CYP3A4: Difference between revisions

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Because water molecules are stripped away when substrate binds, this causes an entropy change of 26 kcal/mol. This entropy driven reaction has a spontaneous free energy change of -7.7kcal/mol at 21ºC <ref name="d">PMID: 15352783</ref>.

The cycle begins with the binding of the substrate to the ferric heme. With the addition of an electron, the heme gets reduced. This can only happen once the substrate is bound because the reduction potential is -300V ~~while in that state and~~ is more electronegative. After substrate binding, the induced conformational shift causes the reduction potential to be more positive at -230V making this a more thermodynamically favorable reaction. Oxygen next binds to the heme and oxidizes the iron. The addition of a second electron cleaves the oxygen-oxygen bond allowing one atom to bind two protons producing water. The second oxygen joins the substrate in what is called a monoxygenation reaction <ref> Devlin, Thomas M., ed. Textbook of Biochemistry with Clinical Correlations. 6th ed. Hoboken: John Wiley, 2006. Print.</ref>.

The cycle begins with the binding of the substrate to the ferric heme. With the addition of an electron, the heme gets reduced. This can only happen once the substrate is bound because the reduction potential is -300V which is more electronegative. After substrate binding, the induced conformational shift causes the reduction potential to be more positive at -230V making this a more thermodynamically favorable reaction. Oxygen next binds to the heme and oxidizes the iron. The addition of a second electron cleaves the oxygen-oxygen bond allowing one atom to bind two protons producing water. The second oxygen joins the substrate in what is called a monoxygenation reaction <ref> Devlin, Thomas M., ed. Textbook of Biochemistry with Clinical Correlations. 6th ed. Hoboken: John Wiley, 2006. Print.</ref>.

[[Image:Proteo.gif]]

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The gene encoding CYP3A4 is located on chromosome 7 in the human genome<ref name="e">PMID: 1391968</ref> and it has been found that there are significant variants of the protein correlating to race <ref name="f"> PMID: 11714865</ref>. This finding is relevant due to the proteins altered ability to react with substrates such as testosterone <ref name="g">PMID: 11714865</ref>.

The ~~metal-binding site, the~~ protein pocket where the reactions are catalyzed, ~~are found in~~ the ~~seqence~~ at position 442~~-442~~ [http://www.uniprot.org/uniprot/P08684].

The protein pocket where the reactions are catalyzed, or the<scene name='72/728174/Heme_binding_site/1'>heme binding site</scene> contains twenty-two residues [[http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=4NY4]] but the main interaction is a Cysteine at position 442, which coordinates with iron. [http://www.uniprot.org/uniprot/P08684].

<Structure load='4NY4' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><scene name='72/728174/N_to_c_terminus/1'>Alpha Helices </scene> can be seen colored in rainbow succession from the N to C terminus.

The ~~<scene name='72/728174/Heme_binding_site/1'>heme binding site</scene> contains Cysteine 442, which coordinates with iron.~~

The

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@@ Line 13: / Line 13: @@
 Because water molecules are stripped away when substrate binds, this causes an entropy change of 26 kcal/mol.  This entropy driven reaction has a spontaneous free energy change of -7.7kcal/mol at 21ºC <ref name="d">PMID: 15352783</ref>.
-The cycle begins with the binding of the substrate to the ferric heme.  With the addition of an electron, the heme gets reduced. This can only happen once the substrate is bound because the reduction potential is -300V while in that state and is more electronegative. After substrate binding, the induced conformational shift causes the reduction potential to be more positive at -230V making this a more thermodynamically favorable reaction.  Oxygen next binds to the heme and oxidizes the iron. The addition of a second electron cleaves the oxygen-oxygen bond allowing one atom to bind two protons producing water. The second oxygen joins the substrate in what is called a monoxygenation reaction  <ref> Devlin, Thomas M., ed. Textbook of Biochemistry with Clinical Correlations. 6th ed. Hoboken: John Wiley, 2006. Print.</ref>.
+The cycle begins with the binding of the substrate to the ferric heme.  With the addition of an electron, the heme gets reduced. This can only happen once the substrate is bound because the reduction potential is -300V which is more electronegative. After substrate binding, the induced conformational shift causes the reduction potential to be more positive at -230V making this a more thermodynamically favorable reaction.  Oxygen next binds to the heme and oxidizes the iron. The addition of a second electron cleaves the oxygen-oxygen bond allowing one atom to bind two protons producing water. The second oxygen joins the substrate in what is called a monoxygenation reaction  <ref> Devlin, Thomas M., ed. Textbook of Biochemistry with Clinical Correlations. 6th ed. Hoboken: John Wiley, 2006. Print.</ref>.
 [[Image:Proteo.gif]]
@@ Line 22: / Line 22: @@
 The gene encoding CYP3A4 is located on chromosome 7 in the human genome<ref name="e">PMID: 1391968</ref> and it has been found that there are significant  variants of the protein correlating to race <ref name="f"> PMID: 11714865</ref>. This finding is relevant due to the proteins altered ability to react with substrates such as testosterone <ref name="g">PMID: 11714865</ref>.
-The metal-binding site, the protein pocket where the reactions are catalyzed, are found in the seqence at position 442-442 [http://www.uniprot.org/uniprot/P08684].
+The protein pocket where the reactions are catalyzed, or the<scene name='72/728174/Heme_binding_site/1'>heme binding site</scene> contains twenty-two residues [[http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=4NY4]] but the main interaction is a Cysteine at position 442, which coordinates with iron. [http://www.uniprot.org/uniprot/P08684].
 <Structure load='4NY4' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><scene name='72/728174/N_to_c_terminus/1'>Alpha Helices </scene> can be seen colored in rainbow succession from the N to C terminus.
-The <scene name='72/728174/Heme_binding_site/1'>heme binding site</scene> contains Cysteine 442, which coordinates with iron.
+The
 == Mutations/Defects ==