Alison Narayan

Vitals

Current Affiliation: University of Michigan

Age: 32

Ph.D. alma mater: University of California, Berkeley

In a world without chemistry, I would be: a lawyer. “I really like constitutional law. Growing up, I dreamed of becoming a judge and eventually a Supreme Court justice.”

Advice for young scientists: “Be bold in your ideas, experiments, and aspirations.”

Codename: Enzyme Mastermind

Like a spy master who convinces an evil agent to work for the good guys, Alison Narayan wants to turn the enzymes used by cyanobacteria to produce a life-threatening paralysis poison—saxitoxin—into machines that build lifesaving drugs.

The enzymes that make saxitoxin have exquisite chemistry skills, including the enviable ability to install oxygen groups in hard-to-reach places on complex carbon molecules. That task is particularly hard for synthetic chemists but is also really important for drug development—those oxygen groups can modify a molecule’s biological activity.

Narayan isn’t the first chemist to try to make enzymes do her bidding. Protein engineers spend months, even years, rejiggering a protein to perform a single task on a single substrate. But Narayan’s plan is to coax enzymes into doing sophisticated chemistry on a wide variety of substrates. To accomplish that, she wants to mine microbial genomes for enzymes with interesting chemistry skills, engineer the enzymes to work across more kinds of substrates, and eventually incorporate the enzymes into traditional syntheses to more efficiently build complex molecules.

During her postdoc at the University of Michigan with David H. Sherman, Narayan proved the idea works. She engineered a cytochrome P450 enzyme to install hydroxyl groups on hard-to-access parts of menthol and other carbon rings, which are not the enzyme’s natural substrate.

Now with her own group, Narayan has her eye on saxitoxin. The deadly molecule indiscriminately attacks all nine types of voltage-gated sodium channels, membrane proteins essential for producing electrical signals in brain, heart, and muscle cells. Making saxitoxin specific to just one type of voltage-gated sodium channel could lead to a nonaddictive painkiller, new chemotherapies, or drugs for neurodegenerative diseases. Narayan’s current challenge is to tweak the enzymes that make saxitoxin so they install oxygens in slightly different locations on the poisonous scaffold.

Narayan says there’s a treasure trove of enzymes to be mined from the newly sequenced genomes of many microorganisms—enzymes that can decorate carbon molecules in ways a synthetic organic chemist can only dream of.

Research at a glance

As a postdoc, Narayan modified the active site of a P450 enzyme so that it could add hydroxyl groups to unnatural substrates. To do so, she tweaked the amino acids in the active site to make it roomier and inserted a chemical arm to orient unnatural substrates, such as menthol, for catalysis. Credit: Gonzalo Jiménez-Osés/Nature Chemistry/C&EN

As a postdoc, Narayan modified the active site of a P450 enzyme so that it could add hydroxyl groups to unnatural substrates. To do so, she tweaked the amino acids in the active site to make it roomier and inserted a chemical arm to orient unnatural substrates, such as menthol, for catalysis. Credit: Gonzalo Jiménez-Osés/Nature Chemistry/C&EN

Three key papers:

“Enzymatic Hydroxylation of an Unactivated Methylene C–H Bond Guided by Molecular Dynamics Simulations” (Nat. Chem. 2015, DOI: 10.1038/nchem.2285)

“Directing Group-Controlled Regioselectivity in an Enzymatic C–H Bond Oxygenation” (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5016052)

“Indolizinones as Synthetic Scaffolds: Fundamental Reactivity and the Relay of Stereochemical Information” (Org. Biomol. Chem. 2012, DOI: 10.1039/clob06423a)

Career paths:

They might be young scientists, but our Talented 12 have already traveled far and wide.

alison_narayan_map

Watch Narayan talk about her research during a special Aug. 22 Talented 12 symposium held at the American Chemical Society national meeting in Philadelphia.

Bill Morandi
Renã Robinson
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