A sweet success

It turns out that licorice is good for treating more than just a sweet tooth—the licorice plant produces a chemical called glycyrrhizin that is not only a potent sweetener but also has wide-ranging pharmacological properties, including anti-inflammatory and antiviral activity (Fig. 1).

Although the value of glycyrrhizin has been understood for some time, it has proven difficult to unlock the multi-step process by which this molecule is produced from the precursor β-amyrin, a commonly found natural compound. Toshiya Muranaka of the RIKEN Plant Science Center in Yokohama has been studying plant metabolic processes for decades, and recalls considerable challenges in his early days of trying to uncover the mysteries of these pathways. “In those days, such biosynthetic pathways were hidden in a ‘black box’,” he says. “Almost no information was available about genes involved in useful secondary metabolite production.”

Fortunately, things have changed with the advent of the post-genomic era, and in a new article, Muranaka describes how he and a multidisciplinary team of colleagues from across Japan successfully identified an important component of the glycyrrhizin biosynthetic process through the careful analysis of a large library of licorice plant genes¹.

The newly identified gene, CYP88D6, is expressed specifically in underground portions of the plant, where glycyrrhizin is known to be produced and accumulate, and appears to catalyze the first step in the processing of β-amyrin.

According to Muranaka, since the identification of this first enzyme, which is now known as β-amyrin 11-oxidase, his group has made considerable further progress in building a complete understanding of the four-stage glycyrrhizin biosynthetic pathway. “We have already cloned the second gene, and we have obtained a strong candidate for the last gene,” he says, “which means that the only one gene—the third gene—remains.”

Large-scale production of glycyrrhizin has proven a considerable challenge; currently, this compound is still extracted directly from harvested plants, a process with potentially severe long-term environmental consequences. As such, the ability to recapitulate this biosynthetic pathway in the laboratory could be a tremendous asset.

However, Muranaka is also excited about the opportunities to explore the properties of intermediates from glycyrrhizin synthesis. “By designing the metabolic pathway we can increase the amount of intermediates in engineered cells, which might be very useful bioactive compounds,” he says. “We may even produce unnatural bioactive compounds through combinations of these genes.”