Kynureninase
Encyclopedia
Kynureninase or L-Kynurenine hydrolase (KYNU) is a PLP
dependent enzyme
that catalyses the cleavage of kynurenine
(Kyn) into anthranilic acid
(Ant). It can also act on 3hKyn
(to produce 3hAnt) and some other (3-arylcarbonyl)-alanine
s. Humans express one kynureninase enzyme that is encoded by the KYNU gene
located on chromosome 2.
KYNU is part of the pathway for the catabolism
of Trp
and the biosynthesis of NAD
cofactor
s from tryptophan
(Trp).
Kynureninase catalyzes the following reaction:
group of aspartate aminotransferase
superfamily of structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes. To date, two structures of human kynureninase have determined by X-ray diffraction with resolutions of 2.0 and 1.7 Å. Forty percent of the amino acids are arranged in an alpha helical and twelve percent are arranged in beta sheets. Docking of the kynurenine substrate into the active site suggests that Asn-333 and His-102 are involved in substrate binding.
reaction but does not hydrolyze the tautomer
ized Schiff base
. The proposed reaction mechanism involves an attack of an enzyme nucleophile
on the carbonyl carbon (Cγ) of the tautomerized 3hKyn-PLP Schiff base. This is followed by Cβ-Cγ bond cleavage to generate an acyl-enzyme intermediate together with a tautomerized Ala-PLP adduct. Hydrolysis of the acyl-enzyme then yields 3hAnt.
Pyridoxal-phosphate
Pyridoxal-phosphate is a prosthetic group of some enzymes. It is the active form of vitamin B6, which comprises three natural organic compounds, pyridoxal, pyridoxamine and pyridoxine.-Role as a coenzyme:...
dependent enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyses the cleavage of kynurenine
Kynurenine
L-Kynurenine is a metabolite of the amino acid L-tryptophan used in the production of niacin. It has been associated with tics.Kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine-oxoglutarate transaminase catabolizes its conversion into kynurenic acid...
(Kyn) into anthranilic acid
Anthranilic acid
Anthranilic acid is the organic compound with the formula C6H4COOH. This amino acid is a white solid when pure, although commercial samples may appear yellow. The molecule consists of a benzene ring with two adjacent functional groups, a carboxylic acid and an amine...
(Ant). It can also act on 3hKyn
3-Hydroxykynurenine
3-Hydroxykynurenine is a metabolite of tryptophan, which filters UV light in the human lens.-See also:* Kynurenine* Ommochrome...
(to produce 3hAnt) and some other (3-arylcarbonyl)-alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
s. Humans express one kynureninase enzyme that is encoded by the KYNU gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
located on chromosome 2.
KYNU is part of the pathway for the catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
of Trp
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
and the biosynthesis of NAD
NAD
NAD may refer to:* No abnormality detected, a medical status description* No apparent distress, a status description in childbirth* NAD Electronics, a Canadian audio equipment manufacturer...
cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
s from tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
(Trp).
Kynureninase catalyzes the following reaction:
- L-kynurenineKynurenineL-Kynurenine is a metabolite of the amino acid L-tryptophan used in the production of niacin. It has been associated with tics.Kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine-oxoglutarate transaminase catabolizes its conversion into kynurenic acid...
+ H2O = anthranilateAnthranilic acidAnthranilic acid is the organic compound with the formula C6H4COOH. This amino acid is a white solid when pure, although commercial samples may appear yellow. The molecule consists of a benzene ring with two adjacent functional groups, a carboxylic acid and an amine...
+ L-alanineAlanineAlanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
Structure
Kynureninase belongs to the class VAminotransferase, class V
Aminotransferase class-V is an evolutionary conserved protein domain. This domain is found in amino transferases, and other enzymes including cysteine desulphurase EC:4.4.1.-....
group of aspartate aminotransferase
Aspartate transaminase
Aspartate transaminase , also called aspartate aminotransferase or serum glutamic oxaloacetic transaminase , is a pyridoxal phosphate -dependent transaminase enzyme . AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in...
superfamily of structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes. To date, two structures of human kynureninase have determined by X-ray diffraction with resolutions of 2.0 and 1.7 Å. Forty percent of the amino acids are arranged in an alpha helical and twelve percent are arranged in beta sheets. Docking of the kynurenine substrate into the active site suggests that Asn-333 and His-102 are involved in substrate binding.
Function
In KYNU reaction, PLP facilitates Cβ-Cγ bond cleavage. The reaction follows the same steps as the transaminationTransamination
There are two chemical reactions known as transamination . The first is the reaction between an amino acid and an alpha-keto acid...
reaction but does not hydrolyze the tautomer
Tautomer
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...
ized Schiff base
Schiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
. The proposed reaction mechanism involves an attack of an enzyme nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
on the carbonyl carbon (Cγ) of the tautomerized 3hKyn-PLP Schiff base. This is followed by Cβ-Cγ bond cleavage to generate an acyl-enzyme intermediate together with a tautomerized Ala-PLP adduct. Hydrolysis of the acyl-enzyme then yields 3hAnt.