	erg1 (Schizosaccharomyces pombe) UniProtKB:Q9C1W3 Family Representative	squalene monooxygenase activity GO:0004506	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg7_activity	ERG7 (Saccharomyces cerevisiae) UniProtKB:P38604 Family Representative	lanosterol synthase activity GO:0000250	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg7_activity	erg7 (Schizosaccharomyces pombe) UniProtKB:Q10231 Family Representative	lanosterol synthase activity GO:0000250	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg11_activity	ERG11 (Saccharomyces cerevisiae) UniProtKB:P10614 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).
erg11_activity	erg11 (Schizosaccharomyces pombe) UniProtKB:Q09736 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).
erg24_activity	ERG24 (Saccharomyces cerevisiae) UniProtKB:P32462 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).
erg24_activity	erg24 (Schizosaccharomyces pombe) UniProtKB:Q09195 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).
erg25_activity	ERG25 (Saccharomyces cerevisiae) UniProtKB:P53045 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).
erg25_activity	erg25 (Schizosaccharomyces pombe) UniProtKB:Q9UUH4 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).
erg28_scaffold_activity	ERG28 (Saccharomyces cerevisiae) UniProtKB:P40030 Family Representative	protein-macromolecule adaptor activity GO:0030674	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg28_scaffold_activity	erg28 (Schizosaccharomyces pombe) UniProtKB:O74820 Family Representative	protein-macromolecule adaptor activity GO:0030674	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg26_activity	ERG26 (Saccharomyces cerevisiae) UniProtKB:P53199 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).
erg26_activity	erg26 (Schizosaccharomyces pombe) UniProtKB:O43050 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).
erg27_activity	ERG27 (Saccharomyces cerevisiae) UniProtKB:Q12452 Family Representative	3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activity GO:0000253	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg27_activity	erg27 (Schizosaccharomyces pombe) UniProtKB:O74732 Family Representative	3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activity GO:0000253	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg6_activity	ERG6 (Saccharomyces cerevisiae) UniProtKB:P25087 Family Representative	sterol 24-C-methyltransferase activity GO:0003838	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg6_activity	erg6 (Schizosaccharomyces pombe) UniProtKB:O14321 Family Representative	sterol 24-C-methyltransferase activity GO:0003838	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg2_activity	ERG2 (Saccharomyces cerevisiae) UniProtKB:P32352 Family Representative	C-8 sterol isomerase activity GO:0000247	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg2_activity	erg2 (Schizosaccharomyces pombe) UniProtKB:P87113 Family Representative	C-8 sterol isomerase activity GO:0000247	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg3_activity	ERG3 (Saccharomyces cerevisiae) UniProtKB:P32353 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).
erg3_activity	erg31 (Schizosaccharomyces pombe) UniProtKB:O94457 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).
erg3_activity	erg32 (Schizosaccharomyces pombe; redundant paralog) UniProtKB:O13666 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).
erg5_activity	ERG5 (Saccharomyces cerevisiae) UniProtKB:P54781 Family Representative	C-22 sterol desaturase (NADPH) activity GO:0000249	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg5_activity	erg5 (Schizosaccharomyces pombe) UniProtKB:O13820 Family Representative	C-22 sterol desaturase (NADPH) activity GO:0000249	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg4_activity	ERG4 (Saccharomyces cerevisiae) UniProtKB:P25340 Family Representative	Delta24(24-1) sterol reductase activity GO:0000246	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg4_activity	erg4 / sts1 (Schizosaccharomyces pombe) UniProtKB:P36209 Family Representative	Delta24(24-1) sterol reductase activity GO:0000246	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ncp1_activity	NCP1 (Saccharomyces cerevisiae) UniProtKB:P16603 Family Representative	NADPH-hemoprotein reductase activity GO:0003958	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ncp1_activity	ccr1 (Schizosaccharomyces pombe) UniProtKB:P36587 Family Representative	NADPH-hemoprotein reductase activity GO:0003958	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyb5_activity	CYB5 (Saccharomyces cerevisiae) UniProtKB:P40312 Family Representative	electron transfer activity GO:0009055	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyb5_activity	cyb502 (Schizosaccharomyces pombe; SPBC29A10.16c) UniProtKB:O94391 Family Representative	electron transfer activity GO:0009055	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyb5_activity	oca8 (Schizosaccharomyces pombe) UniProtKB:Q9USM6 Family Representative	electron transfer activity GO:0009055	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
erg9_activity	Squalene synthase family (FDFT1/ERG9) PANTHER:PTHR11626:SF2 Family	squalene synthase [NAD(P)H] activity GO:0051996	Family Supported Family review supports GO:0051996 for PANTHER:PTHR11626:SF2. 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.
erg1_activity	Squalene monooxygenase family (SQLE/ERG1) PANTHER:PTHR10835:SF0 Family	squalene monooxygenase activity GO:0004506	Family Supported Family review supports GO:0004506 for PANTHER:PTHR10835:SF0. 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.
erg7_activity	Lanosterol synthase subfamily of oxidosqualene cyclases (LSS/ERG7) PANTHER:PTHR11764:SF20 Family	lanosterol synthase activity GO:0000250	Family Supported Family review supports GO:0000250 for PANTHER:PTHR11764:SF20. 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.
erg11_activity	Sterol 14alpha-demethylase family (CYP51) Family	sterol 14-demethylase activity GO:0008398	Family Id Missing The family has no identifier linking it to a curated family review.
erg24_activity	Delta14-sterol reductase subfamily (ERG24/TM7SF2) 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).
erg25_activity	C-4 methylsterol oxidase (MSMO1/ERG25 type) Family	C-4 methylsterol oxidase activity GO:0000254	Family Id Missing The family has no identifier linking it to a curated family review.
erg28_scaffold_activity	Erg28 family PANTHER:PTHR15451 Family	protein-macromolecule adaptor activity GO:0030674	Family Supported Family review supports GO:0030674 FAMILY_WIDE. Asserted by ergosterol_biosynthesis; accepted by ERG28 and erg28.
erg26_activity	NSDHL/ERG26-type sterol C-4 decarboxylase 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.
erg27_activity	Fungal 3-ketosteroid reductase ERG27 subfamily PANTHER:PTHR43647:SF1 Family	3-beta-hydroxysteroid 3-dehydrogenase (NADP+) activity GO:0000253	Family Supported Family review supports GO:0000253 FAMILY_WIDE. Asserted by ergosterol_biosynthesis; accepted by ERG27 and erg27.
erg6_activity	Sterol 24-C-methyltransferase (SMT) family Family	sterol 24-C-methyltransferase activity GO:0003838	Family Id Missing The family has no identifier linking it to a curated family review.
erg2_activity	Fungal ERG2-type C-8 sterol isomerase (sigma-1-receptor-related) Family	C-8 sterol isomerase activity GO:0000247	Family Id Missing The family has no identifier linking it to a curated family review.
erg3_activity	Delta7-sterol C-5 desaturase (SC5D/ERG3 type) Family	delta7-sterol 5(6)-desaturase activity GO:0050046	Family Id Missing The family has no identifier linking it to a curated family review.
erg5_activity	Fungal CYP61 C-22 sterol desaturase subfamily PANTHER:PTHR24286:SF228 Family	C-22 sterol desaturase (NADPH) activity GO:0000249	Family Supported Family review supports GO:0000249 for PANTHER:PTHR24286:SF228. Fungal CYP61 (SF228), as ergosterol_biosynthesis selects.
erg4_activity	Fungal Delta24(28)-sterol reductase ERG4 subfamily PANTHER:PTHR21257:SF31 Family	Delta24(24-1) sterol reductase activity GO:0000246	Family Supported Family review supports GO:0000246 for PANTHER:PTHR21257:SF31. Fungal ERG4 (SF31, selected by ergosterol_biosynthesis) and the Aspergillus ERG4B subfamily (SF48).
ncp1_activity	NADPH-cytochrome P450 reductase (CPR) PANTHER:PTHR19384:SF17 Family	NADPH-hemoprotein reductase activity GO:0003958	Family Supported Family review supports GO:0003958 for PANTHER:PTHR19384:SF17. Safe for the CPR subfamilies, including SF17 used by the ergosterol module for NCP1 and ccr1. Not for MTRR, NDOR1/TAH18, CysJ or MET10, whose acceptors are methionine synthase, the Fe-S assembly machinery and sulfite reductase hemoproteins. SF84 (MTRR) is listed because MTRR shows NADPH-dependent cytochrome c reduction in vitro and its review accepts the term, although its physiological partner is methionine synthase.
cyb5_activity	Cytochrome b5 family PANTHER:PTHR19359 Family	electron transfer activity GO:0009055	Family Supported Family review supports GO:0009055 FAMILY_WIDE. Asserted by ergosterol_biosynthesis; core function of CYB5, cyb502 and oca8.

Gene-review completeness (34/34 grounded genes reviewed)

33 complete review(s) · 16 with deep research · 0 missing review · 18 reviewed but lacking deep research

Gene	Review	Complete	Deep research
ccr1 P36587	✓	✓	✗
CYB5 P40312	✓	✓	✓
cyb502 O94391	✓	✓	✗
ERG1 P32476	✓	✓	✓
erg1 Q9C1W3	✓	✓	✗
ERG11 P10614	✓	26/27	✓
erg11 Q09736	✓	✓	✗
ERG2 P32352	✓	✓	✓
erg2 P87113	✓	✓	✗
ERG24 P32462	✓	✓	✓
erg24 Q09195	✓	✓	✗
ERG25 P53045	✓	✓	✓
erg25 Q9UUH4	✓	✓	✗
erg26 O43050	✓	✓	✗
ERG26 P53199	✓	✓	✓
erg27 O74732	✓	✓	✗
ERG27 Q12452	✓	✓	✓
erg28 O74820	✓	✓	✗
ERG28 P40030	✓	✓	✓
ERG3 P32353	✓	✓	✓
erg31 O94457	✓	✓	✗
erg32 O13666	✓	✓	✗
ERG4 P25340	✓	✓	✓
erg4 P36209	✓	✓	✗
erg5 O13820	✓	✓	✗
ERG5 P54781	✓	✓	✓
erg6 O14321	✓	✓	✗
ERG6 P25087	✓	✓	✓
ERG7 P38604	✓	✓	✓
erg7 Q10231	✓	✓	✗
ERG9 P29704	✓	✓	✓
erg9 P36596	✓	✓	✗
NCP1 P16603	✓	✓	✓
oca8 Q9USM6	✓	✓	✗

Tree

Ergosterol biosynthesis (FPP -> ergosterol)Metabolic Pathwayergosterol_biosynthesis

Parts
1. 1. sterol commitment (FPP -> squalene -> lanosterol), shared with animals
2. Sterol commitment (2 FPP -> squalene -> 2,3-oxidosqualene -> lanosterol)Metabolic Pathwaysqualene_to_lanosterol
  
  Parts
  1. 1. squalene synthesis (committed sterol step)
  2. 2 farnesyl diphosphate + NAD(P)H to squalene (via presqualene diphosphate)Reactionerg9_step
    
    Annotons
    
    squalene synthase (ERG9) Family: Squalene synthase family (FDFT1/ERG9)
  3. 2. squalene epoxidation (allylamine target)
  4. squalene + O2 + reduced P450 reductase to (S)-2,3-epoxysqualeneReactionerg1_step
    
    Annotons
    
    squalene epoxidase (ERG1) Family: Squalene monooxygenase family (SQLE/ERG1)
  5. 3. cyclization to lanosterol
  6. (S)-2,3-epoxysqualene to lanosterolReactionerg7_step
    
    Annotons
    
    lanosterol synthase (ERG7) Family: Lanosterol synthase subfamily of oxidosqualene cyclases (LSS/ERG7)
3. 2. post-lanosterol demethylation and ergosterol-specific tail
4. Lanosterol -> zymosterol -> ergosterolMetabolic Pathwaylanosterol_to_ergosterol
  
  Parts
  1. 1. 14alpha-demethylation (azole target)
  2. lanosterol to 4,4-dimethylcholesta-8,14,24-trienol + formateReactionerg11_step
    
    Annotons
    
    sterol 14alpha-demethylase (ERG11/CYP51) Family: Sterol 14alpha-demethylase family (CYP51)
  3. 2. Delta14 reduction (morpholine target)
  4. 4,4-dimethylcholesta-8,14,24-trienol + NADPH to 4,4-dimethylzymosterolReactionerg24_step
    
    Annotons
    
    Delta14-sterol reductase (ERG24) Family: Delta14-sterol reductase subfamily (ERG24/TM7SF2)
  5. 3. C-4 methyl oxidation (C-4 demethylation complex)
  6. 4-methyl sterol to 4-carboxy sterol (three successive oxidations; twice per sterol)Protein Complexerg25_step
    
    Annotons
    
    C-4 methylsterol oxidase (ERG25) Family: C-4 methylsterol oxidase (MSMO1/ERG25 type)
    
    C-4 demethylation complex scaffold (ERG28) Family: Erg28 family
  7. 4. C-4 decarboxylation / 3-oxidation
  8. 4alpha-carboxy sterol + NAD(P)+ to 3-keto sterol + CO2Reactionerg26_step
    
    Annotons
    
    sterol-4alpha-carboxylate 3-dehydrogenase, decarboxylating (ERG26) Family: NSDHL/ERG26-type sterol C-4 decarboxylase
  9. 5. 3-keto reduction (completes each C-4 demethylation round)
  10. 3-keto sterol + NADPH to 3beta-hydroxy sterol (4-methylzymosterol, then zymosterol)Reactionerg27_step
    
    Annotons
    
    3-ketosteroid reductase (ERG27) Family: Fungal 3-ketosteroid reductase ERG27 subfamily
  11. 6. C-24 methylation (fungal-specific)
  12. zymosterol + SAM to fecosterol + SAHReactionerg6_step
    
    Annotons
    
    sterol 24-C-methyltransferase (ERG6) Family: Sterol 24-C-methyltransferase (SMT) family
  13. 7. Delta8 -> Delta7 isomerisation
  14. fecosterol to episterolReactionerg2_step
    
    Annotons
    
    C-8 sterol isomerase (ERG2) Family: Fungal ERG2-type C-8 sterol isomerase (sigma-1-receptor-related)
  15. 8. C-5 desaturation
  16. episterol to ergosta-5,7,24(28)-trienolReactionerg3_step
    
    Annotons
    
    C-5 sterol desaturase (ERG3) Family: Delta7-sterol C-5 desaturase (SC5D/ERG3 type)
  17. 9. C-22 desaturation (fungal-specific)
  18. ergosta-5,7,24(28)-trienol to ergosta-5,7,22,24(28)-tetraenolReactionerg5_step
    
    Annotons
    
    C-22 sterol desaturase (ERG5/CYP61) Family: Fungal CYP61 C-22 sterol desaturase subfamily
  19. 10. Delta24(28) reduction (final step)
  20. ergosta-5,7,22,24(28)-tetraenol + NADPH to ergosterolReactionerg4_step
    
    Annotons
    
    Delta24(28)-sterol reductase (ERG4) Family: Fungal Delta24(28)-sterol reductase ERG4 subfamily
5. 3. electron supply to the sterol oxygenases
6. Microsomal electron supply (NADPH-P450 reductase and cytochrome b5)Modulesterol_oxygenase_electron_supply
  
  Annotons
  - NADPH-cytochrome P450 reductase (NCP1) Family: NADPH-cytochrome P450 reductase (CPR)
  - microsomal cytochrome b5 (CYB5) Family: Cytochrome b5 family

Details

Context

FungiNCBITaxon:4751

endoplasmic reticulum membraneGO:0005789

Ergosterol biosynthesis (FPP -> ergosterol)Metabolic Pathwayergosterol_biosynthesis

ergosterol biosynthetic processGO:0006696

Context

FungiNCBITaxon:4751

endoplasmic reticulum membraneGO:0005789

New module that merges six YeastCyc frames into one pathway, from FPP to ergosterol: ERGOSTEROL-SYN-PWY-1 (superpathway), PWY3O-31704, PWY-5670-1 (epoxysqualene), PWY-6132 (lanosterol), PWY-6074-1 (zymosterol) and PWY-6075-1 (ergosterol I). The mevalonate and FPP-synthase segments of the superpathway are the separate mevalonate_pathway and isoprenoid_diphosphate_biosynthesis modules. The ERG10 review places ERG10 in the mevalonate segment that feeds this pathway. Structure. Part 1 (ERG9, ERG1, ERG7) conforms to sterol_commitment_squalene_to_lanosterol with identical tier functions; the only deviation is the connection type. Part 2 is one ordered 10-tier post-lanosterol bundle that conforms with deviations to cholesterol_synthesis_post_lanosterol. The shared core is CYP51 (ERG11), the C-4 methyl oxidase (ERG25 = MSMO1), the C-4 decarboxylase (ERG26 = NSDHL), a functionally equivalent but nonhomologous Delta8-Delta7 isomerase (ERG2 vs EBP) and the C-5 desaturase (ERG3 = SC5D). The fungal-specific steps are ERG6 (C-24 methylation), ERG5 (CYP61 C-22 desaturation) and ERG4 (Delta24(28) reduction), which replaces the animal DHCR7. ERG24 and ERG27 are explicit tiers here but abbreviated in the template. YeastCyc corrections. ERG28 (C-4 demethylation scaffold), NCP1 (P450 reductase) and CYB5 (cytochrome b5) were added; YeastCyc does not list them. The three ERG28-family and C-4 complex members are grounded on PMID:12119386, PMID:15522820 and PMID:11160377. DAP1 (heme-binding stabiliser of Erg11, PMID:15713626) is recorded here as a regulator but not modelled as a part. Compartments: YeastCyc-derived GO-CAMs place every activity in cytosol. Here the enzymes are on the ER membrane, and Erg7 is also on lipid droplets (PMID:12842197). Ordering: ERG6 acts on zymosterol after C-4 demethylation, and ERG3 -> ERG5 -> ERG4 is the canonical YeastCyc order. GO-CAM disagreements: (1) all SGD conversions use cytosol; (2) ERG2 (RXN3O-203) is typed GO:0003674 everywhere and ERG5 (RXN3O-9828) is typed GO:0003674 in PWY-6075-1 and the superpathway; (3) PWY-6074-1 has a self-loop causal edge on RXN3O-9822; (4) the PomBase model types the C-5 desaturases erg31/erg32 with GO:0000248 "C-5 sterol desaturase activity", whose GO definition actually describes the C-22 desaturation (ERG5) reaction (5,7,24(28)-ergostatrienol -> 5,7,22,24(28)-ergostatetraenol); GO:0050046 is the correct Delta7-sterol 5(6)-desaturase term and is used here (raise with GO); (5) the PomBase model lacks an erg24 -> erg25 causal edge and wires cytochrome b5 only to erg31/erg32, not to erg25. Sterol esterification (ARE1/ARE2), steryl acetate deacetylation (SAY1) and sterol transport (LTC1 etc.), which are in the PomBase model, are outside this module.

Connections

squalene_to_lanosterol -> lanosterol_to_ergosterol Precedes

Lanosterol from ERG7 is the substrate of ERG11.

erg27_activity -> erg7_step Positively Regulates

Erg27 binds lanosterol synthase Erg7, protects it from degradation and is required for its activity in lipid particles (S. cerevisiae).

PMID:12842197

In yeast sterol biosynthesis the 3-keto reductase protein (Erg27p) is required for oxidosqualene cyclase (Erg7p) activity.

Erg27 co-immunoprecipitates with Erg7 and prevents its digestion.

we present evidence that Erg27p interacts with Erg7p, facilitating the association of Erg7p with lipid particles (LPs) and preventing digestion of Erg7p both in the endoplasmic reticulum (ER) and LPs.

ncp1_activity -> erg1_step Provides Input For

Reduced P450 reductase is a co-substrate of squalene epoxidase.

ncp1_activity -> erg11_step Provides Input For

Reduced P450 reductase supplies the three oxidations of CYP51.

ncp1_activity -> erg5_step Provides Input For

Reduced P450 reductase supplies the CYP61 C-22 desaturase.

cyb5_activity -> erg25_step Provides Input For

Ferrocytochrome b5 supplies the C-4 methyl oxidase.

cyb5_activity -> erg3_step Provides Input For

Ferrocytochrome b5 supplies the C-5 desaturase.

Part 1: sterol commitment (FPP -> squalene -> lanosterol), shared with animals

Sterol commitment (2 FPP -> squalene -> 2,3-oxidosqualene -> lanosterol)Metabolic Pathwaysqualene_to_lanosterol

Connections

erg9_step -> erg1_step Precedes

Squalene from ERG9 is epoxidised by ERG1.

erg1_step -> erg7_step Precedes

2,3-Oxidosqualene from ERG1 is cyclised by ERG7 to lanosterol.

Part 1: squalene synthesis (committed sterol step)

2 farnesyl diphosphate + NAD(P)H to squalene (via presqualene diphosphate)Reactionerg9_step

Annotons

squalene synthase (ERG9)

erg9_activity

Participant: Family: Squalene synthase family (FDFT1/ERG9)

Family:

Squalene synthase family (FDFT1/ERG9)

Representative Members: ERG9 (Saccharomyces cerevisiae)UniProtKB:P29704 erg9 (Schizosaccharomyces pombe)UniProtKB:P36596

Function

squalene synthase [NAD(P)H] activityGO:0051996

Substrates: (2E,6E)-farnesyl diphosphate (x2) NAD(P)H

Products: squalene (via presqualene diphosphate) diphosphate

Locations

endoplasmic reticulum membraneGO:0005789

First committed sterol step, diverting FPP from the branched isoprenoid pool (dolichol, ubiquinone, prenylation) to sterols.

Part 2: squalene epoxidation (allylamine target)

squalene + O2 + reduced P450 reductase to (S)-2,3-epoxysqualeneReactionerg1_step

Annotons

squalene epoxidase (ERG1)

erg1_activity

Participant: Family: Squalene monooxygenase family (SQLE/ERG1)

Family:

Squalene monooxygenase family (SQLE/ERG1)PANTHER:PTHR10835:SF0

Representative Members: ERG1 (Saccharomyces cerevisiae)UniProtKB:P32476 erg1 (Schizosaccharomyces pombe)UniProtKB:Q9C1W3

Function

squalene monooxygenase activityGO:0004506

Substrates: squalene O2 reduced [NADPH-hemoprotein reductase]

Products: (S)-2,3-epoxysqualene (2,3-oxidosqualene)

Locations

endoplasmic reticulum membraneGO:0005789

FAD-dependent epoxidation of squalene; target of allylamine antifungals (terbinafine).

Part 3: cyclization to lanosterol

(S)-2,3-epoxysqualene to lanosterolReactionerg7_step

Annotons

lanosterol synthase (ERG7)

erg7_activity

Participant: Family: Lanosterol synthase subfamily of oxidosqualene cyclases (LSS/ERG7)

Family:

Lanosterol synthase subfamily of oxidosqualene cyclases (LSS/ERG7)PANTHER:PTHR11764:SF20

Representative Members: ERG7 (Saccharomyces cerevisiae)UniProtKB:P38604 erg7 (Schizosaccharomyces pombe)UniProtKB:Q10231

Function

lanosterol synthase activityGO:0000250

Substrates: (S)-2,3-epoxysqualene

Products: lanosterol

Locations

lipid dropletGO:0005811 endoplasmic reticulum membraneGO:0005789

Polycyclization of 2,3-oxidosqualene to lanosterol, the first cyclic sterol. In budding yeast Erg7 requires the C-4 3-ketoreductase Erg27 for stability and activity.

Part 2: post-lanosterol demethylation and ergosterol-specific tail

Lanosterol -> zymosterol -> ergosterolMetabolic Pathwaylanosterol_to_ergosterol

Tiers 1-5 (ERG11, ERG24, ERG25, ERG26, ERG27) convert lanosterol to zymosterol (YeastCyc PWY-6074-1, GO:0036197) and correspond to the demethylation core of the animal post-lanosterol pathway; tiers 6-10 (ERG6, ERG2, ERG3, ERG5, ERG4) are the fungal tail from zymosterol to ergosterol (YeastCyc PWY-6075-1).

Connections

erg11_step -> erg24_step Precedes

erg24_step -> erg25_step Precedes

erg25_step -> erg26_step Precedes

erg26_step -> erg27_step Precedes

The 3-keto sterol from ERG26 is reduced by ERG27; after the first round the 4alpha-methyl sterol returns to ERG25 for the second C-4 methyl.

erg27_step -> erg6_step Precedes

Zymosterol from the second C-4 demethylation round is methylated at C-24 by ERG6.

erg6_step -> erg2_step Precedes

erg2_step -> erg3_step Precedes

erg3_step -> erg5_step Precedes

erg5_step -> erg4_step Precedes

Part 1: 14alpha-demethylation (azole target)

lanosterol to 4,4-dimethylcholesta-8,14,24-trienol + formateReactionerg11_step

Annotons

sterol 14alpha-demethylase (ERG11/CYP51)

erg11_activity

Participant: Family: Sterol 14alpha-demethylase family (CYP51)

Family:

Sterol 14alpha-demethylase family (CYP51) No PANTHER id is asserted: PANTHER places CYP51 proteins in the broad PTHR24304 family (named for CYP7), as in the template module.

Representative Members: ERG11 (Saccharomyces cerevisiae)UniProtKB:P10614 erg11 (Schizosaccharomyces pombe)UniProtKB:Q09736

Function

sterol 14-demethylase activityGO:0008398

Substrates: lanosterol O2 (x3) reduced [NADPH-hemoprotein reductase] (x3)

Products: 4,4-dimethylcholesta-8,14,24-trienol formate

Locations

endoplasmic reticulum membraneGO:0005789

Cytochrome P450 removing the 14alpha-methyl group as formate; the principal azole target. Stabilised by the heme-binding protein Dap1 (PMID:15713626).

Part 2: Delta14 reduction (morpholine target)

4,4-dimethylcholesta-8,14,24-trienol + NADPH to 4,4-dimethylzymosterolReactionerg24_step

Annotons

Delta14-sterol reductase (ERG24)

erg24_activity

Participant: Family: Delta14-sterol reductase subfamily (ERG24/TM7SF2)

Family:

Delta14-sterol reductase subfamily (ERG24/TM7SF2)PANTHER:PTHR21257:SF52 Subfamily of the ERG4/ERG24/DHCR7/LBR sterol reductase family PTHR21257, named for its human member TM7SF2.

Representative Members: ERG24 (Saccharomyces cerevisiae)UniProtKB:P32462 erg24 (Schizosaccharomyces pombe)UniProtKB:Q09195

Function

Delta14-sterol reductase activityGO:0050613

Substrates: 4,4-dimethylcholesta-8,14,24-trienol NADPH

Products: 4,4-dimethylzymosterol

Locations

endoplasmic reticulum membraneGO:0005789

NADPH-dependent reduction of the Delta14 bond created by CYP51; required for aerobic viability in S. cerevisiae.

Part 3: C-4 methyl oxidation (C-4 demethylation complex)

4-methyl sterol to 4-carboxy sterol (three successive oxidations; twice per sterol)Protein Complexerg25_step

Annotons

C-4 methylsterol oxidase (ERG25)

erg25_activity

Participant: Family: C-4 methylsterol oxidase (MSMO1/ERG25 type)

Family:

C-4 methylsterol oxidase (MSMO1/ERG25 type) No PANTHER id is asserted. ERG25 sits in the broad sterol-desaturase family PTHR11863 (used for MSMO1 in the template), but that family also contains C-5 desaturases and cholesterol 25-hydroxylase, and its family review does not grant C-4 methylsterol oxidase family-wide.

Representative Members: ERG25 (Saccharomyces cerevisiae)UniProtKB:P53045 erg25 (Schizosaccharomyces pombe)UniProtKB:Q9UUH4

Function

C-4 methylsterol oxidase activityGO:0000254

Substrates: 4,4-dimethylzymosterol, then 4alpha-methylzymosterol O2 ferrocytochrome b5

Products: 4alpha-carboxy sterol

Locations

endoplasmic reticulum membraneGO:0005789

Non-heme di-iron oxidase converting the C-4 methyl to a carboxylate (methyl -> hydroxymethyl -> formyl -> carboxy); acts twice per sterol.

C-4 demethylation complex scaffold (ERG28)

erg28_scaffold_activity

Participant: Family: Erg28 family

Family:

Erg28 familyPANTHER:PTHR15451

Representative Members: ERG28 (Saccharomyces cerevisiae)UniProtKB:P40030 erg28 (Schizosaccharomyces pombe)UniProtKB:O74820

Function

protein-macromolecule adaptor activityGO:0030674 Transmembrane scaffold that tethers Erg25, Erg26 and Erg27 into an ER-membrane C-4 demethylation complex and bridges it to Erg6 (and, by two-hybrid, to Erg11 and Erg1).

Locations

endoplasmic reticulum membraneGO:0005789

Non-catalytic ER-membrane scaffold of the C-4 demethylation complex; deletion is viable but slow-growing with a C-4 demethylation block.

Part 4: C-4 decarboxylation / 3-oxidation

4alpha-carboxy sterol + NAD(P)+ to 3-keto sterol + CO2Reactionerg26_step

Annotons

sterol-4alpha-carboxylate 3-dehydrogenase, decarboxylating (ERG26)

erg26_activity

Participant: Family: NSDHL/ERG26-type sterol C-4 decarboxylase

Family:

NSDHL/ERG26-type sterol C-4 decarboxylase No PANTHER id is asserted, as in the template (NSDHL): UniProt places ERG26 and erg26 in PTHR43245:SF51 with human NSDHL, but PANTHER's own classification files place them in PTHR10366:SF564.

Representative Members: ERG26 (Saccharomyces cerevisiae)UniProtKB:P53199 erg26 (Schizosaccharomyces pombe)UniProtKB:O43050

Function

3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activityGO:0000252

Substrates: 4alpha-carboxy-3beta-hydroxy sterol NAD(P)+

Products: 3-keto sterol (3-dehydro-4-methylzymosterol, then zymosterone) CO2

Locations

endoplasmic reticulum membraneGO:0005789

NAD(P)+-dependent 3-dehydrogenation with decarboxylation of the 4alpha-carboxy sterol; acts twice per sterol.

Part 5: 3-keto reduction (completes each C-4 demethylation round)

3-keto sterol + NADPH to 3beta-hydroxy sterol (4-methylzymosterol, then zymosterol)Reactionerg27_step

Annotons

3-ketosteroid reductase (ERG27)

erg27_activity

Participant: Family: Fungal 3-ketosteroid reductase ERG27 subfamily

Family:

Fungal 3-ketosteroid reductase ERG27 subfamilyPANTHER:PTHR43647:SF1

Representative Members: ERG27 (Saccharomyces cerevisiae)UniProtKB:Q12452 erg27 (Schizosaccharomyces pombe)UniProtKB:O74732

Function

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

Substrates: 3-keto sterol NADPH

Products: 3beta-hydroxy sterol (4alpha-methylzymosterol; zymosterol)

Locations

endoplasmic reticulum membraneGO:0005789

NADPH-dependent reduction of the 3-keto sterol back to the 3beta-ol, closing each C-4 demethylation round; after the second round the product is zymosterol. Also required for Erg7 activity in budding yeast (PMID:12842197). ERG27 is not in the same PANTHER family as the animal 3-ketosteroid reductase HSD17B7.

Part 6: C-24 methylation (fungal-specific)

zymosterol + SAM to fecosterol + SAHReactionerg6_step

Annotons

sterol 24-C-methyltransferase (ERG6)

erg6_activity

Participant: Family: Sterol 24-C-methyltransferase (SMT) family

Family:

Sterol 24-C-methyltransferase (SMT) family No PANTHER id is asserted: the PANTHER family containing ERG6 (PTHR44068, named for a zebrafish protein) also contains animal proteins, whereas animals lack sterol C-24 methylation.

Representative Members: ERG6 (Saccharomyces cerevisiae)UniProtKB:P25087 erg6 (Schizosaccharomyces pombe)UniProtKB:O14321

Function

sterol 24-C-methyltransferase activityGO:0003838

Substrates: zymosterol S-adenosyl-L-methionine

Products: fecosterol S-adenosyl-L-homocysteine

Locations

endoplasmic reticulum membraneGO:0005789

SAM-dependent C-24 methylation creating the C-28 methyl group that defines ergosterol; first fungal-specific step and branch point away from the cholesterol-type route.

Part 7: Delta8 -> Delta7 isomerisation

fecosterol to episterolReactionerg2_step

Annotons

C-8 sterol isomerase (ERG2)

erg2_activity

Participant: Family: Fungal ERG2-type C-8 sterol isomerase (sigma-1-receptor-related)

Family:

Fungal ERG2-type C-8 sterol isomerase (sigma-1-receptor-related) No PANTHER id is asserted: ERG2 belongs to PTHR10868 (sigma 1-type opioid receptor-related), whose animal members are not sterol isomerases; it is unrelated to the animal EBP isomerase family (PTHR14207) used in the template.

Representative Members: ERG2 (Saccharomyces cerevisiae)UniProtKB:P32352 erg2 (Schizosaccharomyces pombe)UniProtKB:P87113

Function

C-8 sterol isomerase activityGO:0000247

Substrates: fecosterol

Products: episterol

Locations

endoplasmic reticulum membraneGO:0005789

Moves the ring double bond from Delta8 to Delta7; a convergent analogue of animal EBP and a morpholine target.

Part 8: C-5 desaturation

episterol to ergosta-5,7,24(28)-trienolReactionerg3_step

Annotons

C-5 sterol desaturase (ERG3)

erg3_activity

Participant: Family: Delta7-sterol C-5 desaturase (SC5D/ERG3 type)

Family:

Delta7-sterol C-5 desaturase (SC5D/ERG3 type) No PANTHER id is asserted. ERG3 and S. pombe erg31/erg32 sit in the broad sterol-desaturase family PTHR11863 (used for SC5D in the template), which also contains C-4 methylsterol oxidases and cholesterol 25-hydroxylase.

Representative Members: ERG3 (Saccharomyces cerevisiae)UniProtKB:P32353 erg31 (Schizosaccharomyces pombe)UniProtKB:O94457 erg32 (Schizosaccharomyces pombe; redundant paralog)UniProtKB:O13666

Function

delta7-sterol 5(6)-desaturase activityGO:0050046

Substrates: episterol (Delta7-sterol) O2 ferrocytochrome b5

Products: ergosta-5,7,24(28)-trien-3beta-ol (Delta5,7-sterol)

Locations

endoplasmic reticulum membraneGO:0005789

Introduces the Delta5 bond (episterol -> ergosta-5,7,24(28)-trienol); orthologous to animal SC5D. erg3 mutations suppress the lethality of ERG11 disruption in S. cerevisiae (PMID:8277826).

Part 9: C-22 desaturation (fungal-specific)

ergosta-5,7,24(28)-trienol to ergosta-5,7,22,24(28)-tetraenolReactionerg5_step

Annotons

C-22 sterol desaturase (ERG5/CYP61)

erg5_activity

Participant: Family: Fungal CYP61 C-22 sterol desaturase subfamily

Family:

Fungal CYP61 C-22 sterol desaturase subfamilyPANTHER:PTHR24286:SF228

Representative Members: ERG5 (Saccharomyces cerevisiae)UniProtKB:P54781 erg5 (Schizosaccharomyces pombe)UniProtKB:O13820

Function

C-22 sterol desaturase (NADPH) activityGO:0000249

Substrates: ergosta-5,7,24(28)-trien-3beta-ol O2 reduced [NADPH-hemoprotein reductase]

Products: ergosta-5,7,22,24(28)-tetraen-3beta-ol

Locations

endoplasmic reticulum membraneGO:0005789

Cytochrome P450 introducing the side-chain Delta22 double bond; no animal counterpart in cholesterol synthesis.

Part 10: Delta24(28) reduction (final step)

ergosta-5,7,22,24(28)-tetraenol + NADPH to ergosterolReactionerg4_step

Annotons

Delta24(28)-sterol reductase (ERG4)

erg4_activity

Participant: Family: Fungal Delta24(28)-sterol reductase ERG4 subfamily

Family:

Fungal Delta24(28)-sterol reductase ERG4 subfamilyPANTHER:PTHR21257:SF31

Representative Members: ERG4 (Saccharomyces cerevisiae)UniProtKB:P25340 erg4 / sts1 (Schizosaccharomyces pombe)UniProtKB:P36209

Function

Delta24(24-1) sterol reductase activityGO:0000246

Substrates: ergosta-5,7,22,24(28)-tetraen-3beta-ol NADPH

Products: ergosterol

Locations

endoplasmic reticulum membraneGO:0005789

NADPH-dependent reduction of the Delta24(28) methylene to give ergosterol; a PTHR21257 paralog of ERG24 and animal DHCR7.

Part 3: electron supply to the sterol oxygenases

Microsomal electron supply (NADPH-P450 reductase and cytochrome b5)Modulesterol_oxygenase_electron_supply

The P450s (ERG11, ERG5) and the flavoprotein squalene epoxidase (ERG1) take electrons from NADPH-cytochrome P450 reductase; the non-heme di-iron C-4 methyl oxidase (ERG25) and C-5 desaturase (ERG3) take them from cytochrome b5. The supplies partly overlap: an NCP1 deletion is viable, and overexpressed CYB5 supports CYP51 when NCP1 is absent.

Annotons

NADPH-cytochrome P450 reductase (NCP1)

ncp1_activity

Participant: Family: NADPH-cytochrome P450 reductase (CPR)

Family:

NADPH-cytochrome P450 reductase (CPR)PANTHER:PTHR19384:SF17

Representative Members: NCP1 (Saccharomyces cerevisiae)UniProtKB:P16603 ccr1 (Schizosaccharomyces pombe)UniProtKB:P36587

Function

NADPH-hemoprotein reductase activityGO:0003958

Locations

endoplasmic reticulum membraneGO:0005789

Diflavin reductase passing NADPH electrons to ERG11, ERG5 and ERG1 (the "reduced [NADPH-hemoprotein reductase]" reactant in their YeastCyc and EC equations).

microsomal cytochrome b5 (CYB5)

cyb5_activity

Participant: Family: Cytochrome b5 family

Family:

Cytochrome b5 familyPANTHER:PTHR19359

Representative Members: CYB5 (Saccharomyces cerevisiae)UniProtKB:P40312 cyb502 (Schizosaccharomyces pombe; SPBC29A10.16c)UniProtKB:O94391 oca8 (Schizosaccharomyces pombe)UniProtKB:Q9USM6

Function

electron transfer activityGO:0009055

Locations

endoplasmic reticulum membraneGO:0005789

One-electron carrier supplying the C-4 methyl oxidase and C-5 desaturase (the "ferrocytochrome b5" reactant in their YeastCyc equations) and able to support CYP51 in the absence of NCP1.