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Natural Products

Bacteria synthesize terminal-alkyne-containing amino acid from lysine in three steps

Chemists use newly discovered pathway to incorporate the bioorthogonal handle into bacterial proteomes

by Celia Henry Arnaud
March 13, 2019 | A version of this story appeared in Volume 97, Issue 11


Reaction scheme showing lysine and propargylglycine.
Newly discovered biosynthetic pathway makes terminal-alkyne-containing amino acids from lysine.

Researchers have discovered a biosynthetic pathway that makes amino acids containing terminal alkynes. Because such functional groups are rare in natural products, they provide a handle for chemistry that’s not generally found in biological organisms. For example, chemists could use such groups to attach fluorescent dyes to proteins via click chemistry.

Michelle C. Y. Chang and coworkers at the University of California, Berkeley, found the pathway while trying to figure out how Streptomyces cattleya makes β-ethynylserine, a terminal-alkyne-containing amino acid. Cells often form internal alkynes in natural products by desaturating fatty acids, so Chang’s team started knocking out genes for desaturase enzymes. But the microbe still made the amino acid. The researchers decided to look elsewhere.

They found the gene cluster by comparing the S. cattleya genome with that of another microbe known to make terminal alkynes (Nature 2019, DOI: 10.1038/s41586-019-1020-y). The gene cluster encodes six proteins, five of which the scientists propose are involved in the synthesis. They think the remaining one is a protein that transports the amino acid between cellular compartments.

Chang’s team proposes that three of the enzymes catalyze a series of reactions converting L-lysine to L-propargylglycine. Lysine undergoes halogenation, oxidative C–C bond cleavage, and triple-bond formation through an allene intermediate to form propargylglycine. The two other enzymes convert propargylglycine to β-ethynylserine, the team thinks.

The researchers used the genes they discovered to engineer Escherichia coli to produce propargylglycine. They then further engineered the microbe to substitute the terminal alkyne amino acid for all the methionines in the microbe’s proteome.

Chang plans to explore additional bioorthogonal chemistry with the enzymes from the pathway. For example, her group is studying the first enzyme in the pathway to possibly engineer halogenation of amino acids into cells.

The work represents “the first endogenous pathway for biosynthesis of terminal-alkyne-containing amino acids,” says Peng Chen, a bioorthogonal-chemistry expert at Peking University. The value, he says, comes from engineering living cells to make biomolecules with handles that chemists could selectively modify.


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