Modeling and molecular dynamics of glutamine transaminase K/cysteine conjugate beta-lyase.

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Venhorst J, ter Laak AM, Meijer M, van de Wetering I, Commandeur JN, Rooseboom M, Vermeulen NP

Modeling and molecular dynamics of glutamine transaminase K/cysteine conjugate beta-lyase.

J Mol Graph Model. 2003 Sep;22(1):55-70.

PubMed ID

12798391 [ View in PubMed

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Abstract

The homodimeric, pyridoxal 5'-phosphate (PLP)-dependent enzyme glutamine transaminase K/cysteine conjugate beta-lyase (GTK/beta-lyase) has been implicated in the bioactivation of chemopreventive compounds. This paper describes the first homology model of rat renal GTK/beta-lyase and its active site residues, deduced from molecular dynamics (MD) simulations of the binding mode of 13 structurally diverse cysteine S-conjugates and amino acids after Amber-parametrization of PLP. Comparison with Thermus thermophilus aspartate aminotransferase (tAAT) and Trypanosoma cruzi tyrosine aminotransferase (tTAT), used as templates for modeling GTK/beta-lyase, showed that the PLP-binding site of GTK/beta-lyase is highly conserved. Binding of the ligand alpha-carboxylate-group occurred via the conserved residues Arg(432) and Asn(219), and Asn(50) and Gly(70). Two pockets accommodated the various ligand side chains. A small pocket, located directly above PLP, was of a highly hydrophobic and aromatic character. A larger pocket, formed partly by the substrate access channel, was more hydrophilic and notably involved the salt bridge partners Glu(54) and Arg(99*) (* denotes the other subunit). Ligand-binding residues included Leu(51), Phe(71), Tyr(135), Phe(373) and Phe(312*), and pi-stacking interactions were often observed. Tyr(135) and Asn(50) were prominent in hydrogen bonding with the sulfur-atom of cysteine S-conjugates. The observed binding mode of the ligands corresponded well with their experimentally determined inhibitory potency toward GTK/beta-lyase. The current homology model thus provides a starting point for further validation of the role of active site residues in ligand-binding by means of mutagenesis studies. Ultimately, insight in the binding of ligands to GTK/beta-lyase may result in the rational design of new ligands and selective inhibitors.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pyridoxal phosphate	Kynurenine--oxoglutarate transaminase 1	Protein	Humans	Unknown	Cofactor	Details
Pyridoxal phosphate	Tyrosine aminotransferase	Protein	Humans	Unknown	Cofactor	Details