Researchers from the National University of Singapore (NUS) have made a groundbreaking discovery: a remarkable multidomain enzyme that is capable of facilitating two crucial reactions necessary for the synthesis of various pharmaceutical compounds.
Natural compounds, synthesized by a range of living organisms including plants, animals, and microorganisms, play essential roles in survival and defense mechanisms. Notably, many prominent medications such as ibuprofen and penicillin are derived from these natural sources. The intricate biosynthetic enzymes that produce these natural products are responsible for generating unique molecular structures that pose significant challenges for human chemists to replicate. Identifying novel biosynthetic enzymes presents an exciting opportunity to innovate new drug compounds that could lead to improved therapies for serious ailments, including life-threatening infections and cancer.
Under the leadership of Assistant Professor Brandon I. Morinaka from the Department of Pharmacy and Pharmaceutical Sciences at NUS, the team has identified these novel multidomain enzymes that enable two biochemical reactions—cyclization and hydroxylation—on the same peptide substrate. These bacterial biosynthetic enzymes hold the promise of revolutionizing pharmaceutical production, as both transformations are typically challenging to achieve through traditional chemical synthesis methods. The structure of the enzymes reveals two distinct functional domains: a radical SAM domain, which facilitates cyclization, and a hydroxylase domain responsible for hydroxylation. Interestingly, the original assumption that the hydroxylase domain functioned as a protease emerged from its similarity to metalloproteases; however, researchers have now reclassified it into a novel oxygenase family identified as αKG-HExxH. This innovative research was conducted in collaboration with notable scholars: Professor Zhang Qi at Fudan University in China and Professor Yvain Nicolet at the University of Grenoble Alps in France.
The findings were published in the esteemed journal Nature Chemistry.
Asst Prof Morinaka stated, “The combination of a multidomain protein for peptide modification and the discovery of a new oxygenase family will allow new avenues in natural products discovery and enzymology.” He expressed amazement at the complex chemistry evolved by nature, noting, “These reactions are difficult, if not impossible, for humans to design or imagine.”
Looking ahead, the research team is eager to delve into the potential therapeutic applications of the products derived from these enzymes, to better comprehend the mechanisms through which these enzymes facilitate such intricate reaction sequences, and to engineer these systems to generate an even wider array of novel products.
Source:
Journal reference:
Morishita, Y., et al. (2024). Fused radical SAM and αKG-HExxH domain proteins contain a distinct structural fold and catalyse cyclophane formation and β-hydroxylation. Nature Chemistry. doi.org/10.1038/s41557-024-01596-9.
Breaking Down Nature’s Chemistry: NUS’s Enzymatic Marvel
So, get this: scientists from the National University of Singapore (NUS) have stumbled upon a unique multidomain enzyme that can, wait for it, catalyze *two* different types of reactions all on one substrate! It’s like finding out your average Swiss Army knife can also cook dinner. If you’re a pharmaceutical scientist, this is basically your version of winning the lottery—minus the whole standing in line for hours thing.
Nature’s Little Helpers
Now, for those of you not quite in the lab-coat crowd (don’t worry, I’m not either), let’s break it down. Natural products created by our green and not-so-green friends—plants, animals, and some really funky microorganisms—serve a plethora of purposes in nature, not to mention being excellent candidates for drug development. Think ibuprofen, penicillin; all those little wonders that turn us into functioning humans are born from this stuff! These compounds are like Mother Nature’s secret stash, and scientists are basically the kids trying to raid the cookie jar.
Introducing the Rock Star Enzyme
Enter the stage, the star of the show: the multidomain enzyme identified by a team led by Assistant Professor Brandon I. Morinaka. Picture this enzyme as a superhero duo inside your average bacterium: it’s equipped with a radical SAM domain that handles cyclization and a hydroxylase domain that does, you guessed it, hydroxylation! It’s like they came straight out of a Marvel movie, but instead of tights and capes, they come in radical and hydroxylated forms!
Now, don’t let the fancy terms throw you off. Cyclization and hydroxylation might sound like the names of obscure dance moves, but they’re actually pretty tough nuts to crack when it comes to chemical synthesis. If humans were trying to pull these moves, it’d likely end in someone’s lab being fumigated. Thankfully, these enzymes do the job, and do it well!
“We are always amazed by the chemistry that nature has evolved. These reactions are difficult, if not impossible, for humans to design or imagine.”
Brandon I. Morinaka, Assistant Professor, NUS Faculty of Science
A New Family of Oxygenases?
But wait, there’s more! In a twist no one saw coming, the researchers initially thought the hydroxylase domain was a protease because of its structural similarity to metalloproteases. Surprise! It’s actually part of a brand new family of oxygenases, humorously dubbed αKG-HExxH. Because nothing says “serious science” like a name that sounds like a failed end-of-year school project title!
Looking Ahead
As the research rolls on, the team plans to explore the therapeutic applications of their enzyme findings. They want to unpack how these little guys manage to pull off such complex reactions. Essentially, they’re figuring out how to stretch the limits of nature’s chemistry even further. Who knows, maybe one day you’ll be popping a pill made from some superhero enzyme’s handiwork. Now that’s a plot twist worth following!
In conclusion, this discovery has massive implications. We’re not just marveling at nature’s chemistry here; we’re talking about the potential for major breakthroughs in the treatment of life-threatening infections and cancer! It’s a big deal, and honestly, it’s about time we start giving credit where credit’s due—nature really does know how to throw down in the chemistry department.
Source:
National University of Singapore
Journal Reference:
Morishita, Y., et al. (2024). Fused radical SAM and αKG-HExxH domain proteins contain a distinct structural fold and catalyse cyclophane formation and β-hydroxylation. Nature Chemistry. doi.org/10.1038/s41557-024-01596-9.