Hans Renata

Hans Renata is a master of chemoenzymatic synthesis, the science—and one might say, art—of using enzymes during key steps in the synthesis of complex molecules.

At 14, Renata left home in Surabaya, Indonesia, to study at a rigorous boarding school in Singapore, which ultimately led him to Columbia University. As an undergraduate, his chemical problem-solving ability attracted the attention of eminent chemists, including the late Gilbert Stork and Ronald Breslow. “They were telling me they had a genius in their midst,” recalls Phil Baran, a chemist at Scripps Research in California.

Baran recruited Renata to Scripps, where as a graduate student he developed new strategies for synthesizing highly hydroxylated steroids. These molecules can be hard to make because the synthesis requires adding the oxygen-containing hydroxyl groups to specific positions on a steroid’s unreactive 17-carbon skeleton. And with so many carbons, it’s hard to get the hydroxyls positioned and oriented in just the right way.

As a challenge, Baran and Renata decided to synthesize one of the most complex steroids they could think of: ouabagenin, a modified natural product with six hydroxyls. After 5 years of work, Renata devised a way to make the steroid in 21 steps, a huge improvement over a previous synthesis of the molecule that required 41 steps.

The achievement earned Renata a Science publication in 2013, but the work made him “aware of the limitations that traditional synthetic chemistry has,” he says. Renata began to think about how enzymes might help make particularly tricky parts of the synthesis more efficient. So he went to learn from one of the best in the business: California Institute of Technology’s enzyme wizard, Frances Arnold.

Research at a glance

Renata’s lab used a combination of enzymatic and chemical oxidations to convert steviol, the plant-derived sugar substitute, into several complex natural products, each in 10 steps or less.

Arnold is a pioneer of using the technique of directed evolution to create enzymes with new functions, and she won the 2018 Nobel Prize in Chemistry for it. As a postdoc in her lab, Renata learned the ropes of how synthetic biology could be used to make enzymes that catalyze reactions not known to occur in nature.

In 2016, Renata began his own lab at Scripps Research in Florida, where he is particularly interested in synthesizing natural products, especially ones that are notoriously hard to make. “The goal of my lab is to simplify how we make these types of molecules by combining chemistry and synthetic biology,” he says.

Baran points to two papers published in 2020 that highlight Renata’s creative strategy: one in Nature Chemistry on the synthesis of oxidized meroterpenoids, and the second in Science on the synthesis of complex diterpenes. In both reports, Renata’s group used enzymes at key steps in the chemical synthesis of the complex natural products to efficiently add hydroxyl groups to specific carbons of the molecules—the same problem that vexed Renata as a PhD student trying to synthesize ouabagenin.

Baran calls it “a different type of synthesis going on than anything else out there,” and he thinks Renata’s work will spur more chemists to think about incorporating enzymes in the synthesis of complex, highly oxygenated compounds. Renata has also used his chemoenzymatic approach to make a potential anticancer compound and to develop unnatural amino acids that could be used as the building blocks of peptide or protein therapies.

“He makes molecules that others have a really tough time making,” Arnold says. “People just love his papers,” she adds. “And he just continues to knock out one beautiful demonstration after another.”

One of those admirers is Ingo Hartung, director of medicinal chemistry at Merck KGaA. He says that many synthetic chemists would never touch an enzyme, and he calls Renata a pioneer for merging two disparate fields. “It is like two different planets,” he says. “Enzymes allow you to make completely different chemical connections, which if you are trained as a classical organic chemist, you wouldn’t even think about,” Hartung says. “It’s like playing chess and coming up with a completely new move.”