平特五不中 researchers reveal how life-saving molecules are created
平特五不中 researchers have discovered how certain microbes create potent drugs like antibiotics and anti-cancer therapies.
Their surprising findings could change the way scientists approach drug discovery and pave the way to the designing of next-generation medications, explained Martin Schmeing, principal investigator and professor in 平特五不中鈥檚 Department of Biochemistry and Centre for Structural Biology.
Schmeing and his team studied special proteins called nonribosomal peptide synthetases, which act like tiny machines in cells. These 鈥渕achines鈥� build molecules by connecting smaller pieces called amino acids. For decades, exactly how these microbes worked to form life-saving medicines eluded scientists.
To understand the process, the researchers used advanced tools to take highly detailed, 3D pictures of the 鈥渕achines鈥� both before and after they connected the amino acids. To do this, they had to split the 鈥渕achines鈥� in a way that provided the best 鈥減oses鈥� for pictures, and then put them back together.
鈥淭aking 3D pictures of these massive enzymes was like solving a molecular jigsaw puzzle,鈥� added Angelos Pistofidis, lead author and PhD student.
鈥淚t took years of persistence and many setbacks, but the results were worth it. For the first time, we have a smoking-gun view of how these enzymes work, and it鈥檚 not how anyone guessed,鈥� Schmeing said.
鈥淥ur work helps demystify this incredible natural process. We鈥檝e finally unveiled how these microbial machines piece together building blocks to form these lifesaving compounds. It's an achievement decades in the making, and was a great team effort with our UCLA collaborators鈥�.
The microbes are in effect 鈥渆ngaged in an evolutionary arms race with one another,鈥� explained Schmeing, 鈥渁nd we now understand the most important step in how they make these weapons.鈥�
He said scientists traditionally thought that the process involved general base catalysis, but now understand that it鈥檚 through electrostatic stabilization in a concerted reaction pathway.
Designing next-generation drugs
The discovery could have wide-reaching implications for medicine. A detailed understanding of how these enzymes operate stands to unlock new pathways for designing next-generation drugs.
鈥淭he potential is enormous,鈥� Schmeing said. 鈥淭hese microbial machines are already a treasure trove of therapeutics. Understanding their mechanisms could allow us to engineer them for new, custom-designed drugs.鈥� The findings represent an important step forward toward making these machines a go-to tool for drug discovery, the researchers said.
This finding also establishes a new roadmap for studying other complex biological systems.
鈥淭he innovative methods we developed to study these enzymes could pave the way for understanding similarly elusive molecular machines, whether they make medicines, or have a different job,鈥� added Pistofidis.
鈥淔undamental knowledge is important,鈥� Schmeing said. 鈥淎nd sometimes, solving the puzzle of nature opens doors we didn鈥檛 even know existed.鈥�
Schmeing and his team aren鈥檛 finished with this research. 鈥淎lthough this study illuminates the central step in synthesis of these antibiotics, we have lots more to learn from the next 3D pictures of these elegant microbial machines.鈥�
About the study
by Angelos Pistofidis, Pengchen Ma, Zihao Li, Kim Munro, Ken Houk, Martin Schmeing, and their UCLA collaborators was published in Nature. It was funded by the Canadian Institutes of Health Research and Fonds de recherche du Qu茅bec - Sant茅.
