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Circadian watch and fat shift connected through newly discovered mechanism



  Circadian clock and fat metabolism linked through newly discovered mechanism
A new study reveals the mechanism by which the circadian clock enzyme Nocturnin interacts with its target, NADPH, to affect energy regulation and metabolic functions. Credit: Michael Estrella, Jin Du and Alexei Korennykh, Princeton University

The enzyme Nocturnin, which regulates daily tasks such as fat metabolism and energy consumption, works in a completely different way than previously thought, a research group at Princeton University reported. The newly discovered mechanism reveals the molecular link between the enzyme's daily fluctuations and its energy regulating role in the body, according to a study published this week in Nature Communications .

"The realization that Nocturnin works this way will guide our thinking about sleep, oxidative stress and metabolism and eventually can serve as a step towards finding better treatments for metabolic diseases," says Alexei Korennykh, associate professor in molecular biology at Princeton, who led the work.

Nocturnin is part of the circadian clock that alters the metabolism and behavior of liverworms to match the body's needs at different times of the day. For example, Nocturnin levels fluctuate during the day when they occur dramatically when the body first awakens. Nocturnin is also a critical regulator of metabolism; Compared to regular mice, mice lacking the enzyme make less insulin, are protected from fat diseases and are less susceptible to weight gain.

However, the precise function of Nocturnin's inner cells has been unclear. For many years, the enzyme appeared to turn on and off cellular metabolism by breaking down certain cellular messages made from ribonucleic acid or mRNAs. Last year, three groups of researchers, a group from the University of Michigan, showed a group from the University of Minnesota and Korennykh's team that Nocturnin was not capable of degrading RNAs.

To find out how Nocturnin can have such great effects on body metabolism, Korennykh compared to Princeton's Joshua Rabinowitz, a professor of chemistry and Lewis-Sigler Institute for Integrative Genomics, and Paul Schedl, professor of molecular biology. The study was led by postdoctoral research assistant Michael Estrella and graduate student Jin Du in the Alexei laboratory and postdoctoral research associated with Li Chen in the Rabinowitz lab.

Using methods that were groundbreaking by Rabinowitz to screen tissues for the presence of metabolites, the researchers discovered that Nocturnin plays a much more direct role in metabolism than previously appreciated. Instead of degrading mRNAs, the enzyme regulates specific metabolites that aid in energy production and protect cells from damage. The study found that Nocturnin is located in the cell's energy-producing structures, the mitochondria, suggesting that this is where the enzyme performs its function.

  Circadian clock and fat shift linked through newly discovered mechanism
Closeup of the structure of Nocturnin (red) interacts with NADPH (yellow). Credit: Michael Estrella, Jin Du and Alexei Korennykh, Princeton University

The team found that Nocturnin removes a phosphate group from two molecules that are important in metabolism, called NADP + and NADPH. These molecules allow the cell to modulate the levels of reactive oxygen species which act both as harmful agents causing damage and as signal molecules that control metabolism and fat storage. The researchers conclude that Nocturnin is the first known enzyme to perform this reaction on NADP + and NADPH within mitochondria.

Removal of phosphate groups from NADP + and NADPH produces two different but equally important molecules, NAD + and NADH, which are essential for the function of metabolic enzymes – the molecular machines that produce energy by breaking down energetic biomolecules like glucose.

Nocturnin upregulation when an animal first awakens can therefore kick the body's energy production in high gear by giving more NAD + and NADH. "It is tempting to suggest that a physiological function of Nocturnin could be to maximize available NAD + and NADH for energy generation in a search for food using the elevated blood sugar that animals have at the time of awakening," says Korennykh.

Korennykh and colleagues also deciphered the crystal structure of the human Nocturnin bound to NADPH, which at atomic level shows how the reaction is mediated by Nocturnin. NADPH fits perfectly into Nocturnin's active site so that the enzyme can easily remove the molecule's phosphate group.

Finally, the researchers found that the fruit air version of Nocturnin, also known as Curled, is unable to cleave RNA. Instead, Curled uses the same mechanism as human Nocturnin and targets NADP + and NADPH. The Curled gene was first described over 100 years ago by Thomas Hunt Morgan, the groundbreaking geneticist who won a Nobel Prize to demonstrate that genes are carried on chromosomes. Although Curled has been studied by fruit air scientists since then, the biochemical mechanism so far has become a mystery.

"Our work shows that even in the age of genomics and personal medicine, basic biology is still being understood," Korennykh said. "In the example of Nocturnin and Curled, a pathway that regulated some of the major molecules in metabolism was hidden in the ordinary sight for the past 100 years."

The study "The Metabolites NADP + and NADPH are Cadadian's Protein Nocturnin (Curled) Target" by Michael A Estrella, Jin Du, Li Chen, Sneha Rath, Eliza Prangley, Alisha Chitrakar, Tsutomu Aoki, Paul Schedl, Joshua Rabinowitz and Alexei Korennykh, published online in Nature Communications on May 30, 2019.


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More Information:
"The metabolites NADP + and NADPH are the targets of the Circadian Protein Nocturnin (Curled)," Nature Communications (2019). DOI: 10,1038 / s41467-019-10125-z

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Circadian watch and fat shift connected through newly discovered mechanism (2019, May 30)
May 30, 2019
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