all-trans retinoic acid 18-hydroxylase activity
Definition
Target type: molecularfunction
Catalysis of the reaction: all-trans-retinoate + O2 + reduced [NADPH--hemoprotein reductase] = all-trans-18-hydroxyretinoate + H+ + H2O + oxidized [NADPH--hemoprotein reductase]. [PMID:22020119, RHEA:55856]
All-trans retinoic acid 18-hydroxylase activity is a critical enzymatic function involved in the metabolism of retinoic acid, a key regulator of cell growth, differentiation, and development. This enzyme catalyzes the hydroxylation of all-trans retinoic acid at the 18-position, converting it to 18-hydroxy-all-trans retinoic acid. This hydroxylation step is a crucial step in the degradation pathway of retinoic acid, effectively modulating its levels and biological activity.
The enzyme responsible for this activity, known as CYP26A1, belongs to the cytochrome P450 family. It is highly expressed in various tissues, including the liver, skin, and reproductive organs, reflecting the widespread importance of retinoic acid signaling in different physiological processes.
The enzymatic mechanism involves the oxidation of the 18-carbon of all-trans retinoic acid using molecular oxygen and NADPH as cofactors. This reaction occurs within the active site of the enzyme, which contains a heme prosthetic group.
The precise molecular mechanism of the reaction involves the following steps:
1. Binding of all-trans retinoic acid to the active site of CYP26A1.
2. Transfer of an electron from NADPH to the heme group of CYP26A1.
3. Activation of molecular oxygen by the heme group, forming a reactive oxygen species.
4. Hydroxylation of the 18-carbon of all-trans retinoic acid by the activated oxygen species.
5. Release of 18-hydroxy-all-trans retinoic acid from the active site.
This hydroxylation reaction is essential for maintaining appropriate retinoic acid levels in cells and tissues. By converting retinoic acid to its less active form, CYP26A1 prevents excessive retinoic acid signaling, which can lead to developmental abnormalities and cellular dysfunction. Moreover, CYP26A1 plays a role in regulating the spatial and temporal patterns of retinoic acid signaling during development, ensuring proper organogenesis and tissue differentiation.'
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Proteins (3)
| Protein | Definition | Taxonomy |
|---|---|---|
| Cytochrome P450 26B1 | A cytochrome P450 26B1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9NR63] | Homo sapiens (human) |
| Cytochrome P450 3A7 | A cytochrome P450 3A7 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P24462] | Homo sapiens (human) |
| Cytochrome P450 26A1 | A cytochrome P450 26A1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:O43174] | Homo sapiens (human) |
Compounds (14)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| ketoconazole | 1-acetyl-4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine : A dioxolane that is 1,3-dioxolane which is substituted at positions 2, 2, and 4 by imidazol-1-ylmethyl, 2,4-dichlorophenyl, and [para-(4-acetylpiperazin-1-yl)phenoxy]methyl groups, respectively. | dichlorobenzene; dioxolane; ether; imidazoles; N-acylpiperazine; N-arylpiperazine | |
| tranylcypromine | (1R,2S)-tranylcypromine : A 2-phenylcyclopropan-1-amine that is the (1R,2S)-enantiomer of tranylcypromine. tranylcypromine : A racemate comprising equal amounts of (1R,2S)- and (1S,2R)-2-phenylcyclopropan-1-amine. An irreversible monoamine oxidase inhibitor that is used as an antidepressant (INN tranylcypromine). Tranylcypromine: A propylamine formed from the cyclization of the side chain of amphetamine. This monoamine oxidase inhibitor is effective in the treatment of major depression, dysthymic disorder, and atypical depression. It also is useful in panic and phobic disorders. (From AMA Drug Evaluations Annual, 1994, p311) | 2-phenylcyclopropan-1-amine | |
| liarozole | liarozole: inhibits all-trans-retinoic acid 4-hydroxylase; effective against hormone-dependent and hormone-independent tumors; R 75251 is chlorohydrate of R 61405; a potent inhibitor of retinoic acid metabolism; USAN name - liarozole fumarate | benzimidazoles | |
| proadifen hydrochloride | |||
| pirlindole | pirlindole: RN given refers to parent cpd; synonym pyrazidol refers to mono-HCl; structure in Negwer, 5th ed, #2812 | carbazoles | |
| bexarotene | benzoic acids; naphthalenes; retinoid | antineoplastic agent | |
| sr 11237 | SR 11237: structure given in first source | ||
| alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid | |||
| cannabidiol | cannabidiol : An cannabinoid that is cyclohexene which is substituted by a methyl group at position 1, a 2,6-dihydroxy-4-pentylphenyl group at position 3, and a prop-1-en-2-yl group at position 4. Cannabidiol: Compound isolated from Cannabis sativa extract. | olefinic compound; phytocannabinoid; resorcinols | antimicrobial agent; plant metabolite |
| cyclosporine | ramihyphin A: one of the metabolites produced by Fusarium sp. S-435; RN given refers to cpd with unknown MF | homodetic cyclic peptide | anti-asthmatic drug; anticoronaviral agent; antifungal agent; antirheumatic drug; carcinogenic agent; dermatologic drug; EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor; geroprotector; immunosuppressive agent; metabolite |
| geldanamycin | 1,4-benzoquinones; ansamycin; carbamate ester; organic heterobicyclic compound | antimicrobial agent; antineoplastic agent; antiviral agent; cysteine protease inhibitor; Hsp90 inhibitor | |
| bufalin | bufalin : A 14beta-hydroxy steroid that is bufan-20,22-dienolide having hydroxy substituents at the 5beta- and 14beta-positions. It has been isolated from the skin of the toad Bufo bufo. bufalin: cardiotonic; powerful anesthetic & one of the active constituents of the Chinese drug ch'an su(senso); in Japan prepared from skin of Bufo bufo garfarizans; RN given refers to (3beta,5beta)-isomer | 14beta-hydroxy steroid; 3beta-hydroxy steroid | animal metabolite; anti-inflammatory agent; antineoplastic agent; cardiotonic drug |
| r 115866 | N-{4-[2-ethyl-1-(1,2,4-triazol-1-yl)butyl]phenyl}-1,3-benzothiazol-2-amine : A member of the class of benzothiazoles that is 2-amino-1,3-benzothiazole in which one of the amino hydrogens is replaced by a 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl group. R 115866: structure in first source talarozole : A racemate comprising equimolar amounts of (R)- and (S)-talarozole. It is used for the treatment of keratinization disorders, psoriasis and acne. | aromatic amine; benzothiazoles; secondary amino compound; triazoles | |
| kaf156 | ganaplacide: antimalarial |