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Dihydrodipicolinate synthase is a key enzyme in the lysine biosynthesis pathway that catalyzes the condensation of pyruvate and aspartate semi-aldehyde. A series of phenolic ketoacid derivatives that mimic the proposed enzymatic intermediate were designed as potential inhibitors of this enzyme and were synthesized from simple precursors. The ketoacid derivatives were shown to act as slow and slow-tight binding inhibitors. Mass spectrometric experiments provided further evidence to support the proposed model of inhibition, demonstrating either an encounter complex or a condensation product for the slow and slow-tight binding inhibitors, respectively., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Iterative formation of nonpolymeric carbon-carbon bonds has been employed by organisms to synthesize fatty acids, polyketides, and isoprenoids. In these biosynthetic schemes, same reaction cycles are used iteratively for functional modifications that result in the increase in carbon-chain length. This principle has been used in the design of a synthetic module for 2-ketoacid elongation. The system utilizes the Escherichia coli enzymes LeuABCD, which were engineered to accept bulkier nonnatural substrates, and was able to extend the chain length iteratively. The success in achieving a diverse range of 2-ketoacids and alcohols from this module via engineering of the 2-isopropylmalate synthase and ketoacid decarboxylase demonstrates the plasticity of LeuABCD and its feasibility for iterative carbon-chain elongations. In addition, this strategy illustrates a principle of designing novel metabolic modules for nonpolymeric carbon-chain elongation, which is essential in the synthesis of nonnative metabolites in microorganisms., (Copyright © 2011 Elsevier Inc. All rights reserved.)