Acyls lost, dimers arose

A non-enzymatic removal of acyl groups from fluostatins leads to a reactive para-quinone methide species, which serves as a Michael acceptor to form diverse C-C and C-N coupled fluostatin dimers.
Published in Chemistry
Acyls lost, dimers arose

Share this post

Choose a social network to share with, or copy the shortened URL to share elsewhere

This is a representation of how your post may appear on social media. The actual post will vary between social networks

The paper in Nature Communications is here:

Many natural products are isolated as dimers. Dimerization appears to be important to amplify the therapeutic potential of these compounds. But how these dimers are biosynthesized in most cases are not known. Limited examples have been shown that the C–C dimerizations are commonly catalyzed by cytochrome P450 enzymes as in the cases of himastatin, ditryptophenaline, julichrome Q, desertorins, orlandin, and cladofulvin, etc.  Other modes of enzyme-mediated C–C dimerization are also known, such as an alkylating enzyme CylK-catalyzed formation of dimeric cylindrocyclophanes, and  a putative enzymatic [2 + 2] cycloaddition reaction in forming diasteltoxins. In addition, the NmrA family of regulatory proteins have also implicated as the C−C dimerization enzymes in actinorhodins and lomaiviticins. 

Lomaiviticin A and difluostatin A are benzofluorene-containing atypical angucycline dimers. Lomaiviticin A is highly toxic DNA cleavage agent and is currently undergoing preclinical evaluation for antitumor treatment. However, little is known about the dimerization mechanism to form the carbon–carbon (C–C) bonds in lomaiviticin A (C2/C2′, symmetric) and difluostatin A (C1/C5′, asymmetric). In a sharp contrast to a previous speculation that the dimerization of difluostatin A might be catalyzed by the NmrA family regulatory protein FlsQ1, this work demonstrates a non-enzymatic way to form difluostatin A.

The heterologous expression of the fluostatin biosynthetic gene cluster from Micromonospora rosaria SCSIO N160 in Streptomyces albus J1074 afforded several new fluostatin heterodimers/trimers with diverse C–C and C–N-couplings. Serendipitously, acyl fluostatins were found to undergo spontaneous deacylation with simultaneous dimerization to form C–C coupled homodimers. The reaction is illustrated as a chemical process mediated by a reactive para-quinone methide (p-QM) species, which is formed via an autocatalytic 1,6-elimination of the acyl group in fluostatins. The p-QM species can serve as a promiscuous acceptor for 1,6-addition to form diverse C–C and C–N-coupled dimers. These findings have brought an efficient strategy for the facile synthesis of novel dimeric compounds as well as hybrid antibiotic conjugants. Intriguingly, a deacylase FlsH was characterized which may be evolved in the fluostatin pathway to prevent the accumulation of toxic p-QMs by enzymatic hydrolysis of the acyl group.

The results present in this paper highlight that many natural products could be artifacts if their assembly is non-enzyme catalyzed. Also, this work brings an interesting question to rethink about the proposed dimerization strategy for actinohordin and lomaiviticin A: enzymatic or non-enzymatic reaction? It would be highly interesting to unravel the complex biosynthetic enzymology of these pathways.

Please sign in or register for FREE

If you are a registered user on Research Communities by Springer Nature, please sign in

Subscribe to the Topic

Physical Sciences > Chemistry

Related Collections

With collections, you can get published faster and increase your visibility.

Applied Sciences

This collection highlights research and commentary in applied science. The range of topics is large, spanning all scientific disciplines, with the unifying factor being the goal to turn scientific knowledge into positive benefits for society.

Publishing Model: Open Access

Deadline: Ongoing

Cancer and aging

This cross-journal Collection invites original research that explicitly explores the role of aging in cancer and vice versa, from the bench to the bedside.

Publishing Model: Hybrid

Deadline: Jul 31, 2024