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Literature summary for 1.3.1.72 extracted from
- Desmosterol and DHCR24 unexpected new directions for a terminal step in cholesterol synthesis (2013), Prog. Lipid Res., 52, 666-680 .
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| DWF1, phylogenetic tree | Arabidopsis thaliana |
| the DHCR24 gene locus is 1p32.3, spans about 46.4 kb, and comprises eight introns and nine exons, promoter map of human DHCR24, phylogenetic tree | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| E191K | site-directed mutagenesis, mutation of a FAD binding domain residue, 19.9% of wild-type activity remain | Homo sapiens |
| E480K | site-directed mutagenesis, mutation of a C-terminal domain residue, about 50% of wild-type activity remain | Homo sapiens |
| K306N | site-directed mutagenesis, mutation of a C-terminal domain residue, 49.8% of wild-type activity remain | Homo sapiens |
| N294T | site-directed mutagenesis, mutation of a C-terminal domain residue, 14.4% of wild-type activity remain | Homo sapiens |
| R103C | site-directed mutagenesis, mutation of a FAD binding domain residue | Homo sapiens |
| R94H | site-directed mutagenesis, mutation of a FAD binding domain residue, about 20% of wild-type activity remain | Homo sapiens |
| Y471S | site-directed mutagenesis, mutation of a C-terminal domain residue, inactive mutant | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| brassicasterol | competitive | Homo sapiens |  |
| ergosterol | competitive | Homo sapiens | |
| additional information | no feedback inhibition by cholesterol. C-22 unsaturated sterols (phytosterols stigmasterol, brassicasterol, and the yeast sterol ergosterol) competitively inhibit DHCR24 enzyme activity, with no inhibition observed by phytosterols with a saturated side chain (beta-sitosterol and campesterol) | Homo sapiens | |
| stigmasterol | competitive | Homo sapiens | |
| U18666A | an inhibitor of DHCR24 activity, prevents ACTH-induced translocation of the enzyme to the nucleus in adrenal cells but not in prostate cancer cells | Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| endoplasmic reticulum | - |
Homo sapiens | 5783 | - |
| endoplasmic reticulum membrane | - |
Bombyx mori | 5789 | - |
| endoplasmic reticulum membrane | DHCR24 membrane association | Arabidopsis thaliana | 5789 | - |
| Golgi apparatus | - |
Homo sapiens | 5794 | - |
| membrane | DHCR24 membrane association | Homo sapiens | 16020 | - |
| additional information | enzyme DWF1 has a strong membrane association and a cytoplasmic C-terminus | Arabidopsis thaliana | - |
- |
| additional information | smaller variants of DHCR24 (about 40 kDa) produced by caspase cleavage during apoptosis are cytoplasmic | Homo sapiens | - |
- |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| cholesta-5,24-dien-3beta-ol + NADPH + H+ | Arabidopsis thaliana | - |
cholest-5-en-3beta-ol + NADP+ | - |
? | |
| cholesta-5,24-dien-3beta-ol + NADPH + H+ | Homo sapiens | - |
cholest-5-en-3beta-ol + NADP+ | - |
? | |
| additional information | Bombyx mori | the enzyme synthesizes cholesterol by transformation of dietary phytosterols through a dealkylation reaction | ? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Arabidopsis thaliana | - |
- |
- |
| Bombyx mori | - |
- |
- |
| Homo sapiens | Q15392 | - |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| additional information | DHCR24 is also regulated post-translationally, overview | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| adrenal gland | - |
Homo sapiens | - |
| brain | - |
Homo sapiens | - |
| liver | - |
Homo sapiens | - |
| lung | - |
Homo sapiens | - |
| medulla oblongata | - |
Homo sapiens | - |
| additional information | DHCR24 is expressed in all cells/tissues that synthesize cholesterol, with the highest expression in cholesterogenic (brain and liver) and steroidogenic tissues (endocrine glands like adrenal, testes, and ovaries) | Homo sapiens | - |
| nervous system | - |
Homo sapiens | - |
| ovary | - |
Homo sapiens | - |
| prostate | - |
Homo sapiens | - |
| spinal cord | - |
Homo sapiens | - |
| spleen | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| cholesta-5,24-dien-3beta-ol + NADPH + H+ | - |
Arabidopsis thaliana | cholest-5-en-3beta-ol + NADP+ | - |
? | |
| cholesta-5,24-dien-3beta-ol + NADPH + H+ | - |
Homo sapiens | cholest-5-en-3beta-ol + NADP+ | - |
? | |
| additional information | the enzyme synthesizes cholesterol by transformation of dietary phytosterols through a dealkylation reaction | Bombyx mori | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| ? | x * 60100, about, sequence calculation | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| 3beta-hydroxysterol DELTA24-reductase | - |
Arabidopsis thaliana |
| 3beta-hydroxysterol DELTA24-reductase | - |
Homo sapiens |
| DHCR24 | - |
Arabidopsis thaliana |
| DHCR24 | - |
Homo sapiens |
| DIMINUTO/DWARF1 | - |
Arabidopsis thaliana |
| DWF1 | - |
Arabidopsis thaliana |
| seladin-1 | selective Alzheimer's disease indicator 1 | Homo sapiens |
| sterol DELTA24-reductase | - |
Arabidopsis thaliana |
| sterol DELTA24-reductase | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| FAD | dependent on | Bombyx mori | |
| FAD | dependent on | Arabidopsis thaliana | |
| FAD | dependent on | Homo sapiens | |
| NADPH | dependent on | Bombyx mori | |
| NADPH | conversion of desmosterol to cholesterol is strictly dependent on NADPH as the reducing agent with almost no activity detected in its absence in an in vitro enzymatic assay | Arabidopsis thaliana | |
| NADPH | conversion of desmosterol to cholesterol is strictly dependent on NADPH as the reducing agent with almost no activity detected in its absence in an in vitro enzymatic assay. No consensus sequence for NADPH binding is predicted in DHCR24 | Homo sapiens | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | histone acetylation also regulates DHCR24 expression, with a reduction in DHCR24 transcription correlating with recruitment of acetylated histones H3 and H4 to its promoter | down |
| Homo sapiens | the enzyme is regulated by the following transcription factors/proteins: sterol regulatory element binding protein 2, nuclear factor Y (via methylation), specificity protein 1, estrogen receptor, androgen receptor, thyroid hormone receptor, constitutive androstane receptor, and pregnane X receptor. Transcriptional regulation of DHCR24, detailed overview | additional information |
| Homo sapiens | the sterol-regulated region is extremely GC rich and lies within a CpG island, a region of DNA with a high G and C content and a high frequency of CpG dinucleotides, which is conserved in mammals. In addition to containing a specificity protein 1 (Sp1) site required for augmentation of DHCR24 in HCV infection, this region is also important in epigenetic regulation of DHCR24. Methylation of this region decreases DHCR24 expression, with pronounced methylation occurring in cell types with low DHCR24 levels. Sex steroids, such as estrogens and androgens, are positive regulators of DHCR24, increasing gene expression via activation of their respective nuclear receptors, estrogen receptor and androgen receptor, overview. Adrenocorticotropic hormone (ACTH) stimulates the enzyme expression in adrenal gland | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | loss of DHCR24 results in severe developmental and growth defects. Missense mutations in DHCR24, which result in diminished protein activity, can lead to a rare autosomal recessive disorder, desmosterolosis. The single nucleotide polymorphism, rs600491 (T allele) is significantly correlating with Alzheimer's disease risk in men. Four single nucleotide polymorphisms in the DHCR24 promoter correlate with hepatitis C virus (HCV) induced hepatocellular carcinoma and cirrhosis. The enzyme can be involved in Alzheimer's disease and is downregulated in affected regions of Alzheimer's disease (AD) brains, Overexpressing DHCR24 in cell culture protects cells from apoptosis, through inhibiting caspase-3 and amyloid beta toxicity. DHCR24 is implicated in the anti-inflammatory effects of HDL and resulting cardiovascular disease. Altered expression of a subset of androgen receptor-related genes, such as DHCR24, is observed in prostate cancer, overexpression of DHCR24 is a hallmark of prostate cancer, with high levels observed in low-grade prostate cancer, which diminish as the cancer progresses to a higher grade | Homo sapiens |
| malfunction | loss of DWF1 results in severe developmental and growth defects | Arabidopsis thaliana |
| metabolism | DHCR24 catalyzes the ultimate step in the Bloch pathway of cholesterol synthesis | Homo sapiens |
| metabolism | the enzyme catalyzes the final step in cholesterol biosynthesis | Arabidopsis thaliana |
| physiological function | as well as playing an essential role in the regulation of cholesterol synthesis, DHCR24 is important in other cellular processes, such as signaling, the formation of lipid rafts, mediating cell stress responses, and regulating steroidogenesis, in steroidogenesis and bile acid synthesis, cell survival, and chlolesterol homeostasis and membranes. DHCR24 is modulating oxidative stress. DHCR24 or seladin-1 plays an important role in stress signaling and apoptosis: up-regulated in response to cell stress (oxidative- and amyloid b-toxicity) promoting cell survival by inhibiting caspase-3 activation, and deactivated by caspase cleavage during apoptosis. The enzyme is regulated by the following transcription factors/proteins: sterol regulatory element binding protein 2, nuclear factor Y (via methylation), specificity protein 1, estrogen receptor, androgen receptor, thyroid hormone receptor, constitutive androstane receptor, and pregnane X receptor | Homo sapiens |
| physiological function | invertebrates such as Bombyx mori (silkworm), which cannot perform de novo cholesterol synthesis, also possess a DHCR24 homologue. This protein provides the organism with cholesterol by transformation of dietary phytosterols through a dealkylation reaction, similar to the DWF1 catalyzed reaction from Arabidopsis thaliana. Furthermore, this reaction is FAD and NADPH dependent | Bombyx mori |
| physiological function | the enzyme is an important protein in plant sterol (phytosterol) and steroid (brassinosteroid) synthesis, by catalyzing the isomerisation of the DELTA24(28) bond, and the subsequent reduction of the DELTA24(25) bond in various sterol precursors | Arabidopsis thaliana |
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Release 2023.1 (January 2023)
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