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Circadian clock and fat metabolism linked by newly discovered mechanism



  Circadian clock and lipid metabolism linked by newly discovered mechanism
A new study reveals the mechanism by which the circadian clock enzyme nocturnin interacts with its target, NADPH, to influence energy regulation and metabolic functions. Picture credits: Michael Estrella, Jin Du and Alexei Korennykh, Princeton University

The enzyme nocturnin, which regulates daily tasks such as lipid metabolism and energy consumption, works quite differently than previously thought, reported a research team from Princeton University. The newly discovered mechanism reveals the molecular link between the daily fluctuations of the enzyme and its energy-regulating role in the body, as a study published in Nature Communications this week shows.

"The recognition that Nocturnin works in this way will guide our thinking about sleep, oxidative stress and metabolism, and may ultimately serve as a step towards finding better therapies for metabolic diseases," said Alexei Korennykh, Associate Professor of Molecular Biology at Princeton who led the work.

Nocturnin is part of the circadian clock that adjusts the metabolism and behavior of living organisms to the needs of the body at different times of the day. For example, nocturnin levels fluctuate throughout the day, reaching dramatic highs when the body wakes up for the first time. Nocturnin is also a critical regulator of metabolism; Compared to normal mice, mice without enzymes produce less insulin, are protected from fatty liver disease, and less prone to weight gain.

However, the exact function of nocturnin in cells has remained unclear. For many years, it has been thought that the enzyme turns cell metabolism on and off by breaking down certain cellular messages from ribonucleic acid or mRNAs. However, last year three research groups ̵

1; a group from the University of Michigan, a group from the University of Minnesota, and the Korennykh team – discovered that nocturnin can not break down RNAs.

How To Find Out How Nocturnin Can Have It In collaboration with chemistry professor Joshua Rabinowitz of Princeton and the Lewis Sigler Institute of Integrative Genomics and molecular biologist Paul Schedl, Korennykh had a major impact on the body's metabolism. The study was led by postdoctoral researcher Michael Estrella and PhD student Jin Du at the Alexei Laboratory and postdoctoral researcher Li Chen at the Rabinowitz Laboratory.

Using methods developed by Rabinowitz, the researchers studied tissues for the presence of metabolites that found that nocturnin plays a much more direct role in metabolism than previously thought. Instead of breaking down mRNAs, the enzyme regulates certain metabolites that contribute to energy production and protect cells from damage. The study found that nocturnin is present in the cell's energy-producing structures, the mitochondria, suggesting that the enzyme functions here.

  Circadian clock and fat metabolism linked by newly discovered mechanism
the structure of nocturnin (red) interacts with NADPH (yellow). Picture credits: Michael Estrella, Jin Du and Alexei Korennykh, Princeton University

The team found that nocturnin removes a phosphate group from two key metabolizing molecules, NADP + and NADPH. These molecules allow the cell to modulate the level of reactive oxygen species that act as both harmful substances that cause damage and 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 in mitochondria.

Removal of NADP + and NADPH phosphate groups produces two distinct but equally important molecules, NAD + and NADH, which are essential for the function of metabolic enzymes – the molecular machines that generate energy by breaking down energy-rich biomolecules, such as glucose ,

Nocturnin upregulation on the first awakening of an animal could therefore spur the body's energy production by providing more NAD + and NADH. "It is tempting to assume that a physiological function of nocturnin is to maximize the available NAD + and NADH for energy harvesting, using the increased blood sugar that animals have at the time of awakening," said Korennykh.

Korennykh and colleagues were also able to decipher the crystal structure of the human nocturnin bound to NADPH and show, at the atomic level, how the reaction mediated by nocturnin proceeds. NADPH fits perfectly into the active site of Nocturnin, so that the enzyme can easily remove the phosphate group of the molecule.

Finally, the researchers found that the fruit fly version of nocturnin, known as Curled, also can not 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 pioneering geneticist who received a Nobel Prize for demonstrating that genes are transferred to chromosomes. Although Curled has since been studied by fruit fly researchers, its biochemical mechanism has remained a mystery until now.

"Our work shows that basic biology can still be understood in the age of genomics and personalized medicine," said Korennykh. "The example of Nocturnin and Curled hid a metabolic pathway over the last 100 years that regulated some of the most important molecules."

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


Study shows how muscles regulate their oxygen consumption


Further 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 clock and fat metabolism linked by newly discovered mechanism (2019, May 30)
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