Molecule Information

General Information of the Molecule (ID: Mol02011)

• Name: Delta(7)-sterol 5(6)-desaturase ERG3 (ERG3) ,Candida albicans
• Synonyms: ERG3; orf19.767; CAALFM_C104770CA
• Molecule Type: Protein
• Gene Name: ERG3
• Gene ID: 3644776
• Sequence:
  MDIVLEICDYYLFDKVYADVFPKDGAVHEFLKPAIQSFSQIDFPSLPNLDSFDTNSTLIS
  SNNFNISNVNPATIPSYLFSKIASYQDKSEIYGLAPKFFPATDFINTSFLARSNIFRETL
  SLFIITTIFGWLLYFIVAYLSYVFVFDKKIFNHPRYLKNQMSLEIKRATTAIPVMVLLTI
  PFFLLELNGYSFLYLDINECTGGYKAILWQIPKFILFTDCGIYFLHRWLHWPSVYKVLHK
  PHHKWIVCTPFASHAFHPVDGFFQSLPYHLYPLLFPLHKVLYLFLFTFVNFWTVMIHDGS
  YWSNDPVVNGTACHTVHHLYFNYNYGQFTTLWDRLGNSYRRPDDSLFVKDAKAEEEKKIW
  KEQTRKMEEIRGEVEGKVDDREYVEQ
• Function: C-5 sterol desaturase; part of the third module of ergosterol biosynthesis pathway that includes the late steps of the pathwa. ERG3 catalyzes the introduction of a C-5 double bond in the B ring to produce 5-dehydroepisterol. The third module or late pathway involves the ergosterol synthesis itself through consecutive reactions that mainly occur in the endoplasmic reticulum (ER) membrane. Firstly, the squalene synthase ERG9 catalyzes the condensation of 2 farnesyl pyrophosphate moieties to form squalene, which is the precursor of all steroids. Squalene synthase is crucial for balancing the incorporation of farnesyl diphosphate (FPP) into sterol and nonsterol isoprene synthesis. Secondly, the squalene epoxidase ERG1 catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, which is considered to be a rate-limiting enzyme in steroid biosynthesis. Then, the lanosterol synthase ERG7 catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol core. In the next steps, lanosterol is transformed to zymosterol through a complex process involving various demethylation, reduction and desaturation reactions. The lanosterol 14-alpha-demethylase ERG11 (also known as CYP51) catalyzes C14-demethylation of lanosterol to produce 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol, which is critical for ergosterol biosynthesis. The C-14 reductase ERG24 reduces the C14=C15 double bond of 4,4-dimethyl-cholesta-8,14,24-trienol to produce 4,4-dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-cholesta-8,24-dienol is substrate of the C-4 demethylation complex ERG25-ERG26-ERG27 in which ERG25 catalyzes the three-step monooxygenation required for the demethylation of 4,4-dimethyl and 4alpha-methylsterols, ERG26 catalyzes the oxidative decarboxylation that results in a reduction of the 3-beta-hydroxy group at the C-3 carbon to an oxo group, and ERG27 is responsible for the reduction of the keto group on the C-3. ERG28 has a role as a scaffold to help anchor ERG25, ERG26 and ERG27 to the endoplasmic reticulum and ERG29 regulates the activity of the iron-containing C4-methylsterol oxidase ERG25. Then, the sterol 24-C-methyltransferase ERG6 catalyzes the methyl transfer from S-adenosyl-methionine to the C-24 of zymosterol to form fecosterol. The C-8 sterol isomerase ERG2 catalyzes the reaction which results in unsaturation at C-7 in the B ring of sterols and thus converts fecosterol to episterol. The sterol-C5-desaturase ERG3 then catalyzes the introduction of a C-5 double bond in the B ring to produce 5-dehydroepisterol. The C-22 sterol desaturase ERG5 further converts 5-dehydroepisterol into ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23) double bond in the sterol side chain. Finally, ergosta-5,7,22,24(28)-tetraen-3beta-ol is substrate of the C-24(28) sterol reductase ERG4 to produce ergosterol (Probable).
• Uniprot ID: ERG3_CANAL

Kingdom: Fungi
Phylum: Ascomycota
Class: Saccharomycetes
Order: Saccharomycetales
Family: Debaryomycetaceae
Genus: Candida
Species: Candida albicans

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Amphotericin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Amphotericin B
• Molecule Alteration: Mutation; p.H243N+p.T330A+p.D147G
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: In C. albicans, reduced amphotericin B susceptibility can occur through mutations in several ergosterol biosynthesis enzymes, including ERG2,ERG3, ERG5, ERG11.

Fluconazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Recurrent oropharyngeal candidiasis [1]

• Resistant Disease: Recurrent oropharyngeal candidiasis [ICD-11: 1F23.6]
• Resistant Drug: Fluconazole
• Molecule Alteration: Missense mutation; p.A168V+p.S191P+p.G261E+p.T329S+p.A353T
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Candida albicans strain; 5476
• Mechanism Description: A key mechanism through which C. albicans develops resistance to the azoles that is contingent upon stress responses is through alteration of the ergosterol biosynthesis pathway. Loss-of-function mutations in ERG3, which encodes a 5,6-desaturase, block the cellular accumulation of 14-alpha-methyl-3,6-diol, the toxic sterol intermediate that is otherwise produced as a result of Erg11 inhibition by the azoles.106 Alternatively, 14-alpha-methyl fecosterol is incorporated into the fungal cell membrane, allowing for continued growth and replication in the presence of azoles. Azole resistance in C. albicans has been associated with five missense mutations in ERG3 (A168V, S191P, G261E, T329S, and A353T) and two further nonsense mutations (Y325* and Y190*), leading to loss of function.

References

• Ref 1: Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond .Chem Rev. 2021 Mar 24;121(6):3390-3411. doi: 10.1021/acs.chemrev.0c00199. Epub 2020 May 22. 10.1021/acs.chemrev.0c00199