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Missing molecule in chemical production line discovered

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Suzanne Thomas and Joseph Noel

It takes dozens of chemical reactions for a cell to make isoprenoids, a diverse class of molecules found in every type of living organism. Cholesterol, for example, is a large isoprenoid chemical. So is the molecule that gives oranges their citrusy smell and taste.

Now a team led by Joseph Noel, holder of the Arthur and Julie Woodrow Chair, has discovered a missing step in the chain of reactions that some cells use to produce isoprenoids. The findings, published in eLife, have immediate implications for how isoprenoids are produced for commercial use.

All larger isoprenoids are derived from a common building block molecule called IPP, which can be made through two chemical pathways. Animal cells use the mevalonate pathway to make IPP; many bacterial cells use a pathway dubbed DXP; and plant cells use both. But scientists have struggled to understand how some bacteria produce IPP. While many of these organisms lack proteins key to the DXP pathway, they're also missing the proteins that perform two final steps of the mevalonate pathway. Normally, these steps involve first adding phosphate to the intermediate molecule and then removing an atom of carbon.

In 2006, a team of scientists discovered that some bacteria had an enzyme called IPK, which could add phosphate to the precursor molecule only if the carbon had already been removed, suggesting that these two steps of the pathway could be reversed. But a protein that could remove the carbon—called a decarboxylase— hadn't been found.

Noel and his group used bioinformatics to find all organisms with the IPK enzyme, suspecting that these would all also have the decarboxylase they were looking for, and the approach worked. In an unusual type of bacteria that live in hot springs, he and his colleagues pinpointed a decarboxylase that works in conjunction with IPK. First it removes carbon, and then IPK adds a phosphate—the process, reversing the last two steps of the classic mevalonate pathway, still ends in IPP.

For companies that produce isoprenoids—as a source of drugs, scents and flavor molecules— the discovery provides a new potential chemical pathway with which to make their products.