TY - JOUR
T1 - Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia
AU - Rossi, Franca
AU - Garavaglia, Silvia
AU - Montalbano, Valeria
AU - Walsh, Martin A.
AU - Rizzi, Menico
PY - 2008/2/8
Y1 - 2008/2/8
N2 - Kynurenic acid is an endogenous neuroactive compound whose unbalancing is involved in the pathogenesis and progression of several neurological diseases. Kynurenic acid synthesis in the human brain is sustained by the catalytic activity of two kynurenine aminotransferases, hKAT I and hKAT II. A wealth of pharmacological data highlight hKAT II as a sensible target for the treatment of neuropathological conditions characterized by a kynurenic acid excess, such as schizophrenia and cognitive impairment. We have solved the structure of human KAT II by means of the single-wavelength anomalous dispersion method at 2.3-Å resolution. Although closely resembling the classical aminotransferase fold, the hKATII architecture displays unique features. Structural comparison with a prototypical aspartate aminotransferase reveals a novel antiparallel strand-loop-strand motif that forms an unprecedented intersubunit β-sheet in the functional hKAT II dimer. Moreover, the N-terminal regions of hKAT II and aspartate aminotransferase appear to have converged to highly similar although 2-fold symmetry-related conformations, which fulfill the same functional role. A detailed structural comparison of hKAT I and hKAT II reveals a larger and more aliphatic character to the active site of hKAT II due to the absence of the aromatic cage involved in ligand binding in hKAT I. The observed structural differences could be exploited for the rational design of highly selective hKAT II inhibitors.
AB - Kynurenic acid is an endogenous neuroactive compound whose unbalancing is involved in the pathogenesis and progression of several neurological diseases. Kynurenic acid synthesis in the human brain is sustained by the catalytic activity of two kynurenine aminotransferases, hKAT I and hKAT II. A wealth of pharmacological data highlight hKAT II as a sensible target for the treatment of neuropathological conditions characterized by a kynurenic acid excess, such as schizophrenia and cognitive impairment. We have solved the structure of human KAT II by means of the single-wavelength anomalous dispersion method at 2.3-Å resolution. Although closely resembling the classical aminotransferase fold, the hKATII architecture displays unique features. Structural comparison with a prototypical aspartate aminotransferase reveals a novel antiparallel strand-loop-strand motif that forms an unprecedented intersubunit β-sheet in the functional hKAT II dimer. Moreover, the N-terminal regions of hKAT II and aspartate aminotransferase appear to have converged to highly similar although 2-fold symmetry-related conformations, which fulfill the same functional role. A detailed structural comparison of hKAT I and hKAT II reveals a larger and more aliphatic character to the active site of hKAT II due to the absence of the aromatic cage involved in ligand binding in hKAT I. The observed structural differences could be exploited for the rational design of highly selective hKAT II inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=41249087474&partnerID=8YFLogxK
U2 - 10.1074/jbc.M707925200
DO - 10.1074/jbc.M707925200
M3 - Article
SN - 0021-9258
VL - 283
SP - 3559
EP - 3566
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -