Renin: Difference between revisions
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<StructureSection load='2ren' size='450' side='right' scene='' caption=' | <StructureSection load='2ren' size='450' side='right' scene='' caption='Glycosylated human renin (PDB code [[2ren]])'> | ||
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'''Renin''', also known as angiotensinogenase, is an aspartyl protease and belongs to the protein family peptidase A1. Aspartyl proteases are endopeptidases that typically use two aspartate residues in the active site to specifically cleave peptide substrates using an acid-base hydrolysis mechanism. Mature renin circulates in the blood stream and contains 340 amino acid residues and has a mass of approximately 37 kDa. The function of renin is to cleave angiotensinogen to produce angiotensin I. | == Introduction == | ||
'''Renin''', also known as '''angiotensinogenase''', is an aspartyl protease and belongs to the protein family peptidase A1. Aspartyl proteases are endopeptidases that typically use two aspartate residues in the active site to specifically cleave peptide substrates using an acid-base hydrolysis mechanism. Mature renin circulates in the blood stream and contains 340 amino acid residues and has a mass of approximately 37 kDa. The function of renin is to cleave angiotensinogen to produce angiotensin I. | |||
Renin is secreted by the kidneys. The kidneys act both directly and indirectly to regulate arterial blood pressure and provide the major long term mechanism of blood pressure and control. The direct mechanism changes blood volume independently of hormones. When blood pressure and blood volume increase the kidneys can not filter all of the liquids and thus liquids are lost in the urine to decrease blood pressure and blood volume. | Renin is secreted by the kidneys. The kidneys act both directly and indirectly to regulate arterial blood pressure and provide the major long term mechanism of blood pressure and control. The direct mechanism changes blood volume independently of hormones. When blood pressure and blood volume increase the kidneys can not filter all of the liquids and thus liquids are lost in the urine to decrease blood pressure and blood volume. | ||
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==Structure== | ==Structure== | ||
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 29 <scene name='Sandbox_Reserved_489/Betasheetscolors/1'> antiparallel β sheets</scene>, 3 <scene name='Sandbox_Reserved_489/Betabridges/1'> β bridges</scene>, 4 <scene name='Sandbox_Reserved_489/Alphahelixes/1'> α helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'> 2 </scene>3<sub>10</sub><scene name='Sandbox_Reserved_489/310heleices/1'> helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>. The most impressive structural feature of renin is the antiparallel <scene name='Sandbox_Reserved_489/Betasheetspiral/1'> β 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 β hairpin structure, that open and closes to uncover or cover the active site. | The precursor of renin '''prorenin''' 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 29 <scene name='Sandbox_Reserved_489/Betasheetscolors/1'> antiparallel β sheets</scene>, 3 <scene name='Sandbox_Reserved_489/Betabridges/1'> β bridges</scene>, 4 <scene name='Sandbox_Reserved_489/Alphahelixes/1'> α helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'> 2 </scene>3<sub>10</sub><scene name='Sandbox_Reserved_489/310heleices/1'> helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>. The most impressive structural feature of renin is the antiparallel <scene name='Sandbox_Reserved_489/Betasheetspiral/1'> β 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 β hairpin structure, that open and closes to uncover or cover the active site. | ||
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 formed to connect serine residues <scene name='Sandbox_Reserved_489/Disulfidebond1/2'>51 to 58</scene>, <scene name='Sandbox_Reserved_489/Disulfidebond2/2'>217 to 221</scene>, and <scene name='Sandbox_Reserved_489/Disulfidebond3/2'>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> | 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 formed to connect serine residues <scene name='Sandbox_Reserved_489/Disulfidebond1/2'>51 to 58</scene>, <scene name='Sandbox_Reserved_489/Disulfidebond2/2'>217 to 221</scene>, and <scene name='Sandbox_Reserved_489/Disulfidebond3/2'>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> | ||
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[[Image:Aliskiren.jpg|thumb|400px|alt=text|Aliskiren<ref>PMID:15723979</ref>]] | [[Image:Aliskiren.jpg|thumb|400px|alt=text|Aliskiren<ref>PMID:15723979</ref>]] | ||
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<scene name=' | <scene name='10/1020133/Cv/3'>Renin with bound Aliskiren</scene> ([[2v0z]]). | ||
<scene name='10/1020133/Cv/9'>Aliskiren binding site</scene>. Water molecules are shown as red spheres. | |||
[[Aliskiren]] is a hydrophilic molecule. When bound to renin, aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly aliskiren occupies the S3<sup>SP</sup> 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='10/1020133/Asp32/1'>aspartate 32</scene> oxygens. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='10/1020133/Tyr14/1'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='10/1020133/Ser76/1'>serine 76</scene>.<ref>PMID: 20855222</ref> And the terminal amide hydrogen bonds with <scene name='10/1020133/Arg74/1'>arginine 74</scene> in the S2' hydrophobic pocket.<ref>PMID: 21708467</ref> | |||
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 3<sup>rd</sup> 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. | 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 3<sup>rd</sup> 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 approved by the [http://www.fda.gov/ Federal Drug Administration (FDA)] to treat hypertension. | Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration (FDA)] to treat hypertension. | ||
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Familial juvenile hyperuricemic nephropathy type 2 is also caused by defects in the renin gene. Familial juvenile hyperuricemic nephropathy type 2 is characterized by slowly progressive renal failure and anemia. The autosomal dominant disorder is caused by a deletion of leucine 16 or a mutation of leucine 16 to arginine. The mutations effect the hydrophobicity of the signal sequence and disrupt the proper transport of preprorenin into the endoplasmic reticulum and thus effecting prerenin processing. The mutatnt proteins are toxic and reduce the viability of renin expressing cells, eventually causing renal failure.<ref>PMID:19664745</ref> | Familial juvenile hyperuricemic nephropathy type 2 is also caused by defects in the renin gene. Familial juvenile hyperuricemic nephropathy type 2 is characterized by slowly progressive renal failure and anemia. The autosomal dominant disorder is caused by a deletion of leucine 16 or a mutation of leucine 16 to arginine. The mutations effect the hydrophobicity of the signal sequence and disrupt the proper transport of preprorenin into the endoplasmic reticulum and thus effecting prerenin processing. The mutatnt proteins are toxic and reduce the viability of renin expressing cells, eventually causing renal failure.<ref>PMID:19664745</ref> | ||
==3D structures of renin== | ==3D structures of renin== | ||
[[Renin 3D structures]] | |||
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | ||
==References== | ==References== | ||
<references /> | <references /> | ||
</StructureSection> | |||
[[Category:Topic Page]] | [[Category:Topic Page]] | ||