Biochemical and structural studies of the Mycobacterium tuberculosis O6-methylguanine methyltransferase and mutated variants.

Mycobacterium tuberculosis displays remarkable genetic stability despite continuous exposure to the hostile environment represented by the host's infected macrophages. Similarly to other organisms, M. tuberculosis possesses multiple systems to counteract the harmful potential of DNA alkylation.

Human kynurenine aminotransferase II--reactivity with substrates and inhibitors.

Kynurenine aminotransferase (KAT) is a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the conversion of kynurenine, an intermediate of the tryptophan degradation pathway, into kynurenic acid, an endogenous antagonist of ionotropic excitatory amino acid receptors in the central nervous system. KATII is the prevalent isoform in mammalian brain and a drug target for the treatment of schizophrenia. We have carried out a spectroscopic and functional characterization of both the human wild-type KATII and a variant carrying the active site mutation Tyr142→Phe.

Biochemical and structural investigations on kynurenine aminotransferase II: an example of conformation-driven species-specific inhibition?

Kynurenic acid (KYNA), one of the metabolites belonging to the kynurenine pathway, has been described as an important neuroprotective compound, its unbalancing being associated with several pathological conditions. In human brain, the majority of KYNA production is sustained by kynurenine aminotransferase II (KAT II). A selective KAT II inhibitor would be an important pharmacological tool, since it would reduce KYNA formation without causing complete depletion of this neuroprotector.

Crystal structure-based selective targeting of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II for cognitive enhancement.

Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5'-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(-)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs.