Sandbox Reserved 489: Difference between revisions

The substrate of renin, angiotensinogen, is a 452 amino acid residue in humans.  Renin utilizes two aspartate residues in the <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>active site</scene> to cleave the peptide bond between leucine and valine residues on angiotensinogen.  Angiotensin I is an inactive short peptide of 10 amino acids that is produced by the renin cleavage reaction.  The two aspartate residues operate most efficiently at acidic pH because one of the carbonyl groups must be deprotonated to accept a proton from water.  The mechanism of the catalysis is an acid base transfer of water between the two aspartate residues.  Initially one aspartate residue carbonyl is deprotonated and the other is protonated.  The deprotonated aspartate removes a proton from water allowing the water to attack the carbonyl of the beptide bond in the substrate forming a tetrahedral oxyanion intermediate on the substrate.  Rearrangement of the intermediate causes protonation of the amide on the substrate completing the cleavage reaction.

There are three generations of renin inhibitors.  The first two generation molecules were peptide molecules.  These peptide molecules were not specific or effective as renin inhibitors.  Aliskiren, part of the 3rd generation, is a nonpeptide renin inhibitor.  Small molecule nonpeptide inhibitors such as Aliskiren have good pharmokenetics and are very specific for renin and not other protein peptidases.  Advancements in crystallography and molecular modeling allowed the discovery of aliskiren.  Aliskiren inhibits renin activity.  Since renin is the rate limiting step of the RAS renin inhibition is a successful method to lower blood pressure.

Aliskiren is a hydrophilic molecule.  When bound to renin, Aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin.  Most importantly Aliskiren occupise the S3SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity.<ref>PMID: 20731374</ref>  Aliskiren interacts with multiple residues in renin.  The hydroxyl group hydrogen bonds both <scene name='Sandbox_Reserved_489/Asp32/1'>aspartate 32</scene> oxygens.  The amine group hydrogen bonds carboxylic acid group of <scene name='Sandbox_Reserved_489/Asp32andgly132/1'>glycine 217 and the oxygen atom of asparate 32</scene>.  The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='Sandbox_Reserved_489/Tyr14/1'>tyrosine 14</scene>.  The amide group hydrogen bonds with the secondary amine of <scene name='Sandbox_Reserved_489/Ser76/2'>serine 76</scene>.<ref>PMID: 20855222</ref>  And the terminal amide hydrogen bonds with <scene name='Sandbox_Reserved_489/Arg_74/1'>arginine 74</scene> in the S2' hydrophobic pocket.<ref>PMID: 21708467</ref>

The structure of renin bound with the inhibitor Aliskiren has been solved using X-ray diffraction at 3.0 angstrom resolution.<ref>PMID: 10903938</ref>