Theoretical Study on HF Elimination and Aromatization Mechanisms: A Case of Pyridoxal 5 ' Phosphate-Dependent Enzyme


Gokcan H. , KONUKLAR F. A. S.

JOURNAL OF ORGANIC CHEMISTRY, cilt.77, ss.5533-5543, 2012 (SCI İndekslerine Giren Dergi) identifier identifier

  • Cilt numarası: 77 Konu: 13
  • Basım Tarihi: 2012
  • Doi Numarası: 10.1021/jo3005815
  • Dergi Adı: JOURNAL OF ORGANIC CHEMISTRY
  • Sayfa Sayıları: ss.5533-5543

Özet

Pyridoxal 5-phosphate (PLP), the phosphorylated and the oxidized form of vitamin B6 is an organic cofactor. PLP forms a Schiff base with the c-amino group of a lysine residue of PLP-dependent enzymes. gamma-Aminobutyric acid (GABA) aminotransferase is a PLP-dependent enzyme that degrades GABA to succinic semialdehyde, while reduction of GABA concentration in the brain causes convolution besides several neurological diseases. The fluorine-containing substrate analogues for the inactivation of the GABA-AT are synthesized extensively in cases where the inactivation mechanisms involve HF elimination. Although two proposed mechanisms are present for the HF elimination, the details of the base-induced HF elimination are not well identified. In this density functional theory (DFT) study, fluorine-containing substrate analogue, 5-amino-2-fluorocyclohex-3-enecarboxylic acid, is particularly chosen in order to explain the details of the HF elimination reactions. On the other hand, the experimental studies revealed that aromatization competes with Michael addition mechanism in the presence of 5-amino-2-fluorocyclohex-3-enecarboxylic acid. The results allowed us to draw a conclusion for the nature of HF elimination, besides the elucidation of the mechanism preference for the inactivation mechanism. Furthermore, the solvent phase calculations carried out in this study ensure that the proton transfer steps should be assisted either by a water molecule or a base for lower activation energy barriers.