A long-standing mystery in the natural synthesis of the antibiotic fosfomycin has been resolved by chemists in the US. 

The previously-proposed route for the biosynthesis of fosfomycin includes a step in which a methyl group is directly transferred to an aldehyde intermediate. But this step is chemically unlikely, said Wilfred van der Donk from the University of Illinois at Urbana-Champaign. The suggested mechanism is 'fundamentally different' from other methyl transfers that use the same coenzymes, he said. Now, van der Donk and his colleagues have proposed a pathway that they consider much more plausible.

Methyl transfer in the biosynthesis of fosfomycin

The researchers disrupted genes in the Streptomyces bacteria that make fosfomycin and fed the bacteria key intermediates in the biosynthesis. By analysing which combinations of bacteria and intermediates led to the antibiotic, the team showed that the aldehyde is first reduced to an alcohol. The methyl group is then introduced by a radical mechanism.

Perry Frey of the University of Wisconsin-Madison, US, said that van der Donk's mechanism is chemically rational and is compatible with the known chemistry of the coenzymes involved.

The Illinois group will now try to verify their pathway by purifying the enzyme involved and showing that it performs the proposed reaction in the test tube. 'If so, it will be an entirely new way of introducing methyl groups into natural products,' said van der Donk.

The new pathway could also be applicable to other biosyntheses. 'There are many methyl groups in natural products about which scientists have wondered how they were incorporated,' said van der Donk. 'We think that our studies provide the first clues, which we hope to extend in future studies.'

Danièle Gibney