Synthesis of Enzyme Inhibitors of Lysine Biosynthesis

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

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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

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