Sandbox Reserved 489: Difference between revisions
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The precursor of renin is a 406 amino acid residue protein. <scene name='Sandbox_Reserved_489/Signal_domain/1'>Residues 1-23</scene> are a signal peptide sequence and residues 24-66 are cleaved to produce the mature 340 amino acid residue <scene name='Sandbox_Reserved_489/Mature_renin/1'>mature renin</scene>. The secondary structural elements of renin include <scene name='Sandbox_Reserved_489/Betasheetscolors/1'>29 antiparallel beta sheets</scene>, <scene name='Sandbox_Reserved_489/Betabridges/1'>3 beta bridges</scene>, <scene name='Sandbox_Reserved_489/Alphahelixes/1'>4 alpha helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'>2 3-10 helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>. The most impressive structural feature of renin is the <scene name='Sandbox_Reserved_489/Betasheetspiral/1'>antiparallel beta sheet</scene> that forms the two similar lobes of renin. <scene name='Sandbox_Reserved_489/Hydrophobichydrophillic/1'>Hydrophilic (blue) and hydrophobic (red) residues</scene> are located primarily on the outside and inside portions of renin respectively. The most important structure is the <scene name='Sandbox_Reserved_489/Hydrophobicactivesite/1'>hydrophobic pocket</scene> located in the active site that allows substrate binding. The active site of renin contains two essential <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>aspartate residues</scene>. Renin has <scene name='Sandbox_Reserved_489/Catalyticmotifs/1'>two catalytic motifs</scene> after each of the two aspartate residues. Renin also uses a <scene name='Sandbox_Reserved_489/Activesiteflap/1'>active site flap</scene>, a beta hairpin structure, that open and closes to uncover or cover the active site.<ref>PMID: 2493678</ref> | The precursor of renin is a 406 amino acid residue protein. <scene name='Sandbox_Reserved_489/Signal_domain/1'>Residues 1-23</scene> are a signal peptide sequence and residues 24-66 are cleaved to produce the mature 340 amino acid residue <scene name='Sandbox_Reserved_489/Mature_renin/1'>mature renin</scene>. The secondary structural elements of renin include <scene name='Sandbox_Reserved_489/Betasheetscolors/1'>29 antiparallel beta sheets</scene>, <scene name='Sandbox_Reserved_489/Betabridges/1'>3 beta bridges</scene>, <scene name='Sandbox_Reserved_489/Alphahelixes/1'>4 alpha helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'>2 3-10 helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>. The most impressive structural feature of renin is the <scene name='Sandbox_Reserved_489/Betasheetspiral/1'>antiparallel beta sheet</scene> that forms the two similar lobes of renin. <scene name='Sandbox_Reserved_489/Hydrophobichydrophillic/1'>Hydrophilic (blue) and hydrophobic (red) residues</scene> are located primarily on the outside and inside portions of renin respectively. The most important structure is the <scene name='Sandbox_Reserved_489/Hydrophobicactivesite/1'>hydrophobic pocket</scene> located in the active site that allows substrate binding. The active site of renin contains two essential <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>aspartate residues</scene>. Renin has <scene name='Sandbox_Reserved_489/Catalyticmotifs/1'>two catalytic motifs</scene> after each of the two aspartate residues. Renin also uses a <scene name='Sandbox_Reserved_489/Activesiteflap/1'>active site flap</scene>, a beta hairpin structure, that open and closes to uncover or cover the active site.<ref>PMID: 2493678</ref> | ||
Post translational modifications of renin include; precursor cleavage of propetide to produce active mature renin, disulfide bond formation, and glycosylation of certain residues. Disulfide bonds are form to connect serine residues <scene name='Sandbox_Reserved_489/Disulfidebond1/1'>51 to 58</scene>, <scene name='Sandbox_Reserved_489/Disulfidebond2/1'>217 to 221</scene>, and <scene name='Sandbox_Reserved_489/Disulfidebond3/1'>259 to 296</scene>. <scene name='Sandbox_Reserved_489/Glycosylated/2'>Two asparagine residues</scene> at positions 14 and 75 can be glycosylated. The asparagine residue at postion 75 is glycosylated (2-(acetylamino)-2-deoxy-A-D-glucopyranose) in mature renin whereas the residue at postion 14 is not glycosylated. | Post translational modifications of renin include; precursor cleavage of propetide to produce active mature renin, disulfide bond formation, and glycosylation of certain residues. Disulfide bonds are form to connect serine residues <scene name='Sandbox_Reserved_489/Disulfidebond1/1'>51 to 58</scene>, <scene name='Sandbox_Reserved_489/Disulfidebond2/1'>217 to 221</scene>, and <scene name='Sandbox_Reserved_489/Disulfidebond3/1'>259 to 296</scene>. <scene name='Sandbox_Reserved_489/Glycosylated/2'>Two asparagine residues</scene> at positions 14 and 75 can be glycosylated. The asparagine residue at postion 75 is glycosylated (2-(acetylamino)-2-deoxy-A-D-glucopyranose) in mature renin whereas the residue at postion 14 is not glycosylated.<ref>Margrane M. and the UnitProt consortium, '''Uniprot Knowledgebase: a hub of integrated protein data''', Database, 2012: bar009 (2011). Public Accession Number P00797 </ref> | ||
The structure of recombinant human renin has been solved using X-ray diffraction at 2.5 angstrom resolution. | The structure of recombinant human renin has been solved using X-ray diffraction at 2.5 angstrom resolution. | ||
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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. | 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. | ||
Renin can also bind the renin receptor [http://en.wikipedia.org/wiki/ATP6AP2 ATPase H(+)-transporting lysosomal accessory protein 2] (ATP6AP2) to convert angiotensinogen to angiotensin I at a much greater rate. | Renin can also bind the renin receptor [http://en.wikipedia.org/wiki/ATP6AP2 ATPase H(+)-transporting lysosomal accessory protein 2] (ATP6AP2) to convert angiotensinogen to angiotensin I at a much greater rate.<ref>PMID: 12045255</ref> | ||
==Renin Inhibitors== | ==Renin Inhibitors== | ||
