Zinc-binding is vital for regulating pH levels in the brain

Researchers in Oslo, Norway, have discovered that Zinc-binding plays a vital role in the sensing and regulation of pH in the human brain. The findings come as one of the first studies that directly link Zinc-binding with bicarbonate transporters.

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The Morth Group, led by J. Preben Morth, recently published the findings in Scientific Reports. The group is based at the Centre for Molecular Medicine Norway and studies the structure and function of membrane proteins, and their interaction with lipids in the biological membrane.  When we inhale, oxygen is distributed via our red blood cells to every living cell of our body. Human cells use oxygen to produce Adenosine triphosphate (ATP) – the molecule that fuels vital processes in the cells, such as maintaining the electrical potential across the membranes of the cells that allow us to think and feel. In other words, we wouldn’t “work” very efficiently without this process.

ATP generation is directly linked to the citric acid cycle also known as the Krebs cycle, which leads to the complete breakdown of nutrients. This process ultimately generates carbon dioxide (CO2) as the final waste product, which is expelled when we exhale. However, before we can emit the excess CO2, this critical molecule is involved in one of the most important biological functions in our body: It regulates pH in our cells. This process is incredibly important; if the pH in and around our cells is lower than 6.8 or higher than 7.8, then we are in danger of dying due to cell death and tissue damage.

An example of how essential pH levels are to our health is demonstrated by the fact that pH levels in blood from the umbilical cord are always tested in newborn babies. A low pH value is correlated with a low oxygen supply during birth, which can lead to severe brain damage. When in water, CO2 forms bicarbonate (HCO3-) and is transported by specific transport proteins across the cell membrane. How these transport molecules sense what the pH value is inside the cell is still an open question. However, the work performed by Alvadia et al.describes that the transition metal, Zinc, likely interacts with the proteins that facilitate the transport of HCO3– through the membrane.

This Zinc-binding, therefore, plays a vital role in the sensing and regulation of cellular pH, in particular in the transporters found in neurons of the human brain. This is one of the first studies that directly associates Zinc binding with bicarbonate transporters. Preben Morth, Group Leader at NCMM comments, “This is a basic research project, and at this stage, it is difficult to predict what the medical consequences will be. However, it is likely that Zinc may play a key role in the regulation of pH in the brain and therefore has implications for brain function and health.”

The results have recently been published in Scientific Reports from the Nature publishing group. The research group behind the discovery is M.Sc. Carolina Alvadia Dr. Kaare Bjerregaard-Andersen, Dr. Theis Sommer, M.Sc. Michele Montrasio, Asc. Prof. Helle Damkier, Prof. Christian Aalkjaer, Asc. and Nordic EMBL Partnership principal investigator, J. Preben Morth.

Adapted from: Carolina M. Alvadia, Theis Sommer, Kaare Bjerregaard-Andersen, Helle Hasager Damkier, Michele Montrasio, Christian Aalkjaer, J. Preben Morth. The crystal structure of the regulatory domain of the human sodium-driven chloride/bicarbonate exchangerScientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-12409-0

Nutrition Nugget

Pre-Pack Your Meals And Snacks! It’s easy to get caught up with work and meetings during the day, leaving a quick fast-food lunch your only option. Spare yourself the empty calories and money by packing your lunch. Whether you meal prep at the beginning of the week or have leftovers from last night’s healthy dinner, you’re guaranteed a healthy option for lunch. Save even more money when you pack your own snacks to avoid any unnecessary trips to the vending machine!

Inspirational Nugget

Don’t forget to Thank God for keeping you safe through the night and every time you awaken to see a beautiful new day.

 

Neutrons observe vitamin B6-dependent enzyme activity useful for drug development

B6-dependent protein, potentially opening avenues for new antibiotics and drugs to battle diseases such as drug-resistant tuberculosis, malaria, and diabetes.

Image result for Neutrons observe vitamin B6-dependent enzyme activity useful for drug development

Specifically, the team used neutron crystallography to study the location of hydrogen atoms in aspartate aminotransferase, or AAT, an enzyme vital to the metabolism of certain amino acids. “We visualized the first neutron structure of a vitamin B6 enzyme that belongs to a large protein family with hundreds of members that exist in nature,” said Oak Ridge National Laboratory’s (ORNL) Andrey Kovalevsky, a senior co-author of the study, which was published in Nature Communications. Vitamin B6-dependent proteins are part of a diverse group of enzymes that conduct over a hundred different chemical reactions in cells. The enzymes are of interest to biomedical, as well as bioenergy, researchers because of their role in metabolizing amino acids and other cell nutrients.

“These enzymes are unique in that each one performs a specific chemical reaction with exquisite accuracy while suppressing other viable chemical transformations,” Kovalevsky said. “How they accomplish this is not well understood, but it is of great significance for drug design.” The team’s previous research predicted that hydrogen atoms move in and around the enzyme’s active site, where the chemical reaction takes place, indicating that the hydrogen atoms’ positioning controls the reaction type. Knowing the precise location of hydrogen atoms can explain why the behavior of these enzymes is so specific, but hydrogen is hard to detect with standard methods such as X-ray crystallography.

To directly determine the positions of hydrogen atoms within AAT, the ORNL-led team turned to neutron diffraction techniques. The researchers exposed fine protein crystals to neutrons using the IMAGINE beamline at ORNL’s High Flux Isotope Reactor and the LADI-III beamline at the Institut Laue-Langevin in Grenoble, France. Surprisingly, the team observed a reaction within one AAT protein biomolecule while another AAT biomolecule was unchanged, providing a before-and-after perspective of the enzyme-catalyzed chemical reaction. “The data revealed that in one of the enzyme’s biomolecular structures the covalent bonds reorganized after a chemical reaction occurred in the active site and, in another, the reaction had not taken place,” Kovalevsky said. “Essentially, we were able to obtain two structures in one crystal, which has never been done before for any protein using neutrons.”

With this knowledge, the team will run molecular simulations to determine the hydrogen atoms’ specific behavior when interacting with the enzyme. The results could be useful in guiding the future design of novel medicines against multidrug-resistant tuberculosis, malaria, diabetes and antibiotic-resistant bacteria. “This study highlights how neutrons are an unrivaled probe for identifying the location of hydrogen atoms in biological systems, providing us with an unprecedented level of structural detail for this important enzyme,” LADI-III beamline scientist Matthew Blakeley said.

Adapted from: Steven Dajnowicz, Ryne C. Johnston, Jerry M. Parks, Matthew P. Blakeley, David A. Keen, Kevin L. Weiss, Oksana Gerlits, Andrey Kovalevsky, Timothy C. Mueser. Direct visualization of critical hydrogen atoms in a pyridoxal 5′-phosphate enzymeNature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01060-y

Nutrition Daily Nugget

Eat the rainbow! A fun and tasty way to make sure your family is eating a good variety of fruits and vegetables is to eat as many different colors as you can each day.

Daily Inspiration Nugget

Why do we close our eyes when we pray, cry, kiss, dream? Because the most beautiful things in life are not seen but felt only by the heart.

 

 

A dietary supplement dampens the brain hyperexcitability seen in seizures or epilepsy

Researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models. These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes.

Image result for A dietary supplement dampens the brain hyperexcitability seen in seizures or epilepsy

Seizure disorders, including epilepsy, are associated with pathological hyperexcitability in brain neurons. Unfortunately, there are limited available treatments that can prevent this hyperexcitability. However, the *University of Alabama at Birmingham researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models.

 

These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes. Proteins are the workhorses of living cells, and their activities are tightly and rapidly regulated in responses to changing conditions. Adding or removing a phosphoryl group of proteins is a well-known regulator of many proteins, and it is estimated that human proteins may have as many as 230,000 sites for phosphorylation. A lesser-known regulation comes from the addition or removal of N-acetylglucosamine to proteins, which is usually controlled by glucose, the primary fuel for neurons. Several years ago, neuroscientist Lori McMahon, Ph.D., professor of cell, developmental and integrative biology at UAB, found out from her colleague John Chatham, D.Phil., a UAB professor of pathology and a cardiac physiologist, that brain cells had the second-highest amounts of proteins with N-acetylglucosamine, or O-GlcNAcylation, in the body.

At the time, very little was known about how O-GlcNAcylation might affect brain function, so McMahon and Chatham started working together. In 2014, McMahon and Chatham, in a study led by graduate student Erica Taylor and colleagues, reported that acute increases in protein O-GlcNAcylation caused long-term synaptic depression, a reduction in neuronal synaptic strength, in the hippocampus of the brain. This was the first time acute changes in O-GlcNAcylation of neuronal proteins were shown to directly change synaptic function. Since neural excitability in the hippocampus is a crucial feature of seizures and epilepsy, they hypothesized that acutely increasing protein O-GlcNAcylation might dampen the pathological hyperexcitability associated with these brain disorders.

That turned out to be the case, as reported in the Journal of Neuroscience study, “Acute increases in protein O-GlcNAcylation dampen epileptiform activity in the hippocampus.” The study was led by corresponding author McMahon and first author Luke Stewart, a doctoral student in the Neuroscience Theme of the Graduate Biomedical Sciences Program. Stewart is co-mentored by McMahon and Chatham. “Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics,” they wrote in their research significance statement. The researchers caution that the mechanism underlying the dampening is likely to be complicated.

Research details

Glucose, the primary fuel for neurons, also controls the levels of protein O-GlcNAcylation on proteins. However, high levels of the dietary supplement glucosamine, or an inhibitor of the enzyme that removes O-GlcNAcylation, leads to rapid increases in O-GlcNAc levels. In experiments with hippocampal brain slices treated to induce stable and ongoing hyperexcitability, UAB researchers found that an acute rise in protein O-GlcNAcylation significantly decreased the sudden bursts of electrical activity known as epileptiform activity in area CA1 of the hippocampus. An increased protein O-GlcNAcylation in normal cells also protected against a later induction of drug-induced hyperexcitability.

The effects were seen in slices treated with both glucosamine and an inhibitor of the enzyme that removes O-GlcNAc groups. They also found that treatment with glucosamine alone for as short a time as 10 minutes was able to dampen ongoing drug-induced hyperexcitability. In common with the long-term synaptic depression provoked by increased O-GlcNAcylation, the dampening of hyperexcitability required the GluA2 subunit of the AMPA receptor, which is a glutamate-gated ion channel responsible for fast synaptic transmission in the brain. This finding suggested a conserved mechanism for the two changes provoked by increased O-GlcNAcylation — synaptic depression and dampening of hyperexcitability.

The researchers also found that the spontaneous firing of pyramidal neurons in another region of hippocampus, area CA3, was reduced by increased O-GlcNAcylation in normal brain slices and in slices with drug-induced hyperexcitability. This reduction in spontaneous firing of CA3 pyramidal neurons likely contributes to decreased hyperexcitability in area CA1 since the CA3 neurons directly excite those in CA1. Similar to the findings for brain slices, mice that were treated to increase O-GlcNAcylation before getting drug-induced hyperexcitability had fewer of the brain activity spikes associated with epilepsy that are called interictal spikes. Several drug-induced hyperexcitable mice had convulsive seizures during the experiments, this occurred in both the increased O-GlcNAcylation mice and the control mice. Brain activity during the seizures differed between these two groups: The peak power of the brain activity for the mice with increased O-GlcNAcylation occurred at a lower frequency, as compared with the control mice.

*I am very proud to say UA (though UA Tuscaloosa) is my graduate program home!

Adapted from: Luke T. Stewart, Anas U. Khan, Kai Wang, Diana Pizarro, Sandipan Pati, Susan C. Buckingham, Michelle L. Olsen, John C. Chatham, Lori L. McMahon. Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in HippocampusThe Journal of Neuroscience, 2017; 37 (34): 8207 DOI: 10.1523/JNEUROSCI.0173-16.2017

Nutrition Daily Nugget…..and a bit of wine! 

Watch out for added sugars! They add extra calories but no helpful nutrients. Sugar-sweetened beverages and soft drinks are the number one source of added sugars for most of us.

AND….if you are looking for some excellent wine selections, check out Bright Cellars. The link is also on the right side of my blog for future reference.

Daily Inspiration Nugget

Never stop believing in hope. Miracles happen everyday.