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Literature summary for 1.14.14.25 extracted from

  • Anderson, K.W.; Mast, N.; Hudgens, J.W.; Lin, J.B.; Turko, I.V.; Pikuleva, I.A.
    Cholesterol hydroxylase CYP46A1: mapping of the allosteric site for efavirenz, a drug that stimulates enzyme activity (2016), J. Biol. Chem., 291, 11876-81186.
    View publication on PubMedView publication on EuropePMC
Search for more literature for 1.14.14.25

Activating Compound

Activating Compound Comment Organism Structure
efavirenz EFV, activates the enzyme pharmacologically as a potential target for Alzheimers disease Homo sapiens
additional information pharmaceuticals activate CYP46A1 allosterically through binding to the site on the cytosolic protein surface, which is different from the enzyme active site facing the membrane Homo sapiens

Application

Application Comment Organism
medicine the enzyme is a potential target for Alzheimers disease as it can be activated pharmacologically by some of the marketed drugs as exemplified by efavirenz (EFV), the anti-HIV medication Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
gene CYP46A1, recombinant expression of wild-type full-length and mutant truncated forms of enzyme CYP46A1 in Escherichia coli Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
analysis of the crystal structure of cholesterol sulfate-bound CYP46A1, PDB ID 2Q9F Homo sapiens

Protein Variants

Protein Variants Comment Organism
K422A site-directed mutagenesis, the K422A mutant retains the ability to be activated by EFV, although to a slightly lower extent than wild-type CYP46A1. The cholesterol-bound K422A mutant also shows cooperativity similar to cholesterol-bound wild-type CYP46A1. Binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type Homo sapiens
K94A site-directed mutagenesis, the K94A replacement produces inactive P420 protein Homo sapiens
additional information construction of truncated enzyme mutant DELTA(3-27)CYP46A1 Homo sapiens
R138A site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type Homo sapiens
R139A site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type Homo sapiens
R147A site-directed mutagenesis, binding to NADPH cytochrome P450 oxidoreductase is unaltered compared to the wild-type Homo sapiens
R424A site-directed mutagenesis, the R424A mutant shows a total loss of the ability to be activated by EFV. The R424A replacement affects EFV binding to the allosteric site and cholesterol binding to the CYP46A1 active site. Binding to NADPH cytochrome P450 oxidoreductase is reduced compared to the wild-type Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
 additional information Michaelis-Menten kinetics Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
microsome
-
 Homo sapiens
-
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
cholesterol + [reduced NADPH-hemoprotein reductase] + O2 Homo sapiens
-
 (24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9Y6A2 gene CYP46A1
-

Source Tissue

Source Tissue Comment Organism Textmining
brain
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
cholesterol + [reduced NADPH-hemoprotein reductase] + O2
-
 Homo sapiens (24S)-cholest-5-ene-3beta,24-diol + [oxidized NADPH-hemoprotein reductase] + H2O
-
 ?
additional information coupled assay with recombinant Rattus norvegicus NADPH cytochrome P450 oxidoreductase Homo sapiens ?
-
 ?

Synonyms

Synonyms Comment Organism
cholesterol hydroxylase
-
 Homo sapiens
CYP46A1
-
 Homo sapiens
cytochrome P450 46A1
-
 Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.2
-
 assay at Homo sapiens

Cofactor

Cofactor Comment Organism Structure
heme
-
 Homo sapiens
NADPH
-
 Homo sapiens

General Information

General Information Comment Organism
additional information mapping of the binding region for CYP46A1 redox partner oxidoreductase and identification of allosteric and redox partner binding sites which share a common border, by using a combination of hydrogen-deuterium exchange coupled to mass spectrometry, computational modeling, site-directed mutagenesis, and analysis of the CYP46A1 crystal structure, overview. Residues K422 and R424 are important for enzyme activity Homo sapiens
physiological function cholesterol 24-hydroxylase controls cholesterol elimination from the brain Homo sapiens
physiological function mechanism of CYP46A1 allostery and the pathway for the signal transmission from the P450 allosteric site to the active site, overview Homo sapiens