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| | <StructureSection load='7lxl' size='340' side='right'caption='[[7lxl]], [[Resolution|resolution]] 2.75Å' scene=''> | | <StructureSection load='7lxl' size='340' side='right'caption='[[7lxl]], [[Resolution|resolution]] 2.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7lxl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LXL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LXL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7lxl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LXL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LXL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=YNV:17alpha-hydroxy-7alpha-[(2Z)-4-(17beta-hydroxy-3-oxo-8alpha-androst-4-en-7beta-yl)but-2-en-1-yl]-8alpha,10alpha,13alpha,14beta-androst-4-en-3-one'>YNV</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.75Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A4, CYP3A3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=YNV:17alpha-hydroxy-7alpha-[(2Z)-4-(17beta-hydroxy-3-oxo-8alpha-androst-4-en-7beta-yl)but-2-en-1-yl]-8alpha,10alpha,13alpha,14beta-androst-4-en-3-one'>YNV</scene></td></tr> |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lxl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lxl OCA], [https://pdbe.org/7lxl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lxl RCSB], [https://www.ebi.ac.uk/pdbsum/7lxl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lxl ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lxl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lxl OCA], [https://pdbe.org/7lxl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lxl RCSB], [https://www.ebi.ac.uk/pdbsum/7lxl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lxl ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_HUMAN]] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref>
| + | [https://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_HUMAN] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 7lxl" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7lxl" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Sevrioukova, I F]] | + | [[Category: Sevrioukova IF]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Cyp3a4]]
| + | |
| - | [[Category: Ligand]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Testosterone dimer]]
| + | |
| Structural highlights
Function
CP3A4_HUMAN Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.[1]
Publication Abstract from PubMed
The synthesis of two isomeric testosterone dimers and an androstenedione dimer is reported. The design takes advantage of an efficient transformation of testosterone leading to the synthesis of the key diene, 7alpha-(buta-1,3-dienyl)-4-androsten-17beta-ol-3-one, through an elimination reaction. It was found that in some instances the same reaction led to partial epimerization of the 17beta-hydroxyl group into the 17alpha-hydroxyl group. The specific orientation of the hydroxyl function was confirmed by NMR spectroscopy. Capitalizing on this unforeseen side reaction, several dimers were assembled using an olefin metathesis reaction with Hoveyda-Grubbs catalyst. This led to the formation of two isomeric testosterone dimers with 17alpha-OH or 17beta-OH (14alpha and 14beta) as well as an androstenedione dimer (14). The new dimers and their respective precursors were tested on androgen-dependent (LNCaP) and androgen independent (PC3 and DU145) prostate cancer cells. It was discovered that the most active dimer was made of the natural hormone testosterone (14beta) with an average IC50 of 13.3 muM. In LNCaP cells, 14beta was approximately 5 times more active than the antiandrogen drug cyproterone acetate (IC50 of 12.0 muM vs. 59.6 muM, respectively). At low concentrations (0.25-0.5 muM), 14alpha and 14beta were able to completely inhibit LNCaP cell growth induced by testosterone or dihydrotestosterone. Furthermore, cross-reactivity of androgen-based dimers with sterol-metabolizing cytochrome P450 3A4 was explored and the results are disclosed herein.
Innovative C2-symmetric testosterone and androstenedione dimers: Design, synthesis, biological evaluation on prostate cancer cell lines and binding study to recombinant CYP3A4.,Paquin A, Oufqir Y, Sevrioukova IF, Reyes-Moreno C, Berube G Eur J Med Chem. 2021 Apr 24;220:113496. doi: 10.1016/j.ejmech.2021.113496. PMID:33933755[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Miyazawa M, Shindo M, Shimada T. Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes. Drug Metab Dispos. 2001 Feb;29(2):200-5. PMID:11159812
- ↑ Paquin A, Oufqir Y, Sevrioukova IF, Reyes-Moreno C, Berube G. Innovative C2-symmetric testosterone and androstenedione dimers: Design, synthesis, biological evaluation on prostate cancer cell lines and binding study to recombinant CYP3A4. Eur J Med Chem. 2021 Apr 24;220:113496. doi: 10.1016/j.ejmech.2021.113496. PMID:33933755 doi:http://dx.doi.org/10.1016/j.ejmech.2021.113496
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