Protein: Lanosterol 14-alpha demethylase (LDM) (EC 1.14.14.154) (Cytochrome P450 51) (Cytochrome P450-14DM) (Cytochrome P450-LIA1) (CYPLI) (Ergosterol biosynthesis protein 11) (Sterol 14-alpha demethylase) (P10613)
Organism: Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast)
Function: Lanosterol 14-alpha demethylase; part of the third module of ergosterol biosynthesis pathway that includes the late steps of the pathway. 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 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).
Subcellular location: Endoplasmic reticulum membrane {ECO:0000305}; Single-pass membrane protein {ECO:0000255}.
Sequence: MAIVETVIDGINYFLSLSVTQQISILLGVPFVYNLVWQYLYSLRKDRAPLVFYWIPWFGSAASYGQQPYEFFESCRQKYGDVFSFMLLGKIMTVYLGPKGHEFVFNAKLSDVSAEDAYKHLTTPVFGKGVIYDCPNSRLMEQKKFAKFALTTDSFKRYVPKIREEILNYFVTDESFKLKEKTHGVANVMKTQPEITIFTASRSLFGDEMRRIFDRSFAQLYSDLDKGFTPINFVFPNLPLPHYWRRDAAQKKISATYMKEIKSRRERGDIDPNRDLIDSLLIHSTYKDGVKMTDQEIANLLIGILMGGQHTSASTSAWFLLHLGEKPHLQDVIYQEVVELLKEKGGDLNDLTYEDLQKLPSVNNTIKETLRMHMPLHSIFRKVTNPLRIPETNYIVPKGHYVLVSPGYAHTSERYFDNPEDFDPTRWDTAAAKANSVSFNSSDEVDYGFGKVSKGVSSPYLPFGGGRHRCIGEQFAYVQLGTILTTFVYNLRWTIDGYKVPDPDYSSMVVLPTEPAEIIWEKRETCMF
InterPro domains: - IPR036396: Cytochrome P450 superfamily (homologous_superfamily) [39-527]
- IPR017972: Cytochrome P450, conserved site (conserved_site) [463-472]
- IPR001128: Cytochrome P450 (family) [51-519]
- IPR050529: Cytochrome P450, sterol 14-alpha demethylase (family) [40-522]
- IPR002403: Cytochrome P450, E-class, group IV (family) [48-488]
Interaction partners: - Squalene synthase ERG9
- Lanosterol synthase
- Squalene epoxidase ERG1
- Delta
- Sterol 24-C-methyltransferase
- 3-keto-steroid reductase ERG27
- C-8 sterol isomerase ERG2
- Delta
- Ergosterol biosynthetic protein 28
- C-4 methylsterol oxidase
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0032451 (demethylase activity), GO:0005515 (protein binding), GO:0016491 (oxidoreductase activity), GO:0004497 (monooxygenase activity), GO:0016705 (oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen), GO:0016709 (oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0009987 (cellular process), GO:0009058 (biosynthetic process), GO:0044237 (cellular metabolic process), GO:0044281 (small molecule metabolic process), GO:0071704 (organic substance metabolic process), GO:0044238 (primary metabolic process), GO:1901615 (organic hydroxy compound metabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:1901576 (organic substance biosynthetic process), GO:0006629 (lipid metabolic process), GO:0044283 (small molecule biosynthetic process), GO:0044255 (cellular lipid metabolic process), GO:0044249 (cellular biosynthetic process), GO:0006066 (alcohol metabolic process), GO:0044107 (cellular alcohol metabolic process), GO:0016125 (sterol metabolic process), GO:1902652 (secondary alcohol metabolic process), GO:1901362 (organic cyclic compound biosynthetic process), GO:0008204 (ergosterol metabolic process), GO:0008202 (steroid metabolic process), GO:0097384 (cellular lipid biosynthetic process), GO:1901617 (organic hydroxy compound biosynthetic process), GO:0044108 (cellular alcohol biosynthetic process), GO:0046165 (alcohol biosynthetic process), GO:0008610 (lipid biosynthetic process), GO:0016128 (phytosteroid metabolic process), GO:0006696 (ergosterol biosynthetic process), GO:0006694 (steroid biosynthetic process), GO:0016126 (sterol biosynthetic process), GO:0016129 (phytosteroid biosynthetic process), GO:1902653 (secondary alcohol biosynthetic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0071944 (cell periphery), GO:0016020 (membrane), GO:0005886 (plasma membrane)