UniProt: Q8N5Z0 (AADAT_HUMAN). HGNC:17929. Gene synonyms KAT2, KYAT2. 425 aa precursor,
mitochondrial transit peptide 1..29, mature chain 30..425.
AADAT is a PLP-dependent, class-I (fold-type I) aminotransferase that is one and the
same protein as kynurenine aminotransferase II (KAT II). It is a broad-specificity
transaminase with two physiologically prominent activities:
2-aminoadipate aminotransferase (AADAT; EC 2.6.1.39) — transaminates
L-2-aminoadipate + 2-oxoglutarate → 2-oxoadipate + L-glutamate, an intermediate step in
L-lysine degradation (saccharopine/aminoadipate pathway).
[file:human/AADAT/AADAT-uniprot.txt "Reaction=L-2-aminoadipate + 2-oxoglutarate = 2-oxoadipate + L-"]
PMID:12126930
Kynurenine aminotransferase II (KAT II; EC 2.6.1.7) — transaminates L-kynurenine +
2-oxoglutarate → kynurenate (kynurenic acid, KYNA) + L-glutamate, the committed step of
kynurenic acid biosynthesis in the tryptophan/kynurenine pathway.
PMID:18056995
KYNA is a neuroactive metabolite: "KYNA is the only known \nendogenous antagonist of N-methyl-D-aspartate (NMDA) receptors and is also an \nantagonist of 7-nicotinic acetylcholine receptors" PMID:18056995.
KAT II "is a primary enzyme in the brain for catalysing the transamination of kynurenine
to KYNA" PMID:18620547, and is "the principal enzyme responsible for the synthesis of
KYNA in the rodent and human brain" (KAT II knockout mice show a substantial decrease in
brain KYNA) PMID:18620547.
The definitive biochemical study (Han et al. 2008, PMID:18620547, full text available)
screened 24 amino acids and 16 α-oxo acids and found "very broad substrate specificity, is
capable of catalysing the transamination of 16 out of 24 tested amino acids and could
utilize all 16 tested alpha-oxo acids as amino-group acceptors." On kinetic grounds "hKAT
II should be equally efficient in catalysing the transamination of aminoadipate,
kynurenine, methionine and glutamate" PMID:18620547. Preferred amino-group acceptors:
"α-oxoglutarate, α-oxocaproic acid, phenylpyruvate and α-KMB" PMID:18620547. Glyoxylate
is a usable but low-affinity acceptor (used experimentally as the assay acceptor), giving
rise to the various "…:glyoxylate transaminase" activities (glycine, methionine, aromatic
amino acids). These glyoxylate-linked activities are real in vitro but secondary/assay
artifacts of the broad site rather than the principal physiological reactions.
UniProt FUNCTION: "Transaminase with broad substrate specificity. Has transaminase
activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also
towards tryptophan, aspartate and hydroxykynurenine." [file:human/AADAT/AADAT-uniprot.txt]
PLP-dependent: "belongs to the fold-type I pyridoxal 5-phosphate \n(PLP)-dependent enzymes"
PMID:18056995; UniProt COFACTOR pyridoxal 5'-phosphate (evidence PubMed:12126930,
18056995, 18056996). Lys263 forms the internal Schiff base (N6-(pyridoxal phosphate)lysine
at position 263 in UniProt FT).
UniProt calls Mitochondrion (ECO:0000305) based on the N-terminal mitochondrial transit
peptide (1..29) [file:human/AADAT/AADAT-uniprot.txt "SUBCELLULAR LOCATION: Mitochondrion"];
Reactome places the aminoadipate/kynurenine reactions in the mitochondrial matrix
[Reactome:R-HSA-508561, R-HSA-70952, R-HSA-893583]. AADAT is also detected in high-confidence
mitochondrial proteome studies (HTP) PMID:34800366.
HOWEVER, PMID:18620547 introduction states KAT II "is localized in the soluble cytoplasm,"
and Reactome R-HSA-9972889 places a cytosolic AADAT activity (3-hydroxykynurenine →
xanthurenate), noting "The cytosolic localization of human AADAT is inferred from work in
rats (Rzeski et al., 2005)." So both mitochondrial and cytosolic pools/annotations exist in
the literature; mitochondrion/mitochondrial matrix is the UniProt-authoritative core call.
Homodimer [PMID:18056995, PMID:18056996, PMID:18620547]; many crystal structures (e.g. 2R2N
KAT II + PLP + kynurenine; 3DC1 + 2-oxoglutarate). N-terminal fragment (res 15-33) is a
flexible lid that adapts to substrates of different sizes — the structural basis of broad
specificity PMID:18620547.
Highest expression in liver (also heart, brain, kidney, pancreas, prostate, testis, ovary)
[file:human/AADAT/AADAT-uniprot.txt "TISSUE SPECIFICITY: Higher expression in the liver"].
Directionality: hKAT II favours aminoadipate → 2-oxoadipate (Km 0.9 mM for aminoadipate vs
20.9 mM for oxoadipate), consistent with a lysine-degradation role PMID:18620547; the
kynurenine → KYNA direction is effectively irreversible because the α-oxo intermediate
cyclizes spontaneously to KYNA PMID:18620547.