Biohemistry Discoveries of 2019: Modern methods of analysis and research have significantly changed the way biochemical studies operate, and it was especially noticeable in 2019. Advances in analytical methods, for instance, have allowed re-evaluating some commonly accepted measurements, such as BPA exposure levels.
Also, the appearance of high throughput approaches has significantly accelerated drug discovery by analyzing crucial proteins in various organisms, such fungi, as well as cellular proteins in animals and humans. The advances in computer modeling have also provided new insights into how crucial biological molecules work.
In general, the last year was providing researchers with various types of information that can potentially change our lives for the better with new ideas for treatments and a better understanding of current dangers to our health. The list of discoveries presented here showcases these fantastic advances.
Top Biohemistry Discoveries of 2019
Here are the notable biochemistry news in 2019 from around the world:
The worm’s secret: short-lived species of roundworm can live longer due to activation of a vital autophagy protein [USA, December 2019].
Autophagy is a process during which sizable structures inside the cell, such as bulky proteins and mitochondria, get destroyed and recycled. Autophagy was recently found to be selective, and several proteins that are involved in tagging and delivering them to a unique cellular structure called phagosome have been found. A new role in prolonging lifespan was discovered for some of them.
A research team at the Sanford Burnham Prebys Medical Discovery Institute has previously found that a mild heart shock administered at the early stages of life in a roundworm species, C. elegance, has led to a prolonged lifespan in the worms. A thorough analysis of the processes that took place after the shock has shown that:
- The levels of genes that code for proteins p62 and sqst-1 were found to be increased in the worms that have received the heat shock.
- Proteins P62 and sqst-1 were known to participate in the cellular autophagy processes.
- When the researchers have created worms with mutated sqst-1 genes and exposed them to a similar heat shock, it was noted that autophagy activity in the nerve cells of the roundworms was decreased.
- In the typical roundworms with an intact sqst-1 gene, their lifespan was increased for approximately 25-30% after experiencing mild heat shock in the early stages of development.
- In the roundworms with mutated sqst -1, no increase in longevity was observed.
These findings can be especially beneficial for developing treatments against Huntington’s and Alzheimer’s diseases, which are, in part, caused by the accumulation of harmful proteins. Finding methods of inducing autophagy through proteins such as p62 could contribute to the treatment of these diseases. It should be noted that high p62 levels were found to be linked to cancer development, so this particular protein may not be useful for therapy. However, artificial proteins with functions similar to p62 can have a future in pharmacology.
BPA alert: the level of well-know and the dangerous chemical was much higher in humans than anticipated [USA, December 2019]
Bisphenol A (BPA) is a chemical widely used in multiple plastic products. It was proven that BPA interferes with multiple endocrine processes, which may lead to metabolic disorders. BPA exposure during pregnancy is also dangerous for the development of the fetus. In animals, doses as low as 2-5µg/kg could cause significant side effects. A team of researchers at the Washington State University in Pullman has compared traditionally used indirect methods of measuring BPA levels in urine with new direct methods using newly synthesized standards.
- The indirect method involved using an enzyme from a snail Helix pomatia that hydrolyzes BPA metabolite, BPA glucuronide and measuring resulting free BPA.
- The direct method used measuring BPA metabolites by comparing the measurements to certified standards.
- Testing both methods on artificial urine samples has shown that the indirect method detects approximately 2/3 or less of actual free BPA concentrations.
- BPA levels were also measured in the urine of 29 pregnant women, and the indirect method has yielded results 19 times lower than the direct measuring approach.
- The level of BPA in the urine of pregnant women measured by the direct method was 44 times higher than the level of exposure reported by a recent national survey.
- Similar trends were observed in 5 adult men and five non-pregnant women.
The data obtained by the team has shown that widely used BPA measuring methods were flawed and that exposure of the human population to BPA is significantly higher than previously thought. In light of the danger of the low doses of BPA in animals, and a higher likelihood of exposure to BPA in humans, new research needs to be conducted and FDA guidelines revisited.
It is all in the heme: a molecule crucial to the development of obesity discovered in brown fat [USA, November 2019]
Heme is a molecule with multiple functions: it is both a crucial component for many enzymes and proteins (including hemoglobin) and also a signaling molecule that drives various molecular and cellular processes. The functions and the mechanisms of delivery of the heme molecule are still being studied. A group of researchers at the Scripps Research Institute has studied functions of the progesterone receptor membrane component 2 (PGRMC 2). PGRMC 2 is active in the cells of the uterus, liver, and other areas, including brown fat. The research team has focused on the functions of PGRMC 2 in that area. They have found out that:
- PGRMC 2 is required for the delivery of signaling haem molecule to the nucleus.
- Deletion of the PGRMC 2 in brown fat of the mice led to severe mitochondrial dysfunction.
- Mice with the PGRMC 2 deletion could not thermoregulate properly and were at risk of a metabolic disorder if they were fed a diet rich in fat.
- Obese mice treated with PGRMC 2 activator have shown improvement in symptoms of diabetes.
This discovery is crucial for understanding the processes taking place in fat tissues and can point to a potential treatment against metabolic disorders and obesity.
Why thalidomide is dangerous for future babies: a collaborative study has described a protein crucial for the teratogenic effects of thalidomide [Japan-Italy, October 2019]
Thalidomide was a drug widely used in 1950 for morning sickness. A decade later, it was proven that thalidomide use could lead to severe abnormalities in developing babies. In essence, the children of pregnant mothers taking thalidomide had limb malformations and problems with ear development. Currently, it was found that thalidomide can be used in the treatment of blood cancer and leprosy. It is also useful for treating inflammation but is still contraindicated in pregnancy.
Collaboration between Japanese scientists at the Tokyo Medical University and researchers from Universita degli Studi di Milano, Italy, has helped in understanding the mechanisms through which thalidomide interferes with embryonic development. The international team has observed the effects of thalidomide in zebrafish and has revealed that:
- Previously, it was established that one of the critical proteins that govern thalidomide activities in the body is cereblon.
- It was found that cereblon in its turn binds to several isomers of p63, a protein from the p53 family.
- ∆Np63α, an p63 protein isomer, is essential for the limb development.
- Another isomer, TAp63α, is a critical protein in the development of ears.
- Interaction of the chain thalidomide-cereblon-p63 has led to defects in the pectoral fins and otic vesicles in developing zebrafish.
If researchers can be able to understand the mechanisms through which thalidomide causes abnormalities in embryonic development, it could be possible to modulate treatment plans to mitigate the harmful effects of this promising drug agent.
How to calm down parathyroid glands: A new signaling molecule that may help with hyperparathyroidism found [Singapore-India, April 2019]
Hyperparathyroidism is a condition caused by an overgrowth of the tissue in the parathyroid glands. As parathyroid glands are responsible for calcium levels and nervous system regulation, the overgrowth leads to hypercalcemia and neurologic disorders. Currently, this condition is treated by surgery, which is not always successful and can potentially have side effects. A team from the Cardiovascular and metabolic disorders program at the Duke-NUS Medical School in Singapore has studied the activity of parathyroid glands in mice and has found that:
- The levels of a secreted glycoprotein, semaphorin 3d (Sema3d) are high in the developing parathyroid glands in mice.
- Deletion of the gene responsible for Sema3d in mice has led to the overgrowth of the parathyroid glands and symptoms of hyperparathyroidism in these model animals.
- Sema3d blocks the growth of parathyroid tissues through a receptor called EGFR.
- In mice with a deleted Sema3d gene, EGFR levels are increased.
- If the EGFR is blocked by a specific inhibitor, usually used in cancer treatment, the negative symptoms are partially diminished.
This discovery can potentially lead to a treatment of hyperparathyroidism that does not require surgery.
Tumbling enzymes: researchers have described a flexible “production line” of specialized proteins that produce antibiotics [Canada-France, November 2019]
Bacteria produce most of the antibiotics we routinely use for their own protection. In order to produce these compounds, the microorganisms use a unique family of enzymes called non-ribosomal peptide synthases (NRPS). Their role in the bacterial cell is to synthesize small molecules usually used for defensive purposes. For specialists, these molecules can be the basis of future antibiotics.
The process of synthesis involves an assembly of different NRPS proteins that form a modular production line. Currently, the scientists may know the structure and function of separate enzyme modules that participate in this process, but not how the whole line functions. Collaboration between a team from the Department of Biochemistry at McGill University in Montreal, Canada, and Sorbonne, Paris, has helped the scientists understand the process of antibiotic biosynthesis better.
- The researchers have used X-ray crystallography to analyze the structure of the linear gramicidin synthetase subunit A (LgrA), part of the chain responsible for the production of linear gramicidin in Bacillus brevis. .
- The LgrA has two modules that have to work together to perform their relevant functions.
- X-ray crystallography has revealed that there were five different crystal structures of LgrA, and each of them was able to perform their function irrespective of the way they were organized.
- LgrA structures were also found to be very flexible in solutions.
- The modules can interact in different orientations and coordinate with each other only when an intermediate in the reaction is passed from one area of the module to the next.
This discovery shows that protein modules in the assembly line of NRPS are unexpectedly flexible. If researchers understand how the modules interact in the cell, they can potentially replicate the process in the laboratory by adjusting the modules and produce new molecules with desired properties.
Methionine for the strength: the researchers have discovered the critical structure responsible for the properties of the spider silk proteins [Germany, September 2019]
Spider silk is a lovely material for bioengineering specialists. Spider webs are remarkably robust and resilient. They are composed of individual proteins called spidroins. Dr.Neuweiler and his team at the Department of biotechnology and Biophysics of the Julius-Maximilians-University in Würzburg, Germany, decided to analyze the structure of the spidroins in the webs of the nursery web spider, E. australis. It was discovered that:
- Spidroins have N-terminal domains (NTDs) that interact with the corresponding domains of the neighbor proteins and form tight dimers.
- These NTDs contain high levels of an amino acid methionine.
- The researchers have mutated all methionines in the core of the NTD domain of the spidroin and changed them to leucines.
- The structure of the mutated protein was preserved, but these proteins could not form dimers.
- The methionines are also responsible for the protein flexibility, which also contributes to tighter binding between proteins.
This discovery can help with developing a synthetic material similar to spider silk.
The secret of human saliva: an international team has described how proteins in the saliva can lubricate our mouths [Great Britain, November 2019]
One should never underestimate the saliva that regularly forms in our mouths. This biological liquid performs multiple functions: it contains digestive enzymes, has antimicrobial properties, and also continually lubricates the oral cavity. Without lubrication, we would not be able either speak or eat. During the process of lubrication, specialized structures are formed called salivary pellicles. Researchers from the School of Food Science and Nutrition at Leeds, Great Britain, have developed a model of a salivary pellicle that helps explain its lubricating properties:
- In their model, the researchers have used two salivary proteins – mucin (negatively charged) and lactoferrin (positively charged).
- It was shown that mucin forms a network that entraps water molecules.
- Lactoferrin acts as a “glue” between mucin molecules and also between mucin and the surface of the oral cavity, which aids in lubrication.
- Lactoferrin and mucin together with water molecules form a complex structure that proves to be a more effective lubricant than water itself.
- Even though the actual salivary pellicle consists of multiple salivary proteins besides mucin and lactoferrin, the creators of the model feel that it reflects the biological mechanism of lubrication well.
This model can assist in developing effective lubricants and also in the treatment of the condition called dry mouth when the mouth lubrication is insufficient.
What do a scorpion and wasabi have in common: a novel protein from scorpion venom targeting the wasabi receptor may lead to the development of a treatment against chronic pain [USA-Hungary August 2019]
Wasabi receptor is a protein located in the membranes of the cells of the sensory nerve endings in the body. Its scientific name is TRPA1. This protein is activated by irritants such as wasabi spice, smoke, substances from garlic and onions. As a rule, these irritants connect with an area of TRPA1 called the allosteric nexus. By connecting to this area, the irritants cause the initiation of pain signals. Besides pain, they also cause inflammation through the initiation of calcium transport. A team from the University of California – San Francisco has discovered a peptide toxin from the Australian Black Rock scorpion poison and described its unique properties:
- This scorpion component was called the wasabi receptor toxin (WATx).
- The action of WATx was compared to the effect of mustard oil.
- In mice, mustard oil caused both pain and inflammation, while WATx triggered pain response only.
- WATx was shown to interact with the same site as other plant irritants – allosteric nexus.
- Both WATx and components from plant irritants (mustard and onions) can permeate cellular membranes.
- WATx caused the TRPA1 receptor to be permanently open and blocked the influx of calcium.
- Without the influx of calcium, no inflammation has developed.
The researchers consider this newly discovered peptide an essential tool for studying the functions of TRPA1 and potentially elucidating the mechanisms of chronic pain syndromes.
Defense against anxiety: the protein that decreases anxious behaviors discovered in rhesus monkeys [USA, December 2019]
There are people who have so-called anxious temperament – they are prone to see potential danger in most situations. Such anxious temperament can be seen even in early childhood anxiety of this type is not exclusive to humans and can be seen in monkeys as well. A research team led by Andrew Fox from California National Primate center and Tade Souaiaia from the State University of New York Downstate Medical Center have analyzed the proteins in the brain of 46 young rhesus monkeys that have exhibited an anxious temperament in order to understand better the processes that underlie anxiety.
- The researchers have analyzed the proteins in the tissue of the amygdala – a brain region responsible for fear and emotional responses.
- They have found that several of proteins that increase in concentration in response to awaiting something the monkeys deemed dangerous.
- The team has also found that the level of a protein called neurotrophin-3 (NTF3) is decreased when the monkeys experience anxiety.
- Neurotrophin – 3 is a relatively understudied protein responsible for the creation of new neural pathways.
- The researchers have increased the levels of NTF3 with the help of surgery guided by magnetic resonance imaging.
- The increase in NTF3 concentration have decreased the level of anxious behavior in monkeys and levels of the proteins associated with anxiety.
This discovery can help understand anxiety in primate better and can also help in developing treatments for anxiety.
The secret of the shark green camouflage: a new set of small molecules with bioluminescent properties discovered in sharks
Many marine animals are capable of bioluminescence – they use fluorescent molecules to transform blue light into green light. Recently, bioluminescence was discovered in two shark species – swell sharks and chain catsharks. A research team from Yale University has decided to look into the mechanisms in the basis of their bioluminescence. Their research has revealed several things:
- Both shark species have two types of skin: light-toned skin and dark-toned skin.
- The denticles in the light-toned skin areas of the sharks act as optical light guides.
- These dermal denticles also contain chemicals called Bromo-tryptophan-kynurenines.
- These chemicals use a different mechanism for fluorescence compared to the previously known fluorescent proteins such as the green fluorescent protein in cnidarians and corals.
- Bromo-tryptophan kinurenines also have antimicrobial properties.
- These skin compounds are used by sharks for recognizing each other and also as means for protection against microbes.
This study opens a new field of research aimed at understanding the mechanisms and roles of bioluminescence in sharks. It is also essential to understand the mechanisms with the help of which marine animals generate light as fluorescence is a vital laboratory tool.
We could use some stability: a protein that can stabilize amyloid structures in diabetes found [USA, August 2019]
Amyloids are atypical clumps of proteins that can form in cells, disrupting their activity. Amyloids play a role in the development of Parkinson’s and Alzheimer’s diseases, interfering with the normal processes in the nerve cells. Recently, amyloid structures were also found in the islets of the pancreas in type II diabetes. It was also shown that several proteins usually found in mitochondria can interact with these amyloid aggregates in nerve cells. A research team led by Zachary Levine at the Yale School of Medicine have modeled the interactions between one of these proteins, humanin, and amyloid structures in the islets in type II diabetes. The model has shown that:
- Humanin interacts with the amyloid compounds with high precision.
- Humanin does not allow the amyloid clumps to grow further.
- Humanin -amyloid complexes are more stable than amyloids alone.
- Humanin does not contribute to the denaturation of these abnormal proteins.
- The spectroscopy and electron microscopy of the affected islet cells have confirmed the hypothesis created based on the simulation.
This work can help in developing treatments for diabetes and Alzheimer’s disease.
Fungal treasure trove: researchers have created a library of bioactive compounds derived from fungi [Netherlands, November 2019]
Fungi are known to contain various chemicals that are biologically active. Many compounds currently used in medicine are of fungal origin. However, it is slow and cost-effective to find compounds one by one. Current biochemical methods allow fast screening and testing of chemicals that can potentially be of use, and the team of Dutch researchers from the Universities of Utrecht and Leiden, Netherlands, decided to use them for mass screening of potentially useful fungal compounds. In the course of their project the scientists performed the following:
- In order to test the properties of each compound, zebrafish embryos (Danio rerio) were used.
- 10, 207 species of fungi preserved at the Westerdijk Fungal biodiversity Institute were analyzed and their metabolites were measured.
- From all the researched compounds, 15% of fungi produced chemicals that influenced the zebrafish embryonic development.
- The researchers selected 39 fungi for further analysis.
- In these fungi, there were 34 compounds found that caused developmental defects in the embryos.
- Some of the compounds were already known, while others were not studied yet.
- In course of the analysis, a library of metabolites from 10, 207 fungal species was created that can be used in course of other research projects and assays.
This work was unique, as it used methods of mycology, embryology, and biochemistry to analyze potentially active compounds. As a result, it has also provided scientists with an extensive biochemical library that can be used for further studies and drug development.
How to unpack a protein: new approaches help us understand how a crucial enzyme unfolds old proteins that need to be destroyed [USA, August 2019]
The cell constantly destroys old proteins and builds new ones from the released building blocks. One of the crucial proteins that are responsible for the unfolding of the proteins marked for destruction is Cdc48 adenosine phosphatase. Researchers from the University of Utah Health have decided to analyze the structures and activity of this complex protein.
- Cdc48 was purified from yeast cells.
- The researchers have taken time-freeze shots using cryogenic electron microscopy (cryo-EM).
- The method was fast enough to capture the step-by-step process of protein unfolding.
- Cdc48 forms a complex hexamer with a central pore through which a protein is being pulled through.
- The protein is pulled through in a conveyor-like fashion.
- Cdc48 was found to be binding to various other proteins at the same time, and those interactions were not possible to analyze and describe yet.
This research has laid the groundwork for studying the function of Cdc48 and hopefully, it would be analyzed in human cells as well. Cdc48 is known to be crucial for normal function of the body and point mutations in the gene responsible for the protein can lead to severe diseases such as amyotrophic lateral sclerosis (ALS). Understanding its function can be helpful of treating patients with this condition.
Why goat kefir is good for you: research has revealed 11 compounds with various health – promoting properties in kefir made from goat milk [Spain, March 2019]
Kefir is a fermented milk beverage quite popular in several countries. It contains lactic acid and is supposed to have multiple health benefits. Recently, kefir made from goat milk has gained popularity in Spain. The biochemistry and proteomics specialists at the University of Cordoba, Spain have decided to analyze goat milk kefir to understand what useful agents it can contain.
- The researchers have undertaken analysis of all peptides contained in the kefir at various times during the fermenting process.
- There were 2328 unique peptides found in the kefir during the analysis.
- The researchers have chosen 22 peptides of interest and studied the dynamics of their concentration in the beverage using tandem mass spectrometry.
- The highest concentration of peptides was found after 24 hours of fermentation.
- There were 11 peptides with known functions found, most of them caseins.
- The peptides found in kefir had a range of beneficial activities – they could kill bacteria, decrease blood pressure, and capture reactive oxygen species.
This is the first comprehensive analysis done on this type of beverage. It helps substantiate the claims about kefir’s benefits. This research may also promote the popularity of goat milk kefir compared to a similar beverage made from cow’s milk, so it has both commercial and academic implications.
This list of discoveries performed in 2019 shows the chemical complexity and diversity observed in all kingdoms of life currently known to man. By understanding the processes that are taking place in our cells we can potentially get closer to treating conditions previously though virtually untreatable.
Moreover, the answers could be found in unexpected places, like scorpion’s venom and cells of the roundworm. In 2019, even fundamental studies had potential for some biotechnological and pharmacological breakthroughs in the future.
The further studies would probably help us improve our well-being and well-being of our planet even more.