An alternative malonyl-CoA producing pathway in nature

Liu, B.; Zhang, Y.; Cui, Q.; Wu, S.; Tang, S.; Chen, Y.; Ma, Y.; Liu, W.; Tao, Y.

doi:10.1101/2022.10.28.514148

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bioRxiv · 10.1101/2022.10.28.514148

An alternative malonyl-CoA producing pathway in nature

Liu, B.·Zhang, Y.·Cui, Q.·Wu, S.·Tang, S.·Chen, Y.·Ma, Y.·Liu, W.·Tao, Y.

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Abstract

Malonyl-CoA is a key metabolic intermediate for biosynthesis of diverse cellular molecules and natural products. Carboxylation of acetyl-CoA is almost the unique pathway for malonly-CoA biosynthesis. Biotechnological production of numerous value-added malonyl-CoA-derived chemicals require high intracellular supply of malonyl-CoA. However, because of the central role of acetyl-CoA in primary metabolism, it is difficult to develop flexible strategies to balance malonyl-CoA supply with other cellular metabolism. Here we find that there is a natural alternative malonyl-CoA-producing pathway, in which the key reaction is catalyzed by an -keto acid dehydrogenase complex BkdFGH from Streptomyces avermitilis. This dehydrogenase complex could efficiently catalyze biosynthesis of malonyl-CoA from oxaloacetate in addition to recognizing its native substrate branched-chain -keto acid. Oxaloacetate dehydrogenase (OADH) was shown to play important physiological roles during the regulation of biosynthesis of native malonyl-CoA-derived polyketides in Streptomyces. Furthermore, the oxlaocetate dehydrogenation reaction is thermodynamically superior to acetyl-CoA carboxylation and enable efficient bioproduction of diverse malonyl-CoA-derived chemicals in engineering Escherichia coli. This novel malonyl-CoA source thus has great potential in the biotechnological field.

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Liu, B., Zhang, Y., Cui, Q., Wu, S., Tang, S., Chen, Y., Ma, Y., Liu, W., Tao, Y.. 2022-10-30. An alternative malonyl-CoA producing pathway in nature. https://doi.org/10.1101/2022.10.28.514148

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