Review Article

Relevance of Alternative Routes of Kynurenic Acid Production in the Brain

Table 1

Biochemical characteristic of KATs.

EnzymeCellular brain locationCharacteristicOptimum pHSubstrates with higher potency towardsCosubstrateEndogenous inhibitorsReferences

KAT-I/glutamine transaminase K/cysteine conjugate beta-lyase 1Glia, astrocytes (nuclei and cytosol), and neurons (cytoplasmic)(i) KAT I and KAT III share similar genomic structures
(ii) KAT I immunoreactivity was found in ventral medulla, nucleus ambiguus, nucleus of the solitary tract, and intramedio lateral cell column of the spinal cord
(iii) pKa 7.6
(iv) Enzyme partially purified: Km 875 μmol/L, KYN concentrations ranging from 2 μmol/L to 2 mmol/L
(v) Relative percentage of brain activity:
Mouse: 25.7
Rat: 15.5
Human: 9.8
(vi) Present high activity in the cerebellum
9.5–10GlutaminePyruvateGlutamine[8493]
PhenylalanineTryptophan
Kynurenine (hKAT-I under physiological pH)Phenylalanine
Indole-3-pyruvic acid
Cysteine

KAT-II/α-aminoadipate aminotransferaseAstrocytes(i) At physiologic KYN concentrations and pH, KAT II catalyzed around 75% of KYNA synthesis in most brain areas
(ii) pKa 5.7
(iii) Enzyme partially purified: Km 660 μmol/L, KYN concentrations ranging from 2 μmol/L to 2 mmol/L
(iv) Relative percentage of brain activity:
Mouse: 12.3
Rat: 58.7
Human: 54.1
7.4Kynurenineα-KetoglutarateAminoadipate[85, 89, 90, 94, 95]
GlutamatePyruvateAsparagine
AminoadipateGlutamate
MethionineHistidine
Cysteine
Lysine
3-Hydroxykynurenine phenylalanine

KAT-III/cysteine conjugate beta-lyase 2(i) mKAT III shows activity toward a number of amino acids
(ii) mKAT III is more active than hKAT I under basic conditions
(iii) Northern blot analysis showed a strong transcript in the liver, kidney, and heart and to a less extent in the brain and testis
(iv) Has a higher isoelectric point than KAT I
(v) 3-HK decreases mKAT III-catalyzed kynurenine transamination
(vi) pKa 8.7
9-10Glutamineα-KetobutyrateCysteine[9597]
HistidineOxaloacetateGlutamine
MethionineHistidine
PhenylalanineMethionine
Leucine
Phenylalanine

KAT-IV/glutamic-oxaloacetic transaminase 2/mitochondrial aspartate aminotransferaseMitochondria of astrocytes and neurons(i) mKAT I, III, and IV showed high resistance to heat treatment
(ii) pKa 6.9
(iii) Enzyme partially purified: Km 724 μmol/L, KYN concentrations ranging from 2 μmol/L to 2 mmol/L
(iv) Relative percentage of brain activity:
Mouse: 63.0
Rat: 25.8
Human: 36.1
8.5Aspartateα-KetoglutarateAspartate[94, 98]
GlutamateGlutamate