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Natural Products

Synthetic secrets of catnip compound revealed

A newly discovered step in the biosynthesis of the cat crazy compound may help synthetic biologists engineer pathways to pharmaceuticals

by Alla Katsnelson, special to C&EN
December 11, 2018

20181211lnp1-catnip.jpg
Credit: Shutterstock/Anna Hoychuk
Plants in the Nepeta genus produce compounds that make cats go crazy.

Nepetalactone is best known for instigating the euphoric frenzy that cats and other felines experience when they smell catnip. The full chemical tale of the synthesis of this cyclic terpene has been difficult to pin down, however. Now, researchers have discovered that catnip and other plants in the Nepeta genus cyclize the molecule via an unusual two-step pathway (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0185-2). The discovery may help synthetic biologists efficiently synthesize closely related molecules that are widely used as pharmaceuticals.

Normally, organisms make cyclic monoterpenes with the help of terpene synthase, an enzyme that activates and cyclizes a precursor, geranyl diphosphate, through a cationic intermediate. That’s how limonene, a cyclic monoterpene present in the oil of citrus peels, is formed. But nepetalactone is a member of a large family of cyclic monoterpenes called iridoids, which get synthesized a little differently: a precursor, 8-oxogeranial, undergoes a reduction before cyclizing.

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Nepetalactone, the active molecule in catnip, gets cyclized in a two-step process through an enol intermediate. A series of enzymes reduces the starting molecule, cyclizes the intermediate, and then oxidizes the cyclized molecule.

In 2012, Sarah O’Connor, a biochemist at the John Innes Center, discovered iridoid synthase, the enzyme she credited with doing the job. She and her colleagues now report that the pathway is odder than they had thought. Iridoid synthase reduces the precursor, converting it into a highly reactive enol that it then releases. The synthase doesn’t catalyze the cyclization step, the researchers found. Although a bit of cyclization occurs spontaneously, they found that a second enzyme must be present to capture the enol and efficiently finish the job.

“This is a really weird and wonderful route that nature has built up to produce these compounds,” says John Pickett, a biological chemist at Cardiff University who was not involved in the work.

Nepetalactones are made in Nepeta’s trichomes, microscopic glands on the underside of the leaf where many of the plant’s oils and volatile chemicals are produced. The team, led by O’Connor and Benjamin Lichman, a biochemist now at the University of York, screened proteins in the trichomes to identify ones that spurred the synthesis of nepetalactone from its precursor. They came up with a trio of enzymes that they dubbed NEPS1, NEPS2, and NEPS3.

NEPS2 and NEPS3 are mainly responsible for the cyclization reaction, which generates nepetalactol. NEPS1 is a dehydrogenase. While it can cyclize the intermediate enol, its main task is to perform the last step of the reaction, oxidizing nepetalactol to produce nepetalactone. What’s more, explains Lichman, NEPS2 and NEPS3 each make a different stereoisomer of the cyclized molecule.

Nepetalactone doesn’t just affect cats—it’s also an aphid sex hormone that the plant makes to attract the insects to attack pests. It’s not yet clear what role the different isomers play in the plant, but Lichman speculates they are somehow involved in the plant’s interactions with insects.

Nepetalactone’s cis-trans isomer is the one that whips cats into a frenzy. Meanwhile, cis-trans nepetalactol is an intermediate molecule in the synthesis of a class of molecules called monoterpene indole alkaloids. Such molecules include the anticancer compounds vincristine and vinblastine, as well as other molecules with anti-inflammatory and other pharmaceutical properties. Scientists generally extract the alkaloids from plants, but researchers have attempted to recreate their biosynthetic pathways in microorganisms such as yeast to produce large amounts of the compounds. So far these engineered systems have been inefficient.

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“Now that we know you need a cyclase, we can actually take the NEPS enzymes from catnip and add them to these synthetic biological systems,” Lichman says. “We think that will improve the yield because we are adding a missing enzyme.”

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Comments
Carlos Philpott (December 19, 2018 5:11 PM)
Is that Dash?

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