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Metabolic rewiring of synthetic pyruvate dehydrogenase bypasses for acetone production in cyanobacteria.

ABSTRACT: Designing synthetic pathways for efficient CO2 fixation and conversion is essential for sustainable chemical production. Here we have designed a synthetic acetate-acetyl-CoA/malonyl-CoA (AAM) bypass to overcome an enzymatic activity of pyruvate dehydrogenase complex. This synthetic pathway utilizes acetate assimilation and carbon rearrangements using a methyl malonyl-CoA carboxyltransferase. We demonstrated direct conversion of CO2 into acetyl-CoA-derived acetone as an example in photosynthetic Synechococcus elongatus PCC 7942 by increasing the acetyl-CoA pools. The engineered cyanobacterial strain with the AAM-bypass produced 0.41 g/L of acetone at 0.71 m/day of molar productivity. This work clearly shows that the synthetic pyruvate dehydrogenase bypass (AAM-bypass) is a key factor for the high-level production of an acetyl-CoA-derived chemical in photosynthetic organisms.

SUBMITTER: Lee HJ

PROVIDER: S-EPMC7415776 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Metabolic rewiring of synthetic pyruvate dehydrogenase bypasses for acetone production in cyanobacteria.

Lee Hyun Jeong HJ Son Jigyeong J Sim Sang Jun SJ Woo Han Min HM

Plant biotechnology journal 20200203 9

Designing synthetic pathways for efficient CO<sub>2</sub> fixation and conversion is essential for sustainable chemical production. Here we have designed a synthetic acetate-acetyl-CoA/malonyl-CoA (AAM) bypass to overcome an enzymatic activity of pyruvate dehydrogenase complex. This synthetic pathway utilizes acetate assimilation and carbon rearrangements using a methyl malonyl-CoA carboxyltransferase. We demonstrated direct conversion of CO<sub>2</sub> into acetyl-CoA-derived acetone as an exam ...[more]

PMID: 31960579

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Project description:UNLABELLED:Pyruvate dehydrogenase kinases (PDK1-4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate dehydrogenase (PDH) activity to convert pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Metabolic dysregulation and inflammatory processes are two sides of the same coin in several pathophysiological conditions. The lactic acid surge associated with the metabolic shift has been implicated in diverse painful states. In this study, we investigated the role of PDK-PDH-lactic acid axis in the pathogenesis of chronic inflammatory pain. Deficiency of Pdk2 and/or Pdk4 in mice attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivities. Likewise, Pdk2/4 deficiency attenuated the localized lactic acid surge along with hallmarks of peripheral and central inflammation following intraplantar administration of CFA. In vitro studies supported the role of PDK2/4 as promoters of classical proinflammatory activation of macrophages. Moreover, the pharmacological inhibition of PDKs or lactic acid production diminished CFA-induced inflammation and pain hypersensitivities. Thus, a PDK-PDH-lactic acid axis seems to mediate inflammation-driven chronic pain, establishing a connection between metabolism and inflammatory pain. SIGNIFICANCE STATEMENT:The mitochondrial pyruvate dehydrogenase (PDH) kinases (PDKs) and their substrate PDH orchestrate the conversion of pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Lactate, the predominant end product of glycolysis, has recently been identified as a signaling molecule for neuron-glia interactions and neuronal plasticity. Pathological metabolic shift and subsequent lactic acid production are thought to play an important role in diverse painful states; however, their contribution to inflammation-driven pain is still to be comprehended. Here, we report that the PDK-PDH-lactic acid axis constitutes a key component of inflammatory pain pathogenesis. Our findings establish an unanticipated link between metabolism and inflammatory pain. This study unlocks a previously ill-explored research avenue for the metabolic control of inflammatory pain pathogenesis.

Dataset Information

Metabolic rewiring of synthetic pyruvate dehydrogenase bypasses for acetone production in cyanobacteria.

Publications

Metabolic rewiring of synthetic pyruvate dehydrogenase bypasses for acetone production in cyanobacteria.

Similar Datasets

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