Literature summary for 1.14.14.154 extracted from

Eddine, A.N.; von Kries, J.P.; Podust, M.V.; Warrier, T.; Kaufmann, S.H.; Podust, L.M.
X-ray structure of 4,4-dihydroxybenzophenone mimicking sterol substrate in the active site of sterol 14alpha-demethylase (CYP51) (2008), J. Biol. Chem., 283, 15152-15159.

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Application

Application	Comment	Organism
drug development	the enzyme is a primary target in treatment of fungal infections in organisms ranging from humans to plants, and development of more potent and selective CYP51 inhibitors is an important biological objective	Mycobacterium tuberculosis

Crystallization (Commentary)

Crystallization (Comment)	Organism
CYP51 in complex with 4,4'-dihydroxybenzophenone, enzyme in 20 mM Tris-HCl, pH 7.5, 200 mM NaCl, and 0.5 mM EDTA, is mixed with 4,4'-dihydroxybenzophenone, which is dissolved in Me2SO at 100 mM stock concentration, to final concentrations of 0.2 mM for protein and ligand resulting in needle-like crystals, larger crystals are obtained by hanging drop vapor diffusion method from 1.2 M lithium sulfate, 0.1 M HEPES, pH 7.5, and 2% isopropyl alcohol, cryoprotection by 20% glycerol, X-ray diffraction structure determination and analysis at 1.95 A resolution	Mycobacterium tuberculosis

Crystallization (Comment)

Organism

CYP51 in complex with 4,4'-dihydroxybenzophenone, enzyme in 20 mM Tris-HCl, pH 7.5, 200 mM NaCl, and 0.5 mM EDTA, is mixed with 4,4'-dihydroxybenzophenone, which is dissolved in Me2SO at 100 mM stock concentration, to final concentrations of 0.2 mM for protein and ligand resulting in needle-like crystals, larger crystals are obtained by hanging drop vapor diffusion method from 1.2 M lithium sulfate, 0.1 M HEPES, pH 7.5, and 2% isopropyl alcohol, cryoprotection by 20% glycerol, X-ray diffraction structure determination and analysis at 1.95 A resolution

Mycobacterium tuberculosis

Inhibitors

Inhibitors	Comment	Organism
11-ketoestrone	type I binding mechanism	Mycobacterium tuberculosis
2,7-dihydroxy-9-fluorenone	type I binding mechanism	Mycobacterium tuberculosis
4,4'-dihydroxybenzophenone	binds at the active site via a type I mechanism targeting the flexible region, binding structure and kinetics, overview	Mycobacterium tuberculosis
estriol	a substrate analogue	Mycobacterium tuberculosis
fluconazole	a clinical drug	Mycobacterium tuberculosis

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Fe2+	a cytochrome P450 enzyme	Mycobacterium tuberculosis
additional information	divalent metal ion is required for the catalytic reaction	Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.
24,25-dihydrolanosterol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis	-	(3beta,5alpha)-4,4-dimethylcholesta-8,14-dien-3-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
24,25-dihydrolanosterol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis H37Rv	-	(3beta,5alpha)-4,4-dimethylcholesta-8,14-dien-3-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
eburicol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis	-	?	-	?
eburicol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis H37Rv	-	?	-	?
lanosterol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis	-	4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
lanosterol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis H37Rv	-	4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
obtusifoliol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis	-	4alpha-methyl-5alpha-ergosta-8,14,24(28)-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
obtusifoliol + [reduced NADPH-hemoprotein reductase] + O2	Mycobacterium tuberculosis H37Rv	-	4alpha-methyl-5alpha-ergosta-8,14,24(28)-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?

Organism

Organism	UniProt	Comment	Textmining
Mycobacterium tuberculosis	P9WPP9	-	-
Mycobacterium tuberculosis H37Rv	P9WPP9	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
24,25-dihydrolanosterol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis	(3beta,5alpha)-4,4-dimethylcholesta-8,14-dien-3-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
24,25-dihydrolanosterol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis H37Rv	(3beta,5alpha)-4,4-dimethylcholesta-8,14-dien-3-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
eburicol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis	?	-	?
eburicol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis H37Rv	?	-	?
lanosterol + O2 + NADPH + H+	-	Mycobacterium tuberculosis	4,4-dimethyl-5alpha-cholesta-8,14,24-triene-3beta-ol + formate + NADP+ + H2O	-	?
lanosterol + O2 + NADPH + H+	-	Mycobacterium tuberculosis H37Rv	4,4-dimethyl-5alpha-cholesta-8,14,24-triene-3beta-ol + formate + NADP+ + H2O	-	?
lanosterol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis	4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
lanosterol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis H37Rv	4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
obtusifoliol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis	4alpha-methyl-5alpha-ergosta-8,14,24(28)-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?
obtusifoliol + [reduced NADPH-hemoprotein reductase] + O2	-	Mycobacterium tuberculosis H37Rv	4alpha-methyl-5alpha-ergosta-8,14,24(28)-trien-3beta-ol + formate + [oxidized NADPH-hemoprotein reductase] + H2O	-	?

Subunits

Subunits	Comment	Organism
More	three-dimensional modeling	Mycobacterium tuberculosis

Synonyms

Synonyms	Comment	Organism
CYP51	-	Mycobacterium tuberculosis
sterol 14alpha-demethylase	-	Mycobacterium tuberculosis

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Mycobacterium tuberculosis

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.5	-	assay at	Mycobacterium tuberculosis

Cofactor

Cofactor	Comment	Organism	Structure
cytochrome P450	a cytochrome P450 enzyme	Mycobacterium tuberculosis