Natural products from reconstructed bacterial genomes of the Middle and Upper Paleolithic

Abstract

Major advances over the past decade in the field of ancient DNA are providing access to past paleogenomic diversity, but the diverse functions and biosynthetic capabilities of this growing paleome remain largely elusive. Here, we investigated the dental calculus of 12 Neanderthals and 52 anatomically modern humans spanning 100 kya to the present and reconstructed 459 bacterial metagenome-assembled genomes (MAGs). We identified a biosynthetic gene cluster (BGC) shared by seven Middle and Upper Paleolithic individuals that allows for the heterologous production of a class of previously unknown metabolites we name paleofurans. This paleobiotechnological approach demonstrates that viable biosynthetic machinery can be produced from the preserved genetic material of ancient organisms, allowing access to natural products from the Pleistocene and providing a promising area for natural product exploration.

Paleomicrobiology: Tracking the past microbial life from single species to entire microbial communities

“…Besides the direct extraction and characterization of metabolites from ancient samples, 'paleometabolites' can also be produced by genetic engineering. This approach was followed by Klapper et al (2023) who assembled high-quality MAGs from aDNA extracted from dental calculi of seven hominids (H. neanderthalensis and H. sapiens) who lived between the Middle and Upper Palaeolithic. In MAGs affiliated to the genus Chlorobium the authors identified novel putative biosynthetic gene clusters (BCGs).…”

Concise and collective total syntheses of 2,4-disubstituted furan-derived natural products from hydroxyoxetanyl ketones

“…NMR data of these natural products is in accordance with the reported data ( 1 H and 13 C) by Klapper and co-workers (Scheme 3 and Tables S4, S5 †). 7,15 Afterward, we transitioned to the synthetic campaign for tournefolin C (6) by first preparing furyl hydroquinone 26 on a multigram scale employing a known three-step sequence (allyl protection of dihydroxy acetophenone, aldol addition of protected acetophenone to 3-oxetanone and Bi(OTf ) 3 -catalyzed dehydrative cycloisomerization sequence) 11 starting from the commercially available dihydroxy acetophenone 25. The hydroxymethyl fragment within compound 26 was oxidized to its corresponding acid 27 (using HAT protocol).…”

“…1). 7 The isolation of tournefolin C (6) was reported by Lin and co-workers in the year 1999 from the stems of Tournefortia sarmentosa, which was widely used in Chinese herbal medicine as a detoxicant or anti-inflammatory agent. 8 Structurally, 6 features 2,4-disubstituted furan-bearing hydroquinone at the C-2 position and methyl ester at the C-4 position.…”

“…8 Structurally, 6 features 2,4-disubstituted furan-bearing hydroquinone at the C-2 position and methyl ester at the C-4 position. Furthermore, shikonofurans A (7) and B (8) were extracted from the roots of Lithospermum erythrorhizon (LE) (Fig. 1).…”

“…Klapper et al isolated paleofurans A and B, subsequently developed a synthetic route for constructing paleofuran A (4) and its methylated derivative (entries a and b, Scheme 1). 7 In the course of our recent research focused on the stereoselective total synthesis of shikonofurans, we reported an improved synthetic approach for producing C-4-hydroxy methyl-derived polysubstituted furans, which entails a Bi (OTf ) 3 -catalyzed 11 dehydrative cycloisomerization of α-hydroxy oxetanyl ketones 12 (entry c, Scheme 1). In this context, herein, we have expanded upon this method to achieve a unified, and concise total synthesis of 2,4-disubstituted furan-derived natural products 1-8 (Fig.…”