Enhanced succinic acid production by Mannheimia employing optimal malate dehydrogenase

Nature Communications
2020.0

Abstract

<jats:title>Abstract</jats:title><jats:p>Succinic acid (SA), a dicarboxylic acid of industrial importance, can be efficiently produced by metabolically engineered <jats:italic>Mannheimia succiniciproducens</jats:italic>. Malate dehydrogenase (MDH) is one of the key enzymes for SA production, but has not been well characterized. Here we report biochemical and structural analyses of various MDHs and development of hyper-SA producing <jats:italic>M. succiniciproducens</jats:italic> by introducing the best MDH. <jats:italic>Corynebacterium glutamicum</jats:italic> MDH (<jats:italic>Cg</jats:italic>MDH) shows the highest specific activity and least substrate inhibition, whereas <jats:italic>M. succiniciproducens</jats:italic> MDH (<jats:italic>Ms</jats:italic>MDH) shows low specific activity at physiological pH and strong uncompetitive inhibition toward oxaloacetate (<jats:italic>ki</jats:italic> of 67.4 and 588.9 μM for <jats:italic>Ms</jats:italic>MDH and <jats:italic>Cg</jats:italic>MDH, respectively). Structural comparison of the two MDHs reveals a key residue influencing the specific activity and susceptibility to substrate inhibition. A high-inoculum fed-batch fermentation of the final strain expressing <jats:italic>cgmdh</jats:italic> produces 134.25 g L<jats:sup>−1</jats:sup> of SA with the maximum productivity of 21.3 g L<jats:sup>−1</jats:sup> h<jats:sup>−1</jats:sup>, demonstrating the importance of enzyme optimization in strain development.

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