Sandbox CYPMetabolism - Revision history

http://52.214.119.220/wiki/index.php?action=history&feed=atom&title=Sandbox_CYPMetabolism Sandbox CYPMetabolism - Revision history 2026-04-14T17:17:12Z Revision history for this page on the wiki MediaWiki 1.11.2 http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130294&oldid=prev Robin Morgan at 21:59, 19 December 2014 2014-12-19T21:59:58Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:59, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 77:</td> <td colspan="2" class="diff-lineno">Line 77:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug <del style="color: red; font-weight: bold; text-decoration: none;">is </del>the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The next scene shows </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug <ins style="color: red; font-weight: bold; text-decoration: none;">are </ins>the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The next scene shows </div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><scene name='60/609993/Cyp1e2/1'>CYP1E2</scene> bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). If you will now refer back to </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><scene name='60/609993/Cyp1e2/1'>CYP1E2</scene> bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). If you will now refer back to </div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><scene name='60/609993/Cyp3a4/18'>erythromycin bound to CYP3A4</scene>, you will notice that, in comparison to CYP1E2, there is quite a dramatic difference in the size and shape of the active site. Keep in mind that although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small. A few examples would be ethanol, halothane, and aniline.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><scene name='60/609993/Cyp3a4/18'>erythromycin bound to CYP3A4</scene>, you will notice that, in comparison to CYP1E2, there is quite a dramatic difference in the size and shape of the active site. Keep in mind that although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small. A few examples would be ethanol, halothane, and aniline.</div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130293&oldid=prev Robin Morgan at 21:52, 19 December 2014 2014-12-19T21:52:12Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:52, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 77:</td> <td colspan="2" class="diff-lineno">Line 77:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The next scene shows <scene name='60/609993/Cyp1e2/1'><del style="color: red; font-weight: bold; text-decoration: none;">CYP12E</del></scene> bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). If you will now refer back to <scene name='60/609993/Cyp3a4/18'>erythromycin bound to CYP3A4</scene>, you will notice that, in comparison to CYP1E2, there is quite a dramatic difference in the size and shape of the active site. Keep in mind that although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small. A few examples would be ethanol, halothane, and aniline.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The next scene shows </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div><scene name='60/609993/Cyp1e2/1'><ins style="color: red; font-weight: bold; text-decoration: none;">CYP1E2</ins></scene> bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). If you will now refer back to </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div><scene name='60/609993/Cyp3a4/18'>erythromycin bound to CYP3A4</scene>, you will notice that, in comparison to CYP1E2, there is quite a dramatic difference in the size and shape of the active site. Keep in mind that although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small. A few examples would be ethanol, halothane, and aniline.</div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130292&oldid=prev Robin Morgan at 21:51, 19 December 2014 2014-12-19T21:51:04Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:51, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 77:</td> <td colspan="2" class="diff-lineno">Line 77:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The next scene shows CYP12E bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). If you will now refer back to erythromycin bound to CYP3A4, you will notice that, in comparison CYP1E2, there is quite a dramatic difference in the size and shape of the active site. Keep in mind that although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small. A few examples would be ethanol, halothane, and aniline.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The next scene shows <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='60/609993/Cyp1e2/1'></ins>CYP12E<ins style="color: red; font-weight: bold; text-decoration: none;"></scene> </ins>bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). If you will now refer back to <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='60/609993/Cyp3a4/18'></ins>erythromycin bound to CYP3A4<ins style="color: red; font-weight: bold; text-decoration: none;"></scene></ins>, you will notice that, in comparison <ins style="color: red; font-weight: bold; text-decoration: none;">to </ins>CYP1E2, there is quite a dramatic difference in the size and shape of the active site. Keep in mind that although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small. A few examples would be ethanol, halothane, and aniline.</div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130291&oldid=prev Robin Morgan at 21:34, 19 December 2014 2014-12-19T21:34:23Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:34, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 77:</td> <td colspan="2" class="diff-lineno">Line 77:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The <del style="color: red; font-weight: bold; text-decoration: none;">windows below show two CYP450 isoforms with very different selectivity. The first is the structure of CYP2E1, </del>bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). <del style="color: red; font-weight: bold; text-decoration: none;">The second is the structure of CYP3A4 </del>bound to <del style="color: red; font-weight: bold; text-decoration: none;">the inhibitor erythromycin ([[2j0d]]). Make sure </del>that <del style="color: red; font-weight: bold; text-decoration: none;">the check box below the second window </del>is <del style="color: red; font-weight: bold; text-decoration: none;">checked. Now rotate and re-size the structures until you can see the heme group and </del>the size and shape of the active site. </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The <ins style="color: red; font-weight: bold; text-decoration: none;">next scene shows CYP12E </ins>bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). <ins style="color: red; font-weight: bold; text-decoration: none;">If you will now refer back to erythromycin </ins>bound to <ins style="color: red; font-weight: bold; text-decoration: none;">CYP3A4, you will notice </ins>that<ins style="color: red; font-weight: bold; text-decoration: none;">, in comparison CYP1E2, there </ins>is <ins style="color: red; font-weight: bold; text-decoration: none;">quite a dramatic difference in </ins>the size and shape of the active site. <ins style="color: red; font-weight: bold; text-decoration: none;">Keep </ins>in <ins style="color: red; font-weight: bold; text-decoration: none;">mind </ins>that <ins style="color: red; font-weight: bold; text-decoration: none;">although </ins>the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small<ins style="color: red; font-weight: bold; text-decoration: none;">. A few examples would be </ins>ethanol, halothane, and aniline.</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div> </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><del style="color: red; font-weight: bold; text-decoration: none;">Use one of the buttons below each applet to toggle the transparency of the active site </del>in <del style="color: red; font-weight: bold; text-decoration: none;">the CYP2E1 structure and the CYP3A4 structure until you can see how the substrate is bound relative to the heme. If you need to, you can reset the molecules to their original orientation using the other button below the interactive window.</del></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div> </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><del style="color: red; font-weight: bold; text-decoration: none;">Notice the size of the active site in the CYP2E1 structure relative to </del>that <del style="color: red; font-weight: bold; text-decoration: none;">of the CYP3A4 structure. Although </del>the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small<del style="color: red; font-weight: bold; text-decoration: none;">, such as </del>ethanol, halothane, and aniline<del style="color: red; font-weight: bold; text-decoration: none;">. On the opposite end of the spectrum, CYP3A4 can accommodate drugs that are quite large</del>.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130290&oldid=prev Robin Morgan at 21:24, 19 December 2014 2014-12-19T21:24:58Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:24, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 80:</td> <td colspan="2" class="diff-lineno">Line 80:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Use one of the buttons below each applet to toggle the transparency of the active site in the CYP2E1 structure and the CYP3A4 structure until you can see how the substrate is bound relative to the heme. If you need to, you can reset the molecules to their original orientation using the other button below the interactive window.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Use one of the buttons below each applet to toggle the transparency of the active site in the CYP2E1 structure and the CYP3A4 structure until you can see how the substrate is bound relative to the heme. If you need to, you can reset the molecules to their original orientation using the other button below the interactive window.</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"></td><td colspan="2"> </td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Notice the size of the active site in the CYP2E1 structure relative to that of the CYP3A4 structure. Although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small, such as ethanol, halothane, and aniline. On the opposite end of the spectrum, CYP3A4 can accommodate drugs that are quite large.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Notice the size of the active site in the CYP2E1 structure relative to that of the CYP3A4 structure. Although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small, such as ethanol, halothane, and aniline. On the opposite end of the spectrum, CYP3A4 can accommodate drugs that are quite large.</div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130289&oldid=prev Robin Morgan at 21:24, 19 December 2014 2014-12-19T21:24:28Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:24, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 73:</td> <td colspan="2" class="diff-lineno">Line 73:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In this case, we have taken advantage of the inhibition of CYP3A4 to prevent it from metabolizing the other antivirals of which ritonavir is co-administered. As you may expect though, extreme caution must be taken to prevent toxicity when other medications are taken concurrently. This is relatively easy to control when only one pharmacy is dispensing all of the medications a patient is prescribed. When more than one pharmacy is involved, however, serious interactions may be overlooked due to one pharmacy being unaware of the medications a patient is receiving from the other pharmacy. </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In this case, we have taken advantage of the inhibition of CYP3A4 to prevent it from metabolizing the other antivirals of which ritonavir is co-administered. As you may expect though, extreme caution must be taken to prevent toxicity when other medications are taken concurrently. This is relatively easy to control when only one pharmacy is dispensing all of the medications a patient is prescribed. When more than one pharmacy is involved, however, serious interactions may be overlooked due to one pharmacy being unaware of the medications a patient is receiving from the other pharmacy. </div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"></td><td colspan="2"> </td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the next section below, we will examine another factor that causes one drug to be metabolized by one CYP, while another might be metabolized by a second one.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the next section below, we will examine another factor that causes one drug to be metabolized by one CYP, while another might be metabolized by a second one.</div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>== Active site Volume Affects Drug Selectivity==</div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Some of the factors that determine which particular CYP450 isoform metabolizes a given drug is the shape and size of its active site. As we saw above, induced fit can cause the shape of a binding pocket to change. However, induced fit may not be enough to allow a CYP with a small binding pocket to open up enough to allow larger drugs to bind. The windows below show two CYP450 isoforms with very different selectivity. The first is the structure of CYP2E1, bound to the enzyme inhibitor 4-methylpyrazole (PDB code [[3e4e]]). The second is the structure of CYP3A4 bound to the inhibitor erythromycin ([[2j0d]]). Make sure that the check box below the second window is checked. Now rotate and re-size the structures until you can see the heme group and the size and shape of the active site. </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Use one of the buttons below each applet to toggle the transparency of the active site in the CYP2E1 structure and the CYP3A4 structure until you can see how the substrate is bound relative to the heme. If you need to, you can reset the molecules to their original orientation using the other button below the interactive window.</div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Notice the size of the active site in the CYP2E1 structure relative to that of the CYP3A4 structure. Although the size and shape of each cavity can change to accommodate different drugs, CYP2E1 cannot expand to the same degree that CYP3A4 can. In fact, CYP2E1 is known to only metabolize drugs that are quite small, such as ethanol, halothane, and aniline. On the opposite end of the spectrum, CYP3A4 can accommodate drugs that are quite large.</div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130288&oldid=prev Robin Morgan at 21:14, 19 December 2014 2014-12-19T21:14:39Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:14, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 67:</td> <td colspan="2" class="diff-lineno">Line 67:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>It has been demonstrated that two or more smaller molecules may bind within an active site at the same time. In this case, drug metabolism can, strangely enough, actually be increased. It has been proposed that when only one molecule of a smaller drug (let's call this Drug A) is bound to the active site, that the extent of Drug A 's metabolism can be minimal due to the relatively large cavity. One explanation may be that Drug A isn't held in a sufficient orientation to the heme Iron. For optimum metabolism, the heme should bond with an Oxygen of the ligand. However, when two molecules of a smaller drug bind at the same time, one molecule may help in forcing the other molecule to retain proper orientation; thus, improving catalytic efficiency. This theory of two drugs binding simultaneously to a CYP may influence its pharmacokinetics is illustrated by the following structure of ketoconazole bound to a CYP enzyme ([[2v0m]]) <ref>PMID:16954191</ref>. </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>It has been demonstrated that two or more smaller molecules may bind within an active site at the same time. In this case, drug metabolism can, strangely enough, actually be increased. It has been proposed that when only one molecule of a smaller drug (let's call this Drug A) is bound to the active site, that the extent of Drug A 's metabolism can be minimal due to the relatively large cavity. One explanation may be that Drug A isn't held in a sufficient orientation to the heme Iron. For optimum metabolism, the heme should bond with an Oxygen of the ligand. However, when two molecules of a smaller drug bind at the same time, one molecule may help in forcing the other molecule to retain proper orientation; thus, improving catalytic efficiency. This theory of two drugs binding simultaneously to a CYP may influence its pharmacokinetics is illustrated by the following structure of ketoconazole bound to a CYP enzyme ([[2v0m]]) <ref>PMID:16954191</ref>. </div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Ketoconazole is an anti-fungal drug that can have unusual pharmacokinetics; its apparent plasma concentration does not reflect what we would traditionally expect when considering the dose given. In the structure shown next, <scene name='60/609993/Cyp3a4/6'> two molecules of ketoconazole</scene> are bound to the CYP. You <del style="color: red; font-weight: bold; text-decoration: none;">can see this interaction better if we </del><scene name='60/609993/Cyp3a4/<del style="color: red; font-weight: bold; text-decoration: none;">10</del>'><del style="color: red; font-weight: bold; text-decoration: none;">remove the protein</del></scene>. One of the ketoconazole molecules is bound directly to the heme ring, while the second molecule has taken up residence in the pocket and appears to be ensuring the first one remain in place. The unusual pharmacokinetics of ketoconazole may be explained by the fact that as its plasma concentration increases, the activity of the enzyme is altered due to two drugs now being bound.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Ketoconazole is an anti-fungal drug that can have unusual pharmacokinetics; its apparent plasma concentration does not reflect what we would traditionally expect when considering the dose given. In the structure shown next, <scene name='60/609993/Cyp3a4/6'> two molecules of ketoconazole</scene> are bound to the CYP. You <ins style="color: red; font-weight: bold; text-decoration: none;">will also notice that both molecules play a role in the drug being metabolized when the </ins><scene name='60/609993/Cyp3a4/<ins style="color: red; font-weight: bold; text-decoration: none;">11</ins>'><ins style="color: red; font-weight: bold; text-decoration: none;">binding pocket</ins></scene> <ins style="color: red; font-weight: bold; text-decoration: none;">is displayed</ins>. One of the ketoconazole molecules is bound directly to the heme ring, while the second molecule has taken up residence in the pocket and appears to be ensuring the first one remain in place<ins style="color: red; font-weight: bold; text-decoration: none;">. You can see the relationship of the two ketoconazole molecules better if we <scene name='60/609993/Cyp3a4/10'>remove the protein</scene></ins>. The unusual pharmacokinetics of ketoconazole may be explained by the fact that as its plasma concentration increases, the activity of the enzyme is altered due to two drugs now being bound.</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Irreversible inhibition of CYP450s==</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Irreversible inhibition of CYP450s==</div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130287&oldid=prev Robin Morgan at 21:01, 19 December 2014 2014-12-19T21:01:12Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 21:01, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 70:</td> <td colspan="2" class="diff-lineno">Line 70:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Irreversible inhibition of CYP450s==</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>== Irreversible inhibition of CYP450s==</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>When we examined CYP1A2 above, the flavone inhibited the enzyme simply by virtue of having such complementary features to the binding site. It binds so tightly that it physically prevents other drugs from binding to it. Another way that a drug can inhibit CYP450 enzymes is by formation of a covalent bond that deactivates the active site. This happens with a well-known inhibitor of CYP3A4, <scene name='60/609993/Ritonavir/1'>ritonavir</scene>. Ritonavir is a HIV protease inhibitor routinely prescribed in combination with other antivirals. Its efficacy as part of a drug "cocktail" stems from the fact that it is a potent "irreversible inhibitor" of CYP3A4. Irreversible inhibition differs from most cases of competitive inhibition in that the enzyme is permanently deactivated, and must be re-synthesized by the cell.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>When we examined CYP1A2 above, the flavone inhibited the enzyme simply by virtue of having such complementary features to the binding site. It binds so tightly that it physically prevents other drugs from binding to it. Another way that a drug can inhibit CYP450 enzymes is by formation of a covalent bond that deactivates the active site. This happens with a well-known inhibitor of CYP3A4, <scene name='60/609993/Ritonavir/1'>ritonavir</scene>. Ritonavir is a HIV protease inhibitor routinely prescribed in combination with other antivirals. Its efficacy as part of a drug "cocktail" stems from the fact that it is a potent "irreversible inhibitor" of CYP3A4. Irreversible inhibition differs from most cases of competitive inhibition in that the enzyme is permanently deactivated, and must be re-synthesized by the cell. <ins style="color: red; font-weight: bold; text-decoration: none;">In contrast to erythromycin, there has been a covalent bond formed between the <scene name='60/609993/Ritonavir/3'>thiazole ring</scene> of the drug and the heme ring. Do you see how the thiazole has bound to the heme?</ins></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In this case, we have taken advantage of the inhibition of CYP3A4 to prevent it from metabolizing the other antivirals of which ritonavir is co-administered. As you may expect though, extreme caution must be taken to prevent toxicity when other medications are taken concurrently. This is relatively easy to control when only one pharmacy is dispensing all of the medications a patient is prescribed. When more than one pharmacy is involved, however, serious interactions may be overlooked due to one pharmacy being unaware of the medications a patient is receiving from the other pharmacy. </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In this case, we have taken advantage of the inhibition of CYP3A4 to prevent it from metabolizing the other antivirals of which ritonavir is co-administered. As you may expect though, extreme caution must be taken to prevent toxicity when other medications are taken concurrently. This is relatively easy to control when only one pharmacy is dispensing all of the medications a patient is prescribed. When more than one pharmacy is involved, however, serious interactions may be overlooked due to one pharmacy being unaware of the medications a patient is receiving from the other pharmacy. </div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Examine the orientation of ritonavir relative to the heme group. Now let's look at the <scene name='60/609993/Ritonavir/2'>binding pocket</scene>. Notice the complementary shape of the drug to the cavity. In contrast to erythromycin, there has been a covalent bond formed between the <scene name='60/609993/Ritonavir/3'>thiazole ring</scene> of the drug and the heme ring. Do you see how the thiazole has bound to the heme?</div></td><td colspan="2"> </td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the next section below, we will examine another factor that causes one drug to be metabolized by one CYP, while another might be metabolized by a second one.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>In the next section below, we will examine another factor that causes one drug to be metabolized by one CYP, while another might be metabolized by a second one.</div></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130286&oldid=prev Robin Morgan at 20:58, 19 December 2014 2014-12-19T20:58:02Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 20:58, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 59:</td> <td colspan="2" class="diff-lineno">Line 59:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The following scene shows the ligand-free form of <scene name='60/609993/Cyp3a4/1'>CYP3A4</scene>. The next scene shows the <scene name='60/609993/Cyp3a4/15'>binding pocket</scene> of CYP3A4 without a substrate. Examine the size and shape of the cavity by rotating and resizing the molecule. Observe that the cavity extends toward the heme ring and is located more so on the periphery. In order for a drug to be oxidized, it must come quite close to the oxygen atom held by the heme. It is important to realize that a change must occur in order for the binding pocket to be oriented in a way that is conducive to allowing metabolism to occur. </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The following scene shows the ligand-free form of <scene name='60/609993/Cyp3a4/1'>CYP3A4</scene>. The next scene shows the <scene name='60/609993/Cyp3a4/15'>binding pocket</scene> of CYP3A4 without a substrate. Examine the size and shape of the cavity by rotating and resizing the molecule. Observe that the cavity extends toward the heme ring and is located more so on the periphery. In order for a drug to be oxidized, it must come quite close to the oxygen atom held by the heme. It is important to realize that a change must occur in order for the binding pocket to be oriented in a way that is conducive to allowing metabolism to occur. </div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Now, take a look at this scene showing <scene name='60/609993/Cyp3a4/18'>CYP3A4 bound to erythromycin</scene> (PDB entry [[2j0d]]) <del style="color: red; font-weight: bold; text-decoration: none;">with </del>the <del style="color: red; font-weight: bold; text-decoration: none;">surface </del>of <del style="color: red; font-weight: bold; text-decoration: none;">its binding pocket obviously altered</del>. In this case, CYP3A4 has undergone a conformational change as a result of binding to erythromycin<del style="color: red; font-weight: bold; text-decoration: none;">. Note the size and shape of the cavity, and the apparent size of the opening</del>. In comparing the bound and unbound structures, it looks as though the enzyme has adopted a conformation that allows the drug to <del style="color: red; font-weight: bold; text-decoration: none;">bind </del>more <del style="color: red; font-weight: bold; text-decoration: none;">tightly than </del>its <del style="color: red; font-weight: bold; text-decoration: none;">initial interaction</del>. This, again, is induced fit.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Now, take a look at this scene showing <scene name='60/609993/Cyp3a4/18'>CYP3A4 bound to erythromycin</scene> (PDB entry [[2j0d]])<ins style="color: red; font-weight: bold; text-decoration: none;">. The cavity is now in closer proximity to </ins>the <ins style="color: red; font-weight: bold; text-decoration: none;">heme ring and the shape </ins>of <ins style="color: red; font-weight: bold; text-decoration: none;">the cavity has changed as well</ins>. In this case, CYP3A4 has undergone a conformational change as a result of binding to erythromycin. In comparing the bound and unbound structures, it looks as though the enzyme has adopted a conformation that allows the drug to <ins style="color: red; font-weight: bold; text-decoration: none;">occupy the pocket </ins>more <ins style="color: red; font-weight: bold; text-decoration: none;">specifically tailored to </ins>its <ins style="color: red; font-weight: bold; text-decoration: none;">size and shape for a tighter fit. You will also notice that there is an opening in the cavity where erythromycin entered</ins>. This, again, is induced fit.</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div> </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> </table>

Robin Morgan http://52.214.119.220/wiki/index.php?title=Sandbox_CYPMetabolism&diff=2130285&oldid=prev Robin Morgan at 20:45, 19 December 2014 2014-12-19T20:45:09Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 20:45, 19 December 2014</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 59:</td> <td colspan="2" class="diff-lineno">Line 59:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The following scene shows the ligand-free form of <scene name='60/609993/Cyp3a4/1'>CYP3A4</scene>. The next scene shows the <scene name='60/609993/Cyp3a4/15'>binding pocket</scene> of CYP3A4 without a substrate. Examine the size and shape of the cavity by rotating and resizing the molecule. Observe that the cavity extends toward the heme ring and is located more so on the periphery. In order for a drug to be oxidized, it must come quite close to the oxygen atom held by the heme. It is important to realize that a change must occur in order for the binding pocket to be oriented in a way that is conducive to allowing metabolism to occur. </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>The following scene shows the ligand-free form of <scene name='60/609993/Cyp3a4/1'>CYP3A4</scene>. The next scene shows the <scene name='60/609993/Cyp3a4/15'>binding pocket</scene> of CYP3A4 without a substrate. Examine the size and shape of the cavity by rotating and resizing the molecule. Observe that the cavity extends toward the heme ring and is located more so on the periphery. In order for a drug to be oxidized, it must come quite close to the oxygen atom held by the heme. It is important to realize that a change must occur in order for the binding pocket to be oriented in a way that is conducive to allowing metabolism to occur. </div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Now, take a look at this scene showing <scene name='60/609993/Cyp3a4/<del style="color: red; font-weight: bold; text-decoration: none;">17</del>'>CYP3A4 bound to erythromycin</scene> (PDB entry [[2j0d]]) with the surface of its binding pocket obviously altered. In this case, CYP3A4 has undergone a conformational change as a result of binding to erythromycin. Note the size and shape of the cavity, and the apparent size of the opening. In comparing the bound and unbound structures, it looks as though the enzyme has adopted a conformation that allows the drug to bind more tightly than its initial interaction. This, again, is induced fit.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Now, take a look at this scene showing <scene name='60/609993/Cyp3a4/<ins style="color: red; font-weight: bold; text-decoration: none;">18</ins>'>CYP3A4 bound to erythromycin</scene> (PDB entry [[2j0d]]) with the surface of its binding pocket obviously altered. In this case, CYP3A4 has undergone a conformational change as a result of binding to erythromycin. Note the size and shape of the cavity, and the apparent size of the opening. In comparing the bound and unbound structures, it looks as though the enzyme has adopted a conformation that allows the drug to bind more tightly than its initial interaction. This, again, is induced fit.</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> </table>

Robin Morgan