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| | ==Structure of Recombinant Human Cytochrome P450 Aromatase== | | ==Structure of Recombinant Human Cytochrome P450 Aromatase== |
| - | <StructureSection load='4kq8' size='340' side='right' caption='[[4kq8]], [[Resolution|resolution]] 3.29Å' scene=''> | + | <StructureSection load='4kq8' size='340' side='right'caption='[[4kq8]], [[Resolution|resolution]] 3.29Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4kq8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KQ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KQ8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4kq8]] 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=4KQ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KQ8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ASD:4-ANDROSTENE-3-17-DIONE'>ASD</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 3.29Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3eqm|3eqm]], [[4gl5|4gl5]], [[3s7s|3s7s]], [[3s79|3s79]], [[4gl7|4gl7]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ASD:4-ANDROSTENE-3-17-DIONE'>ASD</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP19A1, ARO1, CYAR, CYP19 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4kq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kq8 OCA], [https://pdbe.org/4kq8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kq8 RCSB], [https://www.ebi.ac.uk/pdbsum/4kq8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kq8 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr> | + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4kq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kq8 OCA], [http://pdbe.org/4kq8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4kq8 RCSB], [http://www.ebi.ac.uk/pdbsum/4kq8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4kq8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:[http://omim.org/entry/139300 139300]]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:[http://omim.org/entry/613546 613546]]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.<ref>PMID:8265607</ref> <ref>PMID:8530621</ref> <ref>PMID:9211678</ref> | + | [https://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:[https://omim.org/entry/139300 139300]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:[https://omim.org/entry/613546 613546]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.<ref>PMID:8265607</ref> <ref>PMID:8530621</ref> <ref>PMID:9211678</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Catalyzes the formation of aromatic C18 estrogens from C19 androgens. | + | [https://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN] Catalyzes the formation of aromatic C18 estrogens from C19 androgens. |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Cytochrome P450 aromatase (CYP19A1) is the only enzyme known to catalyze the biosynthesis of estrogens from androgens. The crystal structure of human placental aromatase (pArom) has paved the way toward understanding the structure-function relationships of this remarkable enzyme. Using an amino terminus-truncated recombinant human aromatase (rArom) construct, we investigate the roles of key amino acids in the active site, at the intermolecular interface, inside the access channel, and at the lipid-protein boundary for their roles in enzyme function and higher-order organization. Replacing the active site residue D309 with an N yields an inactive enzyme, consistent with its proposed involvement in aromatization. Mutation of R192 at the lipid interface, pivotal to the proton relay network in the access channel, results in the loss of enzyme activity. In addition to the distal catalytic residues, we show that mutation of K440 and Y361 of the heme-proximal region critically interferes with substrate binding, enzyme activity, and heme stability. The D-E loop deletion mutant Del7 that disrupts the intermolecular interaction significantly reduces enzyme activity. However, the less drastic Del4 and point mutants E181A and E181K do not. Furthermore, native gel electrophoresis, size-exclusion chromatography, and analytical ultracentrifugation are used to show that mutations in the intermolecular interface alter the quaternary organization of the enzyme in solution. As a validation for interpretation of the mutational results in the context of the innate molecule, we determine the crystal structure of rArom to show that the active site, tertiary, and quaternary structures are identical to those of pArom.
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| - | Structural Basis for the Functional Roles of Critical Residues in Human Cytochrome P450 Aromatase.,Lo J, Di Nardo G, Griswold J, Egbuta C, Jiang W, Gilardi G, Ghosh D Biochemistry. 2013 Aug 16. PMID:23899247<ref>PMID:23899247</ref>
| + | ==See Also== |
| - | | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4kq8" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Unspecific monooxygenase]] | + | [[Category: Large Structures]] |
| - | [[Category: Ghosh, D]]
| + | [[Category: Di Nardo G]] |
| - | [[Category: Griswold, J]]
| + | [[Category: Ghosh D]] |
| - | [[Category: Nardo, G Di]] | + | [[Category: Griswold J]] |
| - | [[Category: Androgen]] | + | |
| - | [[Category: Aromatase]] | + | |
| - | [[Category: Cytochrome p450]]
| + | |
| - | [[Category: Cytochrome p450 reductase]]
| + | |
| - | [[Category: Estrogen]]
| + | |
| - | [[Category: Estrogen synthetase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
