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Literature summary extracted from
- Crystal structures of full-length lanosterol 14alpha-demethylases of prominent fungal pathogens Candida albicans and Candida glabrata provide tools for antifungal discovery (2018), Antimicrob. Agents Chemother., 62, e01134-18.
Cloned(Commentary)
| EC Number | Cloned (Comment) | Organism |
|---|---|---|
| 1.14.14.154 | gene CaLDM, recombinant expression of His6-tagged enzyme in Saccharomyces cerevisiae | Candida albicans |
| 1.14.14.154 | gene CgLDM, recombinant expression of His6-tagged enzyme in Saccharomyces cerevisiae | Nakaseomyces glabratus |
Crystallization (Commentary)
| EC Number | Crystallization (Comment) | Organism |
|---|---|---|
| 1.14.14.154 | purified recombinant His6-tagged enzyme, X-ray diffraction structure determination and analysis at 2.4 A resolution, modelling | Nakaseomyces glabratus |
| 1.14.14.154 | purified recombinant His6-tagged enzyme, X-ray diffraction structure determination and analysis at 2.9 A resolution, modelling. The CaLDM6x02His structure is comprised of amino acid residues I25 to E524. The resolved structure lacks the N-terminal amino acid residues that contribute the MH, the turn between MH and TMH, and a single turn of the TMH (PDB ID 5V5Z) | Candida albicans |
Protein Variants
| EC Number | Protein Variants | Comment | Organism |
|---|---|---|---|
| 1.14.14.154 | additional information | analysis of phenotypes of several single-site mutations in CaLDM found in clinical isolates | Candida albicans |
Inhibitors
| EC Number | Inhibitors | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.14.14.154 | itraconazole | enzyme binding structure, analysis, overview | Candida albicans |  |
| 1.14.14.154 | itraconazole | enzyme binding structure, analysis, overview | Nakaseomyces glabratus | |
| 1.14.14.154 | additional information | LDM is the target of the azole drugs used widely to prevent or treat fungal infections in humans. Structure-directed discovery of antifungals that target LDMs of fungal pathogens | Candida albicans | |
| 1.14.14.154 | additional information | LDM is the target of the azole drugs used widely to prevent or treat fungal infections in humans. Structure-directed discovery of antifungals that target LDMs of fungal pathogens | Nakaseomyces glabratus | |
| 1.14.14.154 | posaconazole | enzyme binding structure, analysis, overview | Candida albicans | |
| 1.14.14.154 | posaconazole | enzyme binding structure, analysis, overview | Nakaseomyces glabratus | |
Localization
| EC Number | Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|---|
| 1.14.14.154 | endoplasmic reticulum membrane | eukaryotic CYP51 proteins of the endoplasmic reticulum are bitopic, membrane-monospanning, cytochrome P450 monooxygenases | Candida albicans | 5789 | - |
| 1.14.14.154 | endoplasmic reticulum membrane | eukaryotic CYP51 proteins of the endoplasmic reticulum are bitopic, membrane-monospanning, cytochrome P450 monooxygenases | Nakaseomyces glabratus | 5789 | - |
Metals/Ions
| EC Number | Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.14.14.154 | Fe2+ | in the cytochrome P450 heme | Candida albicans | |
| 1.14.14.154 | Fe2+ | in the cytochrome P450 heme | Nakaseomyces glabratus | |
Molecular Weight [Da]
| EC Number | Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
|---|---|---|---|---|
| 1.14.14.154 | 100000 | - |
recombinant enzyme, gel filtration | Candida albicans |
| 1.14.14.154 | 100000 | - |
recombinant enzyme, gel filtration | Nakaseomyces glabratus |
Natural Substrates/ Products (Substrates)
| EC Number | Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 1.14.14.154 | lanosterol + 3 [reduced NADPH-hemoprotein reductase] + 3 O2 | Candida albicans | - |
4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + formate + 3 [oxidized NADPH-hemoprotein reductase] + 4 H2O | - |
? | |
| 1.14.14.154 | lanosterol + 3 [reduced NADPH-hemoprotein reductase] + 3 O2 | Nakaseomyces glabratus | - |
4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + formate + 3 [oxidized NADPH-hemoprotein reductase] + 4 H2O | - |
? | |
| 1.14.14.154 | lanosterol + 3 [reduced NADPH-hemoprotein reductase] + 3 O2 | Candida albicans ATCC MYA-2876 | - |
4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + formate + 3 [oxidized NADPH-hemoprotein reductase] + 4 H2O | - |
? | |
Organism
| EC Number | Organism | UniProt | Comment | Textmining |
|---|---|---|---|---|
| 1.14.14.154 | Candida albicans | P10613 | - |
- |
| 1.14.14.154 | Candida albicans ATCC MYA-2876 | P10613 | - |
- |
| 1.14.14.154 | Nakaseomyces glabratus | - |
- |
- |
Purification (Commentary)
| EC Number | Purification (Comment) | Organism |
|---|---|---|
| 1.14.14.154 | recombinant His6-tagged enzyme from Saccharomyces cerevisiae by enzyme extraction from crude membranes with detergent n-decyl-beta-D-maltoside, nickel affinity chromatography, gel filtration, and ultrafiltration | Candida albicans |
| 1.14.14.154 | recombinant His6-tagged enzyme from Saccharomyces cerevisiae by enzyme extraction from crude membranes with detergent n-decyl-beta-D-maltoside, nickel affinity chromatography, gel filtration, and ultrafiltration | Nakaseomyces glabratus |
Substrates and Products (Substrate)
| EC Number | Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 1.14.14.154 | lanosterol + 3 [reduced NADPH-hemoprotein reductase] + 3 O2 | - |
Candida albicans | 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + formate + 3 [oxidized NADPH-hemoprotein reductase] + 4 H2O | - |
? | |
| 1.14.14.154 | lanosterol + 3 [reduced NADPH-hemoprotein reductase] + 3 O2 | - |
Nakaseomyces glabratus | 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + formate + 3 [oxidized NADPH-hemoprotein reductase] + 4 H2O | - |
? | |
| 1.14.14.154 | lanosterol + 3 [reduced NADPH-hemoprotein reductase] + 3 O2 | - |
Candida albicans ATCC MYA-2876 | 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + formate + 3 [oxidized NADPH-hemoprotein reductase] + 4 H2O | - |
? | |
Subunits
| EC Number | Subunits | Comment | Organism |
|---|---|---|---|
| 1.14.14.154 | dimer | 2 * 40000, about, recombinant enzyme, SDS-PAGE | Candida albicans |
| 1.14.14.154 | dimer | 2 * 40000, about, recombinant enzyme, SDS-PAGE | Nakaseomyces glabratus |
| 1.14.14.154 | additional information | the enzyme structure has a segment of the amphipathic membrane-associated helix (MH) commencing at L20, leading into the transmembrane helix (TMH, L28-L52), followed by the catalytic domain (PDB ID 5JLC) | Nakaseomyces glabratus |
Synonyms
| EC Number | Synonyms | Comment | Organism |
|---|---|---|---|
| 1.14.14.154 | CaLDM | - |
Candida albicans |
| 1.14.14.154 | CgLDM | - |
Nakaseomyces glabratus |
| 1.14.14.154 | ERG11 | - |
Candida albicans |
| 1.14.14.154 | lanosterol 14alpha-demethylase | - |
Candida albicans |
| 1.14.14.154 | lanosterol 14alpha-demethylase | - |
Nakaseomyces glabratus |
| 1.14.14.154 | LDM | - |
Candida albicans |
| 1.14.14.154 | LDM | - |
Nakaseomyces glabratus |
Cofactor
| EC Number | Cofactor | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.14.14.154 | cytochrome P450 | - |
Candida albicans | |
| 1.14.14.154 | cytochrome P450 | - |
Nakaseomyces glabratus | |
| 1.14.14.154 | heme | - |
Candida albicans | |
| 1.14.14.154 | heme | - |
Nakaseomyces glabratus | |
General Information
| EC Number | General Information | Comment | Organism |
|---|---|---|---|
| 1.14.14.154 | malfunction | targeting lanosterol 14alpha-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are not optimal for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. More than 140 mutations have been found in Candida albicans LDM (CaLDM), which confer azole resistance. The mutations are located within three distinct hot spots in LDM, phenotypes of several single-site mutations in CaLDM | Candida albicans |
| 1.14.14.154 | malfunction | targeting lanosterol 14alpha-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are not optimal for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. Mutations that confer azole resistance in clinical isolates have not been detected in Candida glabrata LDM (CgLDM) thus far | Nakaseomyces glabratus |
| 1.14.14.154 | additional information | structure-function analysis of the enzyme, structure-based insight into the LDM reaction mechanism, ligand binding pocket, overview. The full-length crystal structure of His-tagged shows that its catalytic domain has the same fold and binds itraconazole in conformations nearly identical to that of full-length, His-tagged enzyme ScLDM6 from Saccharomyces cerevisiae. There are minor structural differences within the ligand binding pocket (LBP) comprised of the substrate entry channel (SEC), the heme-containing active site, and a putative product exit channel (PPEC). Interaction analysis between the transmembrane domain and the catalytic domain, and structure comparisons of the enzymes from Saccharoyces cerevisiae, Candida albicans, and Candida glabrata, the most important of the conserved interactions is the hydrogen bond between the TMH Q46/Q47/Q38 side chain amide and the main chain carbonyl of Y61/Y62/Y53 in the adjacent long intervening loop of the ScLDM, CgLDM, and CaLDM structures | Candida albicans |
| 1.14.14.154 | additional information | structure-function analysis of the enzyme, structure-based insight into the LDM reaction mechanism, ligand binding pocket, overview. The full-length crystal structure of His-tagged shows that its catalytic domain has the same fold and binds itraconazole in conformations nearly identical to that of full-length, His-tagged enzyme ScLDM6 from Saccharomyces cerevisiae. There are minor structural differences within the ligand binding pocket (LBP) comprised of the substrate entry channel (SEC), the heme-containing active site, and a putative product exit channel (PPEC). Interaction analysis between the transmembrane domain and the catalytic domain, and structure comparisons of the enzymes from Saccharoyces cerevisiae, Candida albicans, and Candida glabrata, the most important of the conserved interactions is the hydrogen bond between the TMH Q46/Q47/Q38 side chain amide and the main chain carbonyl of Y61/Y62/Y53 in the adjacent long intervening loop of the ScLDM, CgLDM, and CaLDM structures | Nakaseomyces glabratus |
| 1.14.14.154 | physiological function | lanosterol 14alpha-demethylase (LDM) is a key enzyme in the ergosterol biosynthetic pathway of fungi | Candida albicans |
| 1.14.14.154 | physiological function | lanosterol 14alpha-demethylase (LDM) is a key enzyme in the ergosterol biosynthetic pathway of fungi | Nakaseomyces glabratus |
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