NEWLY IDENTIFIED CHEMICAL COMPLEX REGULATES BODY ZINC STORAGE

Zinc deficiency compromises the immune system against viral infections and is a global public health problem affecting up to 20% of the Mexican population

Bellow follows an English translation (with minor modifications) of a press release by Conexión Cinvestav. I am grateful to Efrén Díaz Millán for putting the piece together. You can read the original in Spanish here.

An international scientific collaboration describes a new hormonal function for kynurenine, which regulates organismal zinc, with implications in nutrition and immunity. 

In a study published in the journal Proceedings of the National Academy of Sciences of the U.S.A. entitled “Tryptophan regulates Drosophila zinc stores”, 7 Cinvestav scientists, 3 researchers from the University of Bari Aldo Moro, and 4 synchrotron specialists from the Paul Scherrer Institute and Freie Universität Berlin uncover a new physiological function for tryptophan-derived kynurenine: to facilitate zinc storage sites within cells. 

Confocal images at two magnifications of a vermilion mutant Malpighian tubule from a Drosophila larva expressing the zinc transporter ZnT35C (green) after kynurenine feeding. Applying a combination of spectroscopies, Garay et al. identify in situ chemical complexes of zinc with endogenous chelators 3-hydroxykynurenine and xanthurenic acid, which accumulate in storage granules (red within green). The results suggest that tryptophan derived metabolites have an important role in the intracellular retention of zinc.

This new function discovered in a model organism might explain why Covid-19 patients with the severe form of the disease present high concentration of kynurenine and low concentration of zinc their blood, commented Fanis Missirlis, member of the research team affiliated with Cinvestav’s Department of Physiology, Biophysics and Neurocience. 

Moreover, the research suggests that zinc deficiency – a public health problem affecting around 20 percent of the Mexican population – could be due to a deficient dietary intake of tryptophan, an amino acid component of proteins that is metabolized into kynurenine.

Although programs of the World Health Organization exist for supplementation of zinc to the population in various countries, the researchers suggest that organismal zinc deficiency might not be exclusively related to lack of the metal in the diet, since the animal model showed that under tryptophan deficiency even supplemented metal does not accumulate. 

“We propose that zinc deficiency in the population could be due to low protein consumption. Zinc deficiency was associated with high Covid-19 mortality in epidemiologic studies performed in Japan and India”, explained the researcher. 

The relevance of zinc stems from it being a cofactor for the maturation of up to 10% of the body’s proteins; it is a metal strictly required for many physiological functions, including those of the immunological system. For this reason, it is necessary to regulate its concentration and yet little is known about the mechanisms for zinc regulation at the systemic level.

The research was performed in the fruit fly animal model because it allows genetic analysis, meaning one can work with mutations affecting specific genes. In this case, dozens of mutants were studied with the principal aim to identify the proteins that facilitate the formation of zinc storage granules and the transporters of kynurenine, zinc, protons, and chloride ions, all required to store the metal.

The study was supported by the government of the state of Hidalgo, through its funding call for research projects related to Covid-19, in collaboration with the Swiss Light Source (SLS) in Switzerland, where synchrotron analysis allowed the comparison of material isolated from flies with or lacking zinc stores. These studies revealed the existence of a new chemical complex of zinc with 3-hydroxy-kynurenine and chloride that is essential for zinc storage. 

Alberto Vela Amieva, researcher of the Department of Chemistry of Cinvestav, computed quantum chemistry-based theoretical calculations on the Xiuhcóatl high-performance cluster that yielded a three-dimensional model and theoretical spectrum of the new complex. This spectrum was corroborated by the experimental one obtained in the synchrotron, a technology that works with very high energy X-rays interacting specifically with the zinc atoms at certain energies.

“The zinc complex with 3-hydroxy-kynurenine and chloride, initially described only theoretically, was also synthesized in the lab and analyzed at the synchrotron to verify that it can be detected inside the zinc storage granules of the insect”, stated Fanis Missirlis. A detailed chemical characterization of the complex was performed by the group of Fabio Arnesano at the University of Bari Aldo Moro and by Liliana Quintanar’s laboratory at the Department of Chemistry at Cinvestav.

The next goal for the project is to demonstrate that the findings in the fruit fly are also valid in rodents and human beings. First authors of the work were Erika Garay, funded through a service contract between Cinvestav and Zinpro Co., which produces animal dietary supplements, and Nils Schuth, who is a Deutche Forschungsgemeinschaft (DFG) international postdoctoral research fellow, also based in Cinvestav, Mexico.

To read the original research article press here.

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