Aspartate protease
Encyclopedia
Aspartic proteases are a family
of protease
enzymes that use an aspartate residue 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
.
Aspartic endopeptidases of vertebrate, fungal and retroviral origin have been characterised. More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin and archaean preflagellin have been described.
Eukaryotic aspartic proteases include pepsin
s, cathepsin
s, and renin
s. They have a two-domain structure, arising from ancestral duplication. Retroviral
and retrotransposon
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.
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. One aspartate activates the water by abstracting a proton, enabling the water to attack the carbonyl
carbon of the substrate scissile bond, generating a tetrahedral
oxyanion
intermediate
. Rearrangement of this intermediate leads to protonation of the scissile amide
.
and propeptides
. The animal
pepsin-like endopeptidase propeptides form a distinct family of propeptides, which contain a conserved
motif
approximately 30 residue
s 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.
; BACE1; BACE2
; CTSD
; CTSE
; NAPSA
; PGA5
; PGC
;
REN
;
Protein family
A protein family is a group of evolutionarily-related proteins, and is often nearly synonymous with gene family. The term protein family should not be confused with family as it is used in taxonomy....
of protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
enzymes that use an aspartate residue for catalysis of their peptide substrates. In general, they have two highly-conserved aspartates in the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
and are optimally active at acidic pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
. Nearly all known aspartyl proteases are inhibited by pepstatin
Pepstatin
Pepstatin is a potent inhibitor of aspartyl proteases. It is a hexa-peptide containing the unusual amino acid statine , having the sequence Isovaleryl-Val-Val-Sta-Ala-Sta...
.
Aspartic endopeptidases of vertebrate, fungal and retroviral origin have been characterised. More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin and archaean preflagellin have been described.
Eukaryotic aspartic proteases include pepsin
Pepsin
Pepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
s, cathepsin
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...
s, and renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
s. They have a two-domain structure, arising from ancestral duplication. Retroviral
HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
and retrotransposon
Retrotransposon
Retrotransposons are genetic elements that can amplify themselves in a genome and are ubiquitous components of the DNA of many eukaryotic organisms. They are a subclass of transposon. They are particularly abundant in plants, where they are often a principal component of nuclear DNA...
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.
Examples
- HIV-1 proteaseHIV-1 proteaseHIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
- a major drug-target for treatment of HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive... - ChymosinChymosinChymosin or rennin is an enzyme found in rennet. It is produced by cows in the lining of the abomasum...
(or "rennin") - ReninReninRenin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
- Cathepsin D
- PepsinPepsinPepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
- PlasmepsinPlasmepsinPlasmepsins are a class of at least 10 enzymes produced by the plasmodium parasite. There are ten different isoforms of these proteins and ten genes coding them respectively in plasmodium falciparum . It has been suggested that the plasmpesin family is smaller in other human plasmodium species...
- NepenthesinNepenthesinNepenthesin is an aspartic protease of plant origin that has so far been identified in the pitcher secretions of Nepenthes and in the leaves of Drosera peltata. It is similar to pepsin, but differs in that it also cleaves on either side of Asp residues and at Lys┼Arg...
Catalytic Mechanism
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
carbon of the substrate scissile bond, generating a tetrahedral
Tetrahedron
In geometry, a tetrahedron is a polyhedron composed of four triangular faces, three of which meet at each vertex. A regular tetrahedron is one in which the four triangles are regular, or "equilateral", and is one of the Platonic solids...
oxyanion
Oxyanion
An oxyanion or oxoanion is a chemical compound with the generic formula AxOyz− . Oxoanions are formed by a large majority of the chemical elements. The formulae of simple oxoanions are determined by the octet rule...
intermediate
Reaction intermediate
A reaction intermediate or an intermediate is a molecular entity that is formed from the reactants and reacts further to give the directly observed products of a chemical reaction. Most chemical reactions are stepwise, that is they take more than one elementary step to complete...
. Rearrangement of this intermediate leads to protonation of the scissile amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
.
Propeptide
Many eukaryotic aspartic endopeptidases (MEROPS peptidase family A1) are synthesised with signalSignal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
and propeptides
Protein precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein that can be turned into an active form by posttranslational modification. The name of the precursor for a protein is often prefixed by pro...
. The animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
pepsin-like endopeptidase propeptides form a distinct family of propeptides, which contain a conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
approximately 30 residue
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
s long. In pepsinogen A, the first 11 residues of the mature pepsin
Pepsin
Pepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
sequence are displaced by residues of the propeptide. The propeptide contains two helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
that block the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
cleft, in particular the conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
Asp11 residue, in pepsin, hydrogen bonds to a conserved Arg residue in the propeptide. This hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
stabilises the propeptide conformation and is probably responsible for triggering the conversion of pepsinogen to pepsin under acidic conditions.
Human proteins containing this domain
BACEBace
Bace is a village in the municipality of Prokuplje, Serbia. According to the 2002 census, the village has a population of 284 people.-References:...
; BACE1; BACE2
BACE2
Beta-secretase 2 is an enzyme that in humans is encoded by the BACE2 gene.BACE2 is a close homolog of BACE1, a protease known to be an important enzyme involved in the cellular pathways that some believe lead to Alzheimer's disease...
; CTSD
CTSD
Cathepsin D is a protein that in humans is encoded by the CTSD gene.It has been used as a breast cancer tumor marker.Cathepsin-D is an aspartic protease that depends critically on protonation of its active site Asp residue and gets activated at pH 5 in endosome of hepatocytes where it degrades...
; CTSE
CTSE
Cathepsin E is a protein that in humans is encoded by the CTSE gene.-External links:* The MEROPS online database for peptidases and their inhibitors:...
; NAPSA
NAPSA
Napsin-A is a protein that in humans is encoded by the NAPSA gene.-Further reading:...
; PGA5
PGA5
Pepsin A is a protein that in humans is encoded by the PGA5 gene.-Further reading:...
; PGC
PGC (gene)
Gastricsin also known as pepsinogen C is an enzyme that in humans is encoded by the PGC gene.- Function :Gastricsin is an aspartic proteinase that belongs to the peptidase family A1. The encoded protein is a digestive enzyme that is produced in the stomach and constitutes a major component of the...
;
REN
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
;
External links
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: Aspartic Peptidases - MEROPS family A1