Iso‐maleimycin, a Constitutional Isomer of Maleimycin, from Streptomyces sp. QL37

Abstract

Iso‐maleimycin, a previously unknown constitutional isomer of the antibiotic maleimycin, has been detected in an extract of Streptomyces sp. QL37. Chemical synthesis of both maleimycin (20 % yield over seven steps) and iso‐maleimycin, (15 % yield over six steps) allowed access to reference materials for identification. Gas Chromatography coupled Mass Spectrometry (GC‐MS) analysis demonstrated that of the two isomers, only iso‐maleimycin was present in the extract. This finding supports our hypothesis that iso‐maleimycin is a biosynthetic intermediate of lugdunomycin. Iso‐maleimycin displays low antibiotic activity, with a Minimum Inhibitory Concentration (MIC) value on both E. coli and B. subtilis of 250 µg/mL.

Biomimetic total synthesis and paired omics identify an intermolecular Diels-Alder reaction as the key step in lugdunomycin biosynthesis

“…To establish if the knock-out strain was still capable of producing iso-maleimycin, we compared the metabolomics profiles with chemically synthesized iso-maleimycin 13 , dissolved in methanol, which serves as a standard due to the challenges in detecting iso-maleimycin directly using LC-MS. In this way, iso-maleimycin was readily detected as its methanol adduct [M+CH3OH+H]⁺ (Fig.…”

“…QL37. 13 Understanding the biosynthesis of lugdunomycin is of major importance for better insights into how angucyclines and angucyclinones are synthesized. Its highly unusual structure likely requires complex chemical reaction.…”

Functional and Structural Insights into a Novel Promiscuous Ketoreductase of the Lugdunomycin Biosynthetic Pathway

“…Structural rearrangement and the introduction of a nitrogen atom afford limamycins, which react in a cascade of oxidative C–C bond cleavage and aldol condensation, leading to the production of iso-maleimycin. 15 Finally, the Diels–Alder [4 + 2] cycloaddition step between iso-maleimycin and the hydroxy- o -quinodimethane intermediate resulted in the generation of 1 . In addition to 1 , 11 newly rearranged and nonrearranged angucyclines featuring diverse patterns were discovered.…”

“…The early biosynthetic steps yield the core structure UWM6 ( 2 ) or prejadomycin ( 3 ), which undergoes early stage tailoring reactions and is converted to 8- O -methylrabelomycin ( 4 ) and then 8- O -methyltetrangomycin ( 5 ) and tetrangulol methyl ether ( 6 ), which then serve as the key intermediates for the subsequent Baeyer–Villiger oxidation at the C6a–C7 bond of ring C (Scheme S1). Structural rearrangement and the introduction of a nitrogen atom afford limamycins, which react in a cascade of oxidative C–C bond cleavage and aldol condensation, leading to the production of iso-maleimycin . Finally, the Diels–Alder [4 + 2] cycloaddition step between iso-maleimycin and the hydroxy- o -quinodimethane intermediate resulted in the generation of 1 .…”

“…Structural rearrangement and the introduction of a nitrogen atom afford limamycins, which react in a cascade of oxidative C−C bond cleavage and aldol condensation, leading to the production of iso-maleimycin. 15 Finally, the Diels−Alder [4 + 2] angucyclines featuring diverse patterns were discovered. In light of the intriguing ring cleavages, aldol condensation, and Diels−Alder cycloaddition, the lug gene cluster presents a unique opportunity to study the versatile post-PKS tailoring reactions.…”