This module contains two parallel therapeutic-vulnerability nodes rather than treating Erg1 and Cyp51 as consecutive reactions: many enzymatic intermediates separate squalene epoxidation from lanosterol demethylation. Each target has an INDIRECT_KNOWN_INTERMEDIATES edge to the shared ergosterol-production node, which then supports plasma-membrane organization. Azoles and allylamines point to the applicable local target with an evidence-bearing INHIBITS edge. Resistance is optional context and is not sufficient for positive target conformance.
As a high-precision operational curation boundary, a conforming disorder must identify a fungal infectious agent; model a disease-local Erg1 or Cyp51 target with the corresponding conserved GO process and molecular function; preserve the applicable target-to-ergosterol and ergosterol-to-membrane causal slice; and link a separately modeled azole or allylamine treatment to that local target with treatment_effect INHIBITS. The target edge needs cached class-mechanism evidence and the treatment needs disease-specific use evidence. These conditions are jointly sufficient for high-precision conformance to the applicable target branch, and each is required by this operational boundary. A Cyp51 conformer need not duplicate the Erg1 branch, and an Erg1 conformer need not duplicate the Cyp51 branch. A treatment mention without a local target, mixed antifungal regimens without agent-specific targeting, host steroidogenesis inhibition, incidental fungal complications, and resistance without the normal target pathway are insufficient. Polyene binding, echinocandin wall inhibition, and flucytosine antimetabolism belong to their dedicated modules. This boundary is an operational conformance rule, not a claim that treatment is biologically necessary for the fungal pathway to exist.
Squalene Epoxidation by Squalene Epoxidase (ERG1)
therapeutic vulnerability
Squalene epoxidase (Erg1) catalyzes an early committed reaction in sterol biosynthesis and is the molecular target of allylamines such as terbinafine. Inhibiting this enzyme causes squalene accumulation and ergosterol deficiency. This node represents the normal fungal enzyme activity that is therapeutically vulnerable, not the inhibited state.
Downstream
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Ergosterol Production
The Erg1-catalyzed early sterol step supplies intermediates that proceed through multiple reactions to ergosterol production.
Show evidence (1 reference)
"Terbinafine (Lamisil) has primarily fungicidal action against many fungi as a result of its specific mechanism of squalene epoxidase inhibition."
Biochemical evidence identifies squalene epoxidase as the allylamine target represented by this therapeutic-vulnerability node.
Lanosterol 14-alpha-Demethylation by CYP51 (ERG11)
therapeutic vulnerability
Sterol 14-alpha-demethylase (Cyp51, commonly encoded by ERG11 in fungi) catalyzes demethylation in the ergosterol pathway and is the molecular target of imidazole and triazole antifungals. This node represents the normal fungal enzyme activity that is therapeutically vulnerable; azole inhibition is represented by treatment edges.
Used by disorders
Aspergillosis
as Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase
Mycetoma
as Madurella Lanosterol 14-alpha-Demethylation by CYP51 (ERG11)
Otomycosis
as Otomycosis Fungal Lanosterol 14-alpha-Demethylation by CYP51 (ERG11)
Downstream
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Ergosterol Production
Cyp51-mediated lanosterol demethylation permits the remaining sterol reactions that yield ergosterol.
Show evidence (2 references)
"The fungal cytochrome P450 enzyme sterol 14α-demethylase (SDM) is a key enzyme in the ergosterol biosynthesis pathway."
Review evidence establishes fungal sterol 14-alpha-demethylase as a key enzyme in ergosterol biosynthesis.
"The binding of azoles to the active site of SDM results in a depletion of ergosterol, the accumulation of toxic intermediates and growth inhibition."
Review evidence identifies this enzyme as the azole target and states the consequences of inhibiting it.
Ergosterol Production
effector
Completion of fungal sterol biosynthesis yields ergosterol, the sterol that supplies the fungal plasma membrane. This shared output is downstream of both druggable entry points in the module.
Used by disorders
Mycetoma
as Madurella Ergosterol Production
Otomycosis
as Otomycosis Fungal Ergosterol Production
Downstream
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Ergosterol-Dependent Fungal Plasma-Membrane Organization
Ergosterol produced by the pathway is incorporated into the fungal plasma membrane, where it supports membrane organization.
Show evidence (1 reference)
"Treated fungi accumulate squalene while becoming deficient in ergosterol, an essential component of fungal cell membranes."
Biochemical evidence identifies ergosterol as the pathway product and an essential fungal-membrane component.
Ergosterol-Dependent Fungal Plasma-Membrane Organization
consequence
Ergosterol incorporation supports the organization and integrity of the fungal plasma membrane. This is the normal cellular output of the biosynthetic dependency, not an assertion of drug-induced depletion or cell death.
Used by disorders
Mycetoma
as Madurella Ergosterol-Dependent Plasma-Membrane Organization
Otomycosis
as Otomycosis Fungal Ergosterol-Dependent Plasma-Membrane Organization
Show evidence (1 reference)
"Treated fungi accumulate squalene while becoming deficient in ergosterol, an essential component of fungal cell membranes."
The evidence identifies ergosterol as an essential fungal-membrane component, supporting this cellular membrane-organization output.
Azole Target-Alteration, Overexpression, and Efflux Resistance
adaptive escape
Azole resistance can arise through amino-acid substitutions in sterol 14-alpha-demethylase that reduce drug binding, overexpression of the target, or increased drug efflux. A distinctive environmentally selected mechanism in Aspergillus fumigatus is the TR34/L98H allele — a tandem repeat in the cyp51A promoter combined with an L98H coding mutation — driven by agricultural azole-fungicide use and conferring cross-resistance to clinical triazoles even in azole-naive patients. This adaptive state is recorded independently of the normal biosynthetic graph because normal Cyp51 activity does not cause resistance. Together these routes explain why azole monotherapy can fail against a specific isolate, why azole susceptibility testing and surveillance matter, and why agent choice is mechanism-driven.
Show evidence (4 references)
"Diverse mechanisms are responsible for azole resistance. They include amino acid (AA) substitutions in SDM and overexpression of SDM and/or efflux pumps."
Review evidence directly supports the target-alteration, target-overexpression, and efflux mechanisms represented by this standalone adaptive state.
"Acquired resistance typically arises from mutations in the target enzyme, lanosterol 14-α-demethylase (Cyp51A), reduces the affinity of azole antifungal agents for the enzyme, rendering them less effective"
Review stating that acquired azole resistance arises from Cyp51A target mutations that reduce azole affinity — the principal acquired-resistance mechanism this node encodes. Evidence source is OTHER as this is a review.
"mechanisms involving the target proteins Cyp51 and ATP-binding cassette (ABC) or major facilitator superfamily (MFS) efflux pumps"
Confirms the two further resistance routes encoded here — Cyp51 target alteration and ABC/MFS drug-efflux pumps. Evidence source is OTHER as this is a review article.
+ 1 more reference