Chemists design enzymes to synthesize lactam drugs

By Houk Research Group

Professor Ken Houk, Dr. Pengchen Ma, Dr. Arkajyoti Sengupta, Dr. Ledong Zhu. (Image courtesy: Houk Research Group / UCLA)

This article was originally published by UCLA Chemistry & Biochemistry

Professor Ken Houk’s group and the Rudi Fasan group at the University of Texas Dallas collaborated to pioneer biocatalytic synthetic pathways for 4-6 membered lactams, key structural elements in many biologically active compounds such as the antibiotic Penicillin and the Covid-19 drug Paxlovid.  The team’s paper in Nature Catalysis was recently highlighted in Chemical & Engineering News (C&EN) and the British journal Chemistry World.

Lactam rings are structural motifs that are present in numerous biologically active natural products and pharmaceuticals. The Houk group teamed up with Professor Rudi Fasan’s group at the University of Texas Dallas to develop the first biocatalytic synthetic routes for β-, γ- and δ-lactams with high yields and excellent chemo- and stereoselectivities. Engineered myoglobin mutants catalyzed cyclization of dioxazolone substrates to different-sized ring lactams in an inexpensive and environmental-friendly manner. The enzyme catalyzed routes allowed formation of bioactive alkaloid homaline and a beta-lactam drug – dapoxetine with higher yields and in fewer steps (7–8 vs. 11–12) than in previous total synthesis strategies.

The team’s paper titled “Stereoselective construction of β-, γ- and δ-lactam rings via enzymatic C–H amidation” was published in the December 2023 issue of Nature Catalysis.

(Image courtesy: Houk Research Group / UCLA)

The experiments were performed by postdoc Dr. Satyajit Roy and graduate student David Vargas in Professor Rudi Fasan’s group at the University of Texas Dallas. The computations were performed by postdocs Dr. Pengchen Ma, Dr. Arkajyoti Sengupta, and visiting scholar Dr. Ledong Zhu from Shandong University in the group of Professor Ken Houk, Distinguished Research Professor at UCLA. The computations involved DFT calculations for mechanistic elucidation and molecular dynamic simulations to understand how different mutations of the enzyme catalyst influence stereo-control.

The calculations revealed the reaction mechanism, and how the enzyme binding site controls the stereo- and regioselectivities. The computations showed how the key mutations of amino-acid residues in the active pocket (64V, 68A and 107I) influence the reaction selectivity. The reactions and key residues in active site pocket are shown below.

By coincidence, a second collaboration of the Houk and Fasan groups just came out. Their paper titled “Biocatalytic strategy for the construction of sp3-rich polycyclic compounds from directed evolution and computational modelling” was published in Nature Chemistry on February 13, 2024.