Synthesis of Enzyme Inhibitors of Lysine Biosynthesis

Connell, Susanne Jane (1994) Synthesis of Enzyme Inhibitors of Lysine Biosynthesis. PhD thesis, University of Glasgow.

Abstract

There are two distinct biosynthetic pathways to the essential amino acid L-lysine (A). The diaminopimelate pathway to L-lysine occurs in higher plants and bacteria whereas the -aminoadipate pathway operates in fungi and yeasts. This thesis is concerned with the initial step of the diaminopimelate pathway to L-lysine, catalysed by the enzyme dihydrodipicolinate synthase (DHDPS). The mechanism of formation of L-2,3-dihydrodipicolinate (L-2,3-DHDPA) (B), the product of the reaction catalysed by DHDPS, was investigated. The synthesis and testing of potential inhibitors of DHDPS was also studied. L-Aspartic acid beta-semialdehyde (L-ASA) (C) is a substrate of DHDPS. A former co-worker of ours, Dr. David Tudor, had previously prepared and isolated DL-ASA as the trifluoroacetate salt. The synthesis of DL-ASA was carried out in this work in order to have a supply of DL-ASA for testing of compounds with DHDPS. Manipulation of the synthetic route to DL-ASA (C) allowed us to prepare several imine derivatives (D). These were tested for inhibitory activity with DHDPS. The trifluoroacetate salt of the thiosemicarbazone derivative (E) was a good inhibitor, showing 46% inhibition at 0.1mM with DHDPS.The synthesis of DL-glutamic acid gamma-semialdehyde (DL-GSA) (F) and DL-aminoadipic acid delta-semialdehyde (DL-AASA) (G) was studied. The preparation of the trifluoroacetate salts of DL-GSA (F) and DL-AASA (G) was achieved and these compounds have been tested as inhibitors and substrates of DHDPS. A number of heterocyclic analogues of L-2,3-DHDPA (B) were prepared and tested for inhibitory effects with DHDPS. Dimethyl 4-hydroxy-piperidine-cis-2 6-dicarboxylate (H) showed only 29% inhibition at 5mM with DHDPS. Commercially available 2,2,6,6-tetramethyl-4-piperidinol (I) and 2,2,6,6-tetramethyl-4-piperidone ( J) were more effective inhibitors, showing 46% and 22% inhibition at 0.5 mM respectively. The oxime (K) and methyloxime (L) derivatives were also reasonable inhibitors at 0.5 mill. 1,3-Thiazole-2,4-dinitrile (NI) was an effective inhibitor, showing 18% inhibition at 0.1 mM.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: David Robbins
• Keywords: Biochemistry
• Date of Award: 1994
• Depositing User: Enlighten Team
• Unique ID: glathesis:1994-75367
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 20:24
• Last Modified: 19 Nov 2019 20:24
• URI: https://theses.gla.ac.uk/id/eprint/75367