Aspartic proteases are a catalytic type of
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
enzymes
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that use an activated water molecule bound to one or more
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
residues for catalysis of their peptide substrates. In general, they have two highly conserved
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
s in the
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
and are optimally active at acidic
pH. Nearly all known aspartyl proteases are inhibited by
pepstatin
Pepstatin is a potent inhibitor of aspartyl proteases. It is a hexa-peptide containing the unusual amino acid statine (Sta, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), having the sequence Isovaleryl-Val-Val-Sta-Ala-Sta (Iva-Val-Val-Sta-Al ...
.
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 is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
s,
cathepsin
Cathepsins (Ancient Greek ''kata-'' "down" and ''hepsein'' "boil"; abbreviated CTS) are proteases (enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are di ...
s, and
renin
Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...
s. They have a two-domain structure, arising from ancestral duplication.
Retroviral
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptas ...
and
retrotransposon
Retrotransposons (also called Class I transposable elements or transposons via RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through ...
proteases (
retroviral aspartyl protease
Retroviral aspartyl proteases or retropepsins are single domain aspartyl proteases from retroviruses, retrotransposons, and badnaviruses (plant dsDNA viruses). These proteases are generally part of a larger pol or gag polyprotein. Retroviral ...
s) 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
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
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
or
cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal Chund ...
s 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
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
residues.
One aspartate activates the water by abstracting a proton, enabling the water to perform a
nucleophilic
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
attack on the
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. A compound containing a ...
carbon of the substrate
scissile bond In molecular biology, a scissile bond is a covalent chemical bond that can be broken by an enzyme. Examples would be the cleaved bond in the self-cleaving hammerhead ribozyme or the peptide bond
In organic chemistry, a peptide bond is an amide ...
, generating a
tetrahedral
In geometry, a tetrahedron (plural: tetrahedra or tetrahedrons), also known as a triangular pyramid, is a polyhedron composed of four triangular faces, six straight edges, and four vertex corners. The tetrahedron is the simplest of all the o ...
oxyanion An oxyanion, or oxoanion, is an ion with the generic formula (where A represents a chemical element and O represents an oxygen atom). Oxyanions are formed by a large majority of the chemical elements. The formulae of simple oxyanions are determine ...
intermediate stabilized by hydrogen-bonding with the second aspartic acid. Rearrangement of this intermediate leads to protonation of the scissile
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
which results in the splitting of the substrate peptide into two product peptides.
Inhibition
Pepstatin
Pepstatin is a potent inhibitor of aspartyl proteases. It is a hexa-peptide containing the unusual amino acid statine (Sta, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), having the sequence Isovaleryl-Val-Val-Sta-Ala-Sta (Iva-Val-Val-Sta-Al ...
is an inhibitor of aspartate proteases.
Classification
Five
superfamilies (clans) of aspartic proteases are known, each representing an
independent evolution of the same
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
and
mechanisms. Each superfamily contains several
families
Family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its members and of society. Ideall ...
with similar sequences. The
MEROPS
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitor ...
classification systematic names these clans alphabetically.
*Clan AA (e.g.
Pepsin
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
family)
*Clan AC (e.g.
Signal peptidase II family)
*Clan AD (e.g.
Presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset ...
family)
*Clan AE (e.g.
GPR endopeptidase
GPR endopeptidase (, ''germination proteinase'') is an enzyme. This enzyme catalysis, catalyses the following chemical reaction:
: Endopeptidase action with P4 Glu or Asp, P1 preferably Glu > Asp, P1' hydrophobic and P2' Ala
This enzyme participa ...
family)
*Clan AF (e.g.
Omptin
Omptins (, ''protease VII'', ''protease A'', ''gene ompT proteins'', ''ompT protease'', ''protein a'', ''Pla'', ''OmpT'') are a family of bacterial proteases. They are aspartate proteases, which cleave peptides with the use of a water molecule. F ...
family)
Propeptide
Many
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
aspartic endopeptidases (MEROPS
peptidase
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the fo ...
family A1) are synthesised with
signal
In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...
and
propeptides
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecule ...
. The
animal
Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
pepsin-like endopeptidase propeptides form a distinct family of propeptides, which contain a
conserved motif approximately 30
residue
Residue may refer to:
Chemistry and biology
* An amino acid, within a peptide chain
* Crop residue, materials left after agricultural processes
* Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...
s long. In
pepsinogen
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, whe ...
A, the first 11 residues of the mature
pepsin
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
are displaced by residues of the propeptide. The propeptide contains two
helices
A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helices, ...
that block the
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
cleft, in particular the
conserved Asp11 residue, in pepsin,
hydrogen bonds
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
to a
conserved Arg residue in the propeptide. This
hydrogen bond
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
stabilises the propeptide
conformation and is probably responsible for triggering the conversion of pepsinogen to pepsin under
acidic
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
conditions.
Examples
Human
*
BACE1
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enco ...
,
BACE2
Beta-secretase 2 (, also known as Memapsin-1) is an enzyme that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.
Function
Cerebral deposition of amyloid ...
*
Cathepsin D
Cathepsin D is a protein that in humans is encoded by the ''CTSD'' gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathe ...
*
Cathepsin E
Cathepsin E is an enzyme () that in humans is encoded by the ''CTSE'' gene. The enzyme is also known as ''slow-moving proteinase'', ''erythrocyte membrane aspartic proteinase'', ''SMP'', ''EMAP'', ''non-pepsin proteinase'', ''cathepsin D-like aci ...
*
Chymosin
Chymosin or rennin is a protease found in rennet. It is an aspartic endopeptidase belonging to MEROPS A1 family. It is produced by newborn ruminant animals in the lining of the abomasum to curdle the milk they ingest, allowing a longer residen ...
(or "rennin")
*
Napsin-A
Napsin-A is an aspartic proteinase that is encoded in humans by the NAPSA gene. The name napsin comes from ''n''ovel ''a''spartic ''p''roteinase of the pep''sin'' family.
The activation peptide of an aspartic proteinase acts as an inhibitor o ...
*
Nepenthesin
Nepenthesin (also spelled nepenthacin or nepenthasin) 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 ...
*
Pepsin
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
*
Presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset ...
*
Renin
Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...
Human proteins containing this domain
BACE1
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enco ...
;
BACE2
Beta-secretase 2 (, also known as Memapsin-1) is an enzyme that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.
Function
Cerebral deposition of amyloid ...
;
CTSD
Cathepsin D is a protein that in humans is encoded by the ''CTSD'' gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathe ...
;
CTSE;
NAPSA
Napsin-A is an aspartic proteinase that is encoded in humans by the NAPSA gene. The name napsin comes from ''n''ovel ''a''spartic ''p''roteinase of the pep''sin'' family.
The activation peptide of an aspartic proteinase acts as an inhibitor of ...
;
PGA5;
PGC;
REN Ren or REN may refer to:
Abbreviations
* Orenburg Tsentralny Airport, IATA code REN, civil airport in Russia
* Redes Energéticas Nacionais (REN), Portuguese company
* Renanthera, abbreviated as Ren, orchid genus
* Ringer equivalence number ( ...
;
Other organisms
*
HIV-1 protease
HIV-1 protease (PR) is a retroviral aspartyl protease (retropepsin), an enzyme involved with peptide bond hydrolysis in retroviruses, that is essential for the life-cycle of HIV, the retrovirus that causes AIDS. HIV protease cleaves newly synthes ...
– a major drug-target for treatment of
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
*
Plasmepsin
Plasmepsins are a class of at least 10 enzymes ( and ) produced by the ''Plasmodium falciparum'' parasite. There are ten different isoforms of these proteins and ten genes coding them respectively in ''Plasmodium'' (Plm I, II, III, IV, V, VI, VII ...
– a group of aspartyl proteases found in the
Malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
-causing parasite
Plasmodium
''Plasmodium'' is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of ''Plasmodium'' species involve development in a blood-feeding insect host which then injects parasites into a vert ...
See also
*
Glutamic protease
Glutamic proteases are a group of proteolytic enzymes containing a glutamic acid residue within the active site. This type of protease was first described in 2004 and became the sixth catalytic type of protease. Members of this group of protease ha ...
*
The Proteolysis Map
The Proteolysis MAP (PMAP) is an integrated web resource focused on proteases.
Rationale
PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.
History and funding
PMAP was originally created at ...
References
External links
* The
MEROPS
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitor ...
online database for peptidases and their inhibitors
Aspartic Peptidases*
MEROPS family A1
{{DEFAULTSORT:Aspartate Protease
Protein domains
Protein families
Peripheral membrane proteins
EC 3.4.23