Intermediates Released from a Polyether‐Producing Polyketide Synthase Provide Insight into the Mechanism of Oxidative Cyclization

Abstract

Stereochemistry resolved: The introduction of hybrid polyketide synthases in Streptomyces cinnamonensis has shown that the E forms of a tetraketide and pentaketide are intermediates in the biosynthesis of the antibiotic ionophore monensin A (see structure). Furthermore, the trans double bond present in these intermediates has been identified as one of the targets for the epoxidase that initiates oxidative cyclization.

The Catalytic Diversity of Multimodular Polyketide Synthases: Natural Product Biosynthesis Beyond Textbook Assembly Rules

“…The mechanism of polyether formation has thoroughly been studied for 4, showing the cyclases MonBI and MonBII to act on polyepoxide 69 derived from oxidation of an E,E, E-configured triene 70 by the epoxidase MonCI, leading to the impressive overall molecular structure equipped with tetrahydropyran and -furan ring systems (Fig. 26b) [33,[181][182][183]. Homologous genes are also located in the clusters encoding for 67 and 68 and thought to initiate similar reactions in the final biosynthetic steps towards these compounds [179,180].…”

Minimally Invasive Mutagenesis Gives Rise to a Biosynthetic Polyketide Library

“…[3,4] A representative example of these complex enzymes is found in the biosynthetic pathway toward the polyether monensin. [5,6] The monensin PKS genes span roughly 80 000 base pairs with large open reading frames; [7][8][9] these conditions test the limits of modern enzyme engineering, especially when a significant number of enzyme variants must be generated. [3] The modular organization of the biosynthesis has sparked interest in engineering PKS to give rise to novel natural product analogues, leading to the field of combinatorial biosynthesis.…”

Aufbau einer biosynthetischen Polyketid‐Bibliothek durch minimalinvasive Mutagenese

“…[5,6] Die Monensin-PKS wird durch einen Gencluster von ca. 80 000 Basenpaaren Grçße mit teilweise sehr langen offenen Leserastern (ORF) kodiert; [7][8][9] diese Bedingungen bringen die Techniken des modernen Enzym-Engineerings an ihre Grenzen, insbesondere, wenn eine grçßere Anzahl an Enzymvarianten erzeugt werden soll. [3] Der modulare Aufbau der Biosyntheselogik hat das Interesse an der Manipulation von PKS zur Erzeugung neuer Naturstoffanaloga angeregt, woraus das Forschungsfeld der kombinatorischen Biosynthese entstanden ist.…”