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Aspartic protease

Aspartic proteases (also "aspartyl proteases", "aspartic endopeptidases") are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues for catalysis of their peptide substrates. In general, they have two highly conserved aspartates in the active site and are optimally active at acidic pH. Nearly all known aspartyl proteases are inhibited by pepstatin.[1]

Eukaryotic aspartyl protease
Structure of the dimeric aspartic protease HIV protease in white and grey, with peptide substrate in black and active site aspartate side chains in red. (PDB: 1KJF​)
Identifiers
SymbolAsp
PfamPF00026
InterProIPR001461
PROSITEPDOC00128
SCOP21mpp / SCOPe / SUPFAM
OPM superfamily100
OPM protein1lyb
Membranome315
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Aspartic endopeptidases EC 3.4.23. of vertebrate, fungal and retroviral origin have been characterised.[2] More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin[3] and archaean preflagellin have been described.[4][5]

Eukaryotic aspartic proteases include pepsins, cathepsins, and renins. They have a two-domain structure, arising from ancestral duplication. Retroviral and retrotransposon proteases (retroviral aspartyl proteases) are much smaller and appear to be homologous to a single domain of the eukaryotic aspartyl proteases. Each domain contributes a catalytic Asp residue, with an extended active site cleft localized between the two lobes of the molecule. One lobe has probably evolved from the other through a gene duplication event in the distant past. In modern-day enzymes, although the three-dimensional structures are very similar, the amino acid sequences are more divergent, except for the catalytic site motif, which is very conserved. The presence and position of disulfide bridges are other conserved features of aspartic peptidases.

Catalytic mechanism edit

 
Proposed mechanism of peptide cleavage by aspartyl proteases.[6]

Aspartyl proteases are a highly specific family of proteases – they tend to cleave dipeptide bonds that have hydrophobic residues as well as a beta-methylene group. Unlike serine or cysteine proteases these proteases do not form a covalent intermediate during cleavage. Proteolysis therefore occurs in a single step.

While a number of different mechanisms for aspartyl proteases have been proposed, the most widely accepted is a general acid-base mechanism involving coordination of a water molecule between the two highly conserved aspartate residues.[6][7] One aspartate activates the water by abstracting a proton, enabling the water to perform a nucleophilic attack on the carbonyl carbon of the substrate scissile bond, generating a tetrahedral oxyanion intermediate stabilized by hydrogen-bonding with the second aspartic acid. Rearrangement of this intermediate leads to protonation of the scissile amide which results in the splitting of the substrate peptide into two product peptides.

Inhibition edit

Pepstatin is an inhibitor of aspartate proteases.[1]

Classification edit

Five superfamilies (clans) of aspartic proteases are known, each representing an independent evolution of the same active site and mechanisms. Each superfamily contains several families with similar sequences. The MEROPS classification systematic names these clans alphabetically.

Propeptide edit

A1_Propeptide
 
crystal and molecular structures of human progastricsin at 1.62 angstroms resolution
Identifiers
SymbolA1_Propeptide
PfamPF07966
InterProIPR012848
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Many eukaryotic aspartic endopeptidases (MEROPS peptidase family A1) are synthesised with signal and propeptides. The animal pepsin-like endopeptidase propeptides form a distinct family of propeptides, which contain a conserved motif approximately 30 residues long. In pepsinogen A, the first 11 residues of the mature pepsin sequence are displaced by residues of the propeptide. The propeptide contains two helices that block the active site cleft, in particular the conserved Asp11 residue, in pepsin, hydrogen bonds to a conserved Arg residue in the propeptide. This hydrogen bond stabilises the propeptide conformation and is probably responsible for triggering the conversion of pepsinogen to pepsin under acidic conditions.[8][9]

Examples edit

Human edit

Human proteins containing this domain edit

BACE1; BACE2; CTSD; CTSE; NAPSA; PGA5; PGC; REN;

Other organisms edit

See also edit

References edit

  1. ^ a b Fusek M, Mares M, Vetvicka V (2013-01-01). "Chapter 8 - Cathepsin D". In Rawlings ND, Salvesen G (eds.). Handbook of Proteolytic Enzymes (Third ed.). Academic Press. pp. 54–63. doi:10.1016/b978-0-12-382219-2.00008-9. ISBN 978-0-12-382219-2.
  2. ^ Szecsi PB (1992). "The aspartic proteases". Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum. 210: 5–22. doi:10.3109/00365519209104650. PMID 1455179.
  3. ^ LaPointe CF, Taylor RK (January 2000). "The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases". The Journal of Biological Chemistry. 275 (2): 1502–10. doi:10.1074/jbc.275.2.1502. PMID 10625704.
  4. ^ Ng SY, Chaban B, Jarrell KF (2006). "Archaeal flagella, bacterial flagella and type IV pili: a comparison of genes and posttranslational modifications". Journal of Molecular Microbiology and Biotechnology. 11 (3–5): 167–91. doi:10.1159/000094053. PMID 16983194. S2CID 30386932.
  5. ^ Bardy SL, Jarrell KF (November 2003). "Cleavage of preflagellins by an aspartic acid signal peptidase is essential for flagellation in the archaeon Methanococcus voltae". Molecular Microbiology. 50 (4): 1339–47. doi:10.1046/j.1365-2958.2003.03758.x. PMID 14622420. S2CID 11913649.
  6. ^ a b Suguna K, Padlan EA, Smith CW, Carlson WD, Davies DR (October 1987). "Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action". Proceedings of the National Academy of Sciences of the United States of America. 84 (20): 7009–13. Bibcode:1987PNAS...84.7009S. doi:10.1073/pnas.84.20.7009. PMC 299218. PMID 3313384.
  7. ^ Brik A, Wong CH (January 2003). "HIV-1 protease: mechanism and drug discovery". Organic & Biomolecular Chemistry. 1 (1): 5–14. doi:10.1039/b208248a. PMID 12929379.
  8. ^ Hartsuck JA, Koelsch G, Remington SJ (May 1992). "The high-resolution crystal structure of porcine pepsinogen". Proteins. 13 (1): 1–25. doi:10.1002/prot.340130102. PMID 1594574. S2CID 43462673.
  9. ^ Sielecki AR, Fujinaga M, Read RJ, James MN (June 1991). "Refined structure of porcine pepsinogen at 1.8 A resolution". Journal of Molecular Biology. 219 (4): 671–92. doi:10.1016/0022-2836(91)90664-R. PMID 2056534.

External links edit

  • The MEROPS online database for peptidases and their inhibitors: Aspartic Peptidases
  • Aspartic+Endopeptidases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • MEROPS family A1
This article incorporates text from the public domain Pfam and InterPro: IPR000036
This article incorporates text from the public domain Pfam and InterPro: IPR012848

aspartic, protease, also, aspartyl, proteases, aspartic, endopeptidases, catalytic, type, protease, enzymes, that, activated, water, molecule, bound, more, aspartate, residues, catalysis, their, peptide, substrates, general, they, have, highly, conserved, aspa. Aspartic proteases also aspartyl proteases aspartic endopeptidases are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues for catalysis of their peptide substrates In general they have two highly conserved aspartates in the active site and are optimally active at acidic pH Nearly all known aspartyl proteases are inhibited by pepstatin 1 Eukaryotic aspartyl proteaseStructure of the dimeric aspartic protease HIV protease in white and grey with peptide substrate in black and active site aspartate side chains in red PDB 1KJF IdentifiersSymbolAspPfamPF00026InterProIPR001461PROSITEPDOC00128SCOP21mpp SCOPe SUPFAMOPM superfamily100OPM protein1lybMembranome315Available protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryAspartic endopeptidases EC 3 4 23 of vertebrate fungal and retroviral origin have been characterised 2 More recently aspartic endopeptidases associated with the processing of bacterial type 4 prepilin 3 and archaean preflagellin have been described 4 5 Eukaryotic aspartic proteases include pepsins cathepsins and renins They have a two domain structure arising from ancestral duplication Retroviral and retrotransposon proteases retroviral aspartyl proteases are much smaller and appear to be homologous to a single domain of the eukaryotic aspartyl proteases Each domain contributes a catalytic Asp residue with an extended active site cleft localized between the two lobes of the molecule One lobe has probably evolved from the other through a gene duplication event in the distant past In modern day enzymes although the three dimensional structures are very similar the amino acid sequences are more divergent except for the catalytic site motif which is very conserved The presence and position of disulfide bridges are other conserved features of aspartic peptidases Contents 1 Catalytic mechanism 2 Inhibition 3 Classification 4 Propeptide 5 Examples 5 1 Human 5 2 Human proteins containing this domain 5 3 Other organisms 6 See also 7 References 8 External linksCatalytic mechanism edit nbsp Proposed mechanism of peptide cleavage by aspartyl proteases 6 Aspartyl proteases are a highly specific family of proteases they tend to cleave dipeptide bonds that have hydrophobic residues as well as a beta methylene group Unlike serine or cysteine proteases these proteases do not form a covalent intermediate during cleavage Proteolysis therefore occurs in a single step While a number of different mechanisms for aspartyl proteases have been proposed the most widely accepted is a general acid base mechanism involving coordination of a water molecule between the two highly conserved aspartate residues 6 7 One aspartate activates the water by abstracting a proton enabling the water to perform a nucleophilic attack on the carbonyl carbon of the substrate scissile bond generating a tetrahedral oxyanion intermediate stabilized by hydrogen bonding with the second aspartic acid Rearrangement of this intermediate leads to protonation of the scissile amide which results in the splitting of the substrate peptide into two product peptides Inhibition editPepstatin is an inhibitor of aspartate proteases 1 Classification editFive superfamilies clans of aspartic proteases are known each representing an independent evolution of the same active site and mechanisms Each superfamily contains several families with similar sequences The MEROPS classification systematic names these clans alphabetically Clan AA e g Pepsin family Clan AC e g Signal peptidase II family Clan AD e g Presenilin family Clan AE e g GPR endopeptidase family Clan AF e g Omptin family Propeptide editA1 Propeptide nbsp crystal and molecular structures of human progastricsin at 1 62 angstroms resolutionIdentifiersSymbolA1 PropeptidePfamPF07966InterProIPR012848Available protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryMany eukaryotic aspartic endopeptidases MEROPS peptidase family A1 are synthesised with signal and propeptides The animal pepsin like endopeptidase propeptides form a distinct family of propeptides which contain a conserved motif approximately 30 residues long In pepsinogen A the first 11 residues of the mature pepsin sequence are displaced by residues of the propeptide The propeptide contains two helices that block the active site cleft in particular the conserved Asp11 residue in pepsin hydrogen bonds to a conserved Arg residue in the propeptide This hydrogen bond stabilises the propeptide conformation and is probably responsible for triggering the conversion of pepsinogen to pepsin under acidic conditions 8 9 Examples editHuman edit BACE1 BACE2 Cathepsin D Cathepsin E Chymosin or rennin Napsin A Nepenthesin Pepsin Presenilin ReninHuman proteins containing this domain edit BACE1 BACE2 CTSD CTSE NAPSA PGA5 PGC REN Other organisms edit HIV 1 protease a major drug target for treatment of HIV Plasmepsin a group of aspartyl proteases found in the Malaria causing parasite PlasmodiumSee also editGlutamic protease The Proteolysis MapReferences edit a b Fusek M Mares M Vetvicka V 2013 01 01 Chapter 8 Cathepsin D In Rawlings ND Salvesen G eds Handbook of Proteolytic Enzymes Third ed Academic Press pp 54 63 doi 10 1016 b978 0 12 382219 2 00008 9 ISBN 978 0 12 382219 2 Szecsi PB 1992 The aspartic proteases Scandinavian Journal of Clinical and Laboratory Investigation Supplementum 210 5 22 doi 10 3109 00365519209104650 PMID 1455179 LaPointe CF Taylor RK January 2000 The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases The Journal of Biological Chemistry 275 2 1502 10 doi 10 1074 jbc 275 2 1502 PMID 10625704 Ng SY Chaban B Jarrell KF 2006 Archaeal flagella bacterial flagella and type IV pili a comparison of genes and posttranslational modifications Journal of Molecular Microbiology and Biotechnology 11 3 5 167 91 doi 10 1159 000094053 PMID 16983194 S2CID 30386932 Bardy SL Jarrell KF November 2003 Cleavage of preflagellins by an aspartic acid signal peptidase is essential for flagellation in the archaeon Methanococcus voltae Molecular Microbiology 50 4 1339 47 doi 10 1046 j 1365 2958 2003 03758 x PMID 14622420 S2CID 11913649 a b Suguna K Padlan EA Smith CW Carlson WD Davies DR October 1987 Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis implications for a mechanism of action Proceedings of the National Academy of Sciences of the United States of America 84 20 7009 13 Bibcode 1987PNAS 84 7009S doi 10 1073 pnas 84 20 7009 PMC 299218 PMID 3313384 Brik A Wong CH January 2003 HIV 1 protease mechanism and drug discovery Organic amp Biomolecular Chemistry 1 1 5 14 doi 10 1039 b208248a PMID 12929379 Hartsuck JA Koelsch G Remington SJ May 1992 The high resolution crystal structure of porcine pepsinogen Proteins 13 1 1 25 doi 10 1002 prot 340130102 PMID 1594574 S2CID 43462673 Sielecki AR Fujinaga M Read RJ James MN June 1991 Refined structure of porcine pepsinogen at 1 8 A resolution Journal of Molecular Biology 219 4 671 92 doi 10 1016 0022 2836 91 90664 R PMID 2056534 External links editThe MEROPS online database for peptidases and their inhibitors Aspartic Peptidases Aspartic Endopeptidases at the U S National Library of Medicine Medical Subject Headings MeSH MEROPS family A1This article incorporates text from the public domain Pfam and InterPro IPR000036 This article incorporates text from the public domain Pfam and InterPro IPR012848 Portal nbsp Biology Retrieved from https en wikipedia org w index php title Aspartic protease amp oldid 1141074837, wikipedia, wiki, book, books, library,

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