When we browse through molecules - the building blocks of the universe - and their utilization in organisms, we observe a preference or a trend towards a direction (right or left). Functional groups of molecules have right or left placements based on an axis just like preferences of humans regarding left or right hand use. These molecules feature the same chemical structure or molecular formula but have different placements (mirror projections) that also display different functions. These differences generated during the synthesis of bio-molecules in living systems are called "chirality." This type of difference is not observed in objects like a globe or equilateral triangle, which have the same mirror image as copies of their original forms. This feature of molecules is defined as L (left) and D (right) enantiomeric form. Five carbon ribose or deoxyribose (sugar) carrying D-enantiomeric forms are found in the structure of nucleic acids that encode the genetic information in living things.

Despite that, there are more than 100 types of amino acids found in nature; only 20 of them are employed for protein synthesis. Among these 20 amino acids, excepting glycine, which does not display chirality, only the L-form of the 19 is used for protein synthesis. This is because ribosomes, where protein synthesis occurs, do not feature the utilization of D-form amino acids. As nothing in the universe exists in vain but with multiple tasks, D-amino acids have a job in the maintenance of life after protein synthesis in very different fashions. The way D-amino acids are employed in the execution and control of physiological preferences amazes scientists.

Up until recent times, D-amino acids were believed to be synthesized mostly by bacteria and plants, unlike mammals, and were considered dysfunctional as they passed, via consumption of nutrients, from bacteria and plants. However when D-amino acids were noticed for having roles as important as L-amino acids during the 1990s, the field gained significance. It was demonstrated that D-amino acids were found widely in invertebrates, vertebrates, and humans as free forms or inside proteins, undertaking critical functions in the nervous and endocrine systems. The most interesting point is the conversion of amino acids from the L-form into the D-form after the protein synthesis occurs in the peptides that are present in the venomous secretions of various animals. This conversion leads to the alteration of the peptide identity and function. Racemase and isomerase (epimerase) enzymes are utilized as they are created for this task. Usually, one or two amino acids of the D-form peptides are in D-form.

When chemist Gunther Kreil of the Austrian Academy of Sciences learned about the use of South American poisonous tree frogs (Phyllomedusa sauvagei ) during Shamanic hunting ceremonies by local Peruvian tribe (Matses), he studied this poison in detail. Participants of the ceremony first caused a burn on their chest region, then applied the poison they obtained from the frog skin over it. Diarrhea and tachycardia started within a minute, followed by a brief faintness. Once they recovered after a few minutes, they were to find themselves in a much more vigorous and exhilarated state of mind. The poison they were applying to their chest contained the dermorphin peptide, which has psychoactive, hallucinogenic effects and a D-amino acid. This peptide is a pain killer 30-40 times more effective than morphine. Among the 7 amino acids found in this peptide (heptapeptide), all are in L-form, except for one. Only the alanine, as the second in the peptide sequence, is in D-form and is produced via the isomerase enzyme from the L-alanine after the protein synthesis. G. Kreil discovered this D-form synthesizing enzyme in 2005. When this peptide was synthesized artificially in the laboratory, it did not display any biological activity or hallucinogenic effect. After a careful investigation of the case, it was found that frog skin based peptide had a D-form alanine second in its sequence; however, the one produced in laboratory had an L-form alanine. It was the presence of only one D-amino acid that made the difference in discovering the identity and function to the natural peptide in the poison.

In recent years dermorphin has started to be used as an illegal performance enhancer during horse races because of its pain killer feature. Horses on dermorphin can run longer and faster since they cannot feel the pain related to foot fatigue.

P. Kuchel of Sydney University also showed a D-amino acid presence in the peptide structured of the poison in the Platypus, a semiaquatic egg-laying mammal. Males use this poison as a weapon to fend off competitors. In 2009, Matthew Waldor and his friends at Harvard University discovered that the sugar-protein mix (matrix) called peptidoglycan found in the composition of bacterial cell walls is structured in a way to contain primarily D-alanine, D-methionine, and D-leucine. More interestingly, D-amino acids of the peptidoglycan structure were able to play a stimulatory role in coordinating the activities of other bacteria in the colony. For example, they acted as light houses in the use of florescence and helped in the formation of thin layers (bio-films) on various surfaces in bacteria. Once we understand the way D-amino acids help in communication between bacteria, it will be possible to use them as a drug. It’s possible they can be used to disintegrate bacteria that forms on teeth, in the lungs of cystic fibrosis patients, on clogs in fuel lines and water tanks, and in medical devices such as catheters.

D-amino acid containing peptides found in lobsters help maintain salinity levels and facilitate courtship in mating seasons. In recent years, D-amino acid containing antimicrobial peptides were discovered (bombinines) in the secretion glands of fire-bellied toad skins (Bombina sp). In this peptide, the second amino acid was in the D-form (D-allo-isoleucine). Two different peptides were found containing D-amino acids in the second position of the amino acid sequence of the poison secreted by Platypus males.

One of the reasons for D-amino acids to exist in animal poisons is that peptides containing D-Amino acids can not be easily degraded by the proteases (peptide bond breaking enzyme) of the host or opponents. Even though proteases can quickly and easily digest proteins composed of L-form amino acids, they struggle to do so with peptide bonds between D and L form amino acids. Pharmaceutical companies are trying to add D-amino acids to the peptide-structured drugs to prevent the quick degradation of peptides and proteins used for treatments when ingested. However, the addition of a D-form amino acid brings the high possibility of a situation that changes the function of a peptide or protein, or causes the loss of a protein. Nonetheless, specialists in this field point out that at least some amount of the D-amino acids that are produced by trillions of bacteria found on the skin, in the digestive track, and among other parts of the body can still be utilized for human health and convenience.

The D-serine of the mammalian nerve systems (glial cells and neurons), the D-aspartate of the neuro-endcorine, endocrine tissues, and testicles, and the D-alanine and D-aspartate amino acids of aquatic animals are abundant. D-Serine in the brain is synthesized by the conversion of L-serine into D-serine by the serine racemase enzyme. D-aspartate is in charge of hormone synthesis and secretion, and the regulation of spermatogenesis, and is produced by aspartate racemase and degraded by D-aspartate oxidase. It is also predicted to play role in the synthesis of hormones such as melatonin and testosterone.

As of now, four enzymes have been detected to be in charge of D-amino acid metabolism in mammals. How these are controlled is still unknown.

Publications pertaining to the association of epilepsy, schizophrenia, and bipolar disorders with enzymes in charge of D-amino acid synthesis and break down have increased in recent years. From this point of view, serine racemase and D-amino oxidase can be used to develop new potential drugs regarding the treatment of similar NMDA receptor associated diseases.

The first data demonstrating the use of D-amino acids in saliva in organs outside of the human brain was obtained by Y. Nagata and his team at the University of Nihon, Tokyo. A team led by Kenji Hamase of the Kyushu University discovered high levels of D-alanine storage in the beta cells of the rat pancreas. Kuchel, who discovered the enzymes converting the L-amino acids in to D forms in duck-billed Platypus poison, also found similar enzymes in the hearts of mice and humans. According to Kuchel, the physiological roles of those in humans remain to be unknown.

As a result, the common feature of toxins and antimicrobial peptides that are produced and secreted by animals is to contain D-amino acid. These peptides can be the source of a potential drug in the treatment of diseases such as cystic fibrosis, schizophrenia, and macular degeneration of the eye.

These prove that, especially in biology, exceptions are common; life is enriched via examples of extraordinary lives, processes, and mechanisms in unexpected places by unpredictable molecules or interesting reactions that can’t be predicted. Such discoveries help deepen our wonder at the intricacy and wisdom of creation.