Researchers reveal structure of mega-enzymes in bacteria and fungi

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Researchers have discovered the structure of non-tribosomal peptide synthetases (NRPS), an important ingredient in drug production.

Bacteria and fungi

New research has helped scientists better understand the structures of non-tribosomal peptide synthetases (NRPS), mega-enzymes from microbes such as bacteria and fungi that are used in drugs.

A research team led by McGill University in Canada used their results to shed light on the processes by which NRPS works. According to the team, this study could potentially allow bacteria and fungi to be exploited for the production of new desired compounds and lead to the creation of powerful new antibiotics, immunosuppressants and other modern drugs.

“NRPS are really fantastic enzymes that take small molecules like amino acids or other building blocks of similar size and assemble them into natural, biologically active and potent compounds, many of which are drugs,” said Martin Schmeing , Associate Professor in the Department of Biochemistry at McGill University and corresponding author of the study. “An NRPS works like a factory assembly line consisting of a series of robotic workstations. Each station has multi-stage workflows and moving parts that allow it to add building substrate to the growing drug, lengthen and modify it, and then move it to the next small workstation, the all on the same huge enzyme. “

In their article, the team reports visualizing a NRPS mechanical system, using the CMCF beamline at the Canadian light source (CLS). The CLS is a Canadian national laboratory that produces the ultra-intense X-rays needed to image proteins, because mega-enzymes are too small to be seen with an optical microscope.

Researchers have discovered that NRPS are made up of sequences of adenylation domains and ketoreductase, which are separated by residues that form a “split pseudoA”.under‘Field. They point out that this is structurally important for the synthetic cycle of mega-enzymes.

“Scientists have long been excited about the potential of bioengineering NRPSs by identifying the order of building blocks and rearranging workstations in the enzyme to create new drugs, but the effort has rarely been crowned of success, “said Schmeing. “This is the first time that anyone has seen how these enzymes transform keto acids into a building block that can be transformed into a peptide. This helps us understand how NRPS can use so many building blocks to make the many different compounds and therapies. “

The results were published in the journal Nature Chemical Biology.

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