Catalytic triad

triadactive sitecatalytic tryadtriads
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes.wikipedia
225 Related Articles

Protease

proteasespeptidaseproteinase
Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylases, lipases and β-lactamases).
One way to make a nucleophile is by a catalytic triad, where a histidine residue is used to activate serine, cysteine, or threonine as a nucleophile.

Lipase

lipaseslipase LIPFE1104
Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylases, lipases and β-lactamases). The same triad has also convergently evolved in α/β hydrolases such as some lipases and esterases, however orientation of the triad members is reversed.
However, most are built on an alpha/beta hydrolase fold and employ a chymotrypsin-like hydrolysis mechanism using a catalytic triad consisting of a serine nucleophile, a histidine base, and an acid residue, usually aspartic acid.

Convergent evolution

convergentconvergenceanalogous
As well as divergent evolution of function (and even the triad's nucleophile), catalytic triads show some of the best examples of convergent evolution.
In biochemistry, physical and chemical constraints on mechanisms have caused some active site arrangements such as the catalytic triad to evolve independently in separate enzyme superfamilies.

Papain

Accuzymemeat tenderizerpapayotin
Simultaneously, the structures of the evolutionarily unrelated papain and subtilisin proteases were found to contain analogous triads. Several families of cysteine proteases use this triad set, for example TEV protease and papain.
This cleft contains the active site, which contains a catalytic diad that has been likened to the catalytic triad of chymotrypsin.

Selenocysteine

L-selenocysteineSeC 3 NO 2 H 7 selenoamino acid
The nucleophile is most commonly a serine or cysteine amino acid, but occasionally threonine or even selenocysteine.
Selenoenzymes have been found to employ catalytic triad structures that influence the nucleophilicity of the active site selenocysteine.

Trypsin

trypticanti-tryptictrypsin serine proteases
The enzymes trypsin and chymotrypsin were first purified in the 1930s.
These enzymes contain a catalytic triad consisting of histidine-57, aspartate-102, and serine-195.

Active site

catalytic domaincatalytic siteactive sites
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes.
In the active site of this enzyme, three amino acid residues work together to form a catalytic triad which makes up the catalytic site.

Threonine protease

threonine-threoninethreonines
Alternatively, threonine proteases use the secondary hydroxyl of threonine, however due to steric hindrance of the side chain's extra methyl group such proteases use their N-terminal amide as the base, rather than a separate amino acid.
The prototype members of this class of enzymes are the catalytic subunits of the proteasome, however the acyltransferases convergently evolved the same active site geometry and mechanism.

Amidase

acylase
Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylases, lipases and β-lactamases).
These enzymes possess a unique, highly conserved Ser-Ser-Lys catalytic triad used for amide hydrolysis, although the catalytic mechanism for acyl-enzyme intermediate formation can differ between enzymes.

Cysteine protease

cysteinecysteine peptidasecysteine endopeptidase
Several families of cysteine proteases use this triad set, for example TEV protease and papain.
These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.

Alpha/beta hydrolase superfamily

Alpha/beta hydrolase foldalpha/beta hydrolaseα/β hydrolase
The same triad has also convergently evolved in α/β hydrolases such as some lipases and esterases, however orientation of the triad members is reversed.
All have a catalytic triad, the elements of which are borne on loops, which are the best-conserved structural features of the fold.

PA clan of proteases

PA clanPAPA superfamily
The triad is exemplified by chymotrypsin, a model serine protease from the PA superfamily which uses its triad to hydrolyse protein backbones.
The common use of the catalytic triad for hydrolysis by multiple clans of proteases, including the PA clan, represents an example of convergent evolution.

Subtilisin

alcalasesavinasesubtilin
Simultaneously, the structures of the evolutionarily unrelated papain and subtilisin proteases were found to contain analogous triads.
It is structurally unrelated to the chymotrypsin-clan of serine proteases, but uses the same type of catalytic triad in the active site.

Acetylcholinesterase

acetylcholine esteraseAChEacetycholinesterase
The equivalent Ser-His-Glu triad is used in acetylcholinesterase.
The esteratic subsite, where acetylcholine is hydrolyzed to acetate and choline, contains the catalytic triad of three amino acids: serine 200, histidine 440 and glutamate 327.

Chymotrypsin

Alpha Chymaralpha-chymotrypsinbovine alpha-chymotrypsin
The enzymes trypsin and chymotrypsin were first purified in the 1930s. The triad is exemplified by chymotrypsin, a model serine protease from the PA superfamily which uses its triad to hydrolyse protein backbones.
Along with histidine 57 and aspartic acid 102, this serine residue constitutes the catalytic triad of the active site.

Thiol

mercaptansulfhydrylthiols
The most commonly used nucleophiles are the hydroxyl (OH) of serine and the thiol/thiolate ion (SH/S − ) of cysteine.
Sulfhydryl groups in the active site of an enzyme can form noncovalent bonds with the enzyme's substrate as well, contributing to covalent catalytic activity in catalytic triads.

MEROPS

MEROPS database
The MEROPS classification system in the 1990s and 2000s began classing proteases into structurally related enzyme superfamilies and so acts as a database of the convergent evolution of triads in over 20 superfamilies.

Peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase

EC 3.5.1.52N''-glycanasePNGase F
This triad is also used by some amidases, such as N-glycanase to hydrolyse non-peptide C-N bonds.
The enzyme uses a catalytic triad of cysteine-histidine-aspartate in its active site for hydrolysis by covalent catalysis.

Enzyme

enzymologyenzymesenzymatic
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes.

Amidophosphoribosyltransferase

phosphoribosyl pyrophosphate amidotransferasePPATamidophosphoribosyl transferase
Additionally, an alternative transferase mechanism has been evolved by amidophosphoribosyltransferases, which has two active sites.
A terminal cysteine residue acts as the nucleophile in the first part of the reaction, analogous to the cysteine of a catalytic triad.

Protein superfamily

superfamilysuperfamiliesprotein fold
The MEROPS classification system in the 1990s and 2000s began classing proteases into structurally related enzyme superfamilies and so acts as a database of the convergent evolution of triads in over 20 superfamilies. Chemical constraints on catalysis have led to the same catalytic solution independently evolving in at least 23 separate superfamilies.
In the PA clan of proteases, for example, not a single residue is conserved through the superfamily, not even those in the catalytic triad.

Enzyme catalysis

catalytic mechanisminduced fitenzymatic reaction
Their mechanism of action is consequently one of the best studied in biochemistry.
This mechanism is utilised by the catalytic triad of enzymes such as proteases like chymotrypsin and trypsin, where an acyl-enzyme intermediate is formed.

CAPN6

Calpamodulin
The CA clan contains catalytically inactive members with mutated triads (calpamodulin has lysine in place of its cysteine nucleophile) and with intact triads but inactivating mutations elsewhere (rat testin retains a Cys-His-Asn triad).
The protein lacks a critical catalytic triad residue in its active site (cysteine nucleophile mutated to lysine) and thus is suggested to be proteolytically inactive.

TEV protease

Tobacco etch virus proteaseC3 protease
As more protease structures were solved by X-ray crystallography in the 1970s and 80s, homologous (such as TEV protease) and analogous (such as papain) triads were found.
Covalent catalysis is performed with an Asp-His-Cys triad, split between the two barrels (Asp on β1 and His and Cys on β2).

Amino acid

amino acidsresiduesresidue
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes.