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Stereoselective semi-synthesis of the neuroprotective natural product, serofendic acid.

ABSTRACT: We have recently demonstrated a synthetic biology-enabled semi-synthesis of the potent neuroprotective compound, serofendic acid. An engineered bacterium produces ent-atis-16-en-19-oic acid, which has six of eight chiral carbons configured with the appropriate stereochemistry. Setting the configuration of the C15 hydroxyl group and C16 methylene is a critical step that occurs late in each published total or formal synthesis. Here we explore the use of alternative reducing reagents, stereochemical directing agents, reaction order, and product recycling to improve the diastereoselectivity of this step. We find that installing and oxidizing the C17 methylsulfide prior to reducing the C15 ketone provides the greatest yield of the desired C15,C16 diastereomer. This represents an improved total synthesis of serofendic acid.

SUBMITTER: Perusse D

PROVIDER: S-EPMC6595966 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Stereoselective semi-synthesis of the neuroprotective natural product, serofendic acid.

Perusse Dimitri D Smanski Michael J MJ

MedChemComm 20190423 6

We have recently demonstrated a synthetic biology-enabled semi-synthesis of the potent neuroprotective compound, serofendic acid. An engineered bacterium produces <i>ent</i>-atis-16-en-19-oic acid, which has six of eight chiral carbons configured with the appropriate stereochemistry. Setting the configuration of the C15 hydroxyl group and C16 methylene is a critical step that occurs late in each published total or formal synthesis. Here we explore the use of alternative reducing reagents, stereo ...[more]

PMID: 31303993

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Project description:BackgroundPhenylpropanoids such as p-coumaric acid represent important precursors for the synthesis of a broad range of plant secondary metabolites including stilbenoids, flavonoids, and lignans, which are of pharmacological interest due to their health-promoting properties. Although extraction from plant material or chemical synthesis is possible, microbial synthesis of p-coumaric acid from glucose has the advantage of being less expensive and more resource efficient. In this study, Corynebacterium glutamicum was engineered for the production of the plant polyphenol precursor p-coumaric acid from glucose.ResultsHeterologous expression of the tyrosine ammonia-lyase encoding gene from Flavobacterium johnsoniae enabled the conversion of endogenously provided tyrosine to p-coumaric acid. Product consumption was avoided by abolishing essential reactions of the phenylpropanoid degradation pathway. Accumulation of anthranilate as a major byproduct was eliminated by reducing the activity of anthranilate synthase through targeted mutagenesis to avoid tryptophan auxotrophy. Subsequently, the carbon flux into the shikimate pathway was increased, phenylalanine biosynthesis was reduced, and phosphoenolpyruvate availability was improved to boost p-coumaric acid accumulation. A maximum titer of 661 mg/L p-coumaric acid (4 mM) in defined mineral medium was reached. Finally, the production strain was utilized in co-cultivations with a C. glutamicum strain previously engineered for the conversion of p-coumaric acid into the polyphenol resveratrol. These co-cultivations enabled the synthesis of 31.2 mg/L (0.14 mM) resveratrol from glucose without any p-coumaric acid supplementation.ConclusionsThe utilization of a heterologous tyrosine ammonia-lyase in combination with optimization of the shikimate pathway enabled the efficient production of p-coumaric acid with C. glutamicum. Reducing the carbon flux into the phenylalanine and tryptophan branches was the key to success along with the introduction of feedback-resistant enzyme variants.

Dataset Information

Stereoselective semi-synthesis of the neuroprotective natural product, serofendic acid.

Publications

Stereoselective semi-synthesis of the neuroprotective natural product, serofendic acid.

Similar Datasets

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