Mirror molecules / Sarah Everts

The chemistry of life almost always favors "left-handed" amino acids. Why then are there so many exceptions in nature?

If you try to annoy a flat-footed duck (platypus) in its heat season, you may find that its thick and clumsy hind legs are wrapped around you and a series of sharp, venom-filled spurs threaten you. The painful sting poison limps away competing males, and is also very useful as a defense against pesky humans and dogs. But the chemical composition of the venom is somewhat unusual, as might be expected from such a strange, egg-laying, duck-billed Australian mammal. The duck venom has a series of molecules that biologists previously thought were found in nature only in the microscopic world of bacteria.

These molecules are mirror images of the amino acids, the molecules that the body cells of all living things weave together to create the proteins essential for their proper functioning. These molecular mirror images consist of exactly the same atoms that make up the approximately 20 "standard" amino acids that populate biology's toolbox. And what's more, these atoms are connected to each other in exactly the same order. However, the spatial orientation of the bonds is slightly different, so these molecules differ from the classical amino acid molecules in the same way that our left palm differs from our right palm. And yet in biochemical reactions it is impossible to switch between the forms. Due to the comparison with the palms, the classic amino acids are called "left-handed", while their mirror images are called "right-handed". [Chemists call this geometric feature "chirality", which comes from the word "hand" in Greek - the editors.]

In the past, it was believed that right-handed amino acids play a negligible role in the biochemistry of terrestrial animals because they should not fit into the molecular mechanism of most plants and animals and therefore should not function in them. However, in recent years, biologically active right-handed amino acids have appeared in all sorts of unexpected places, starting with substances that lobsters produce to initiate sexual intercourse and ending with a hallucinogenic drug used by indigenous hunters in Peru. And most fascinating of all, it turns out that right-handed amino acids also perform important tasks in human physiology, and they hold an exciting promise for the development of new treatments, including treatments for cystic fibrosis, schizophrenia and macular degeneration of the retina.

Solomon Schneider, a neuroscientist at Johns Hopkins University, who conducted most of the first studies dealing with the function of right-handed amino acids in the brain, says that he encountered a lot of resistance when he tried to publish his first articles on the subject. He found these materials fascinating precisely because they seemed to "break the first law of mammalian biology," as he put it. "As happens in most cases in science, when something new or really different is discovered, there will be those who will say: 'This is ridiculous.'"

But it turns out that from a biochemical point of view, a few simple steps are enough to turn a left-handed amino acid into its mirror image. Thus it seems inevitable that evolution would experiment with producing right-handed amino acids. "Nature has been smart enough to use them all these years," says Richard Losick, a cell biologist at Harvard Medical School. "We were just too late to recognize that."

A useful glitch

How did it happen that the left-handed amino acids took over their right-handed sisters, so much so that their biological roles escaped due attention even though they were already characterized in the late 19th century? Some scientists claim that the advantage of left-handed amino acids is due to a cosmological event equivalent to a coin toss. The first chemical entities capable of successfully replicating themselves happened to use left-handed amino acids, and this bias was fixed, suggests Robert Hazen, a geophysicist and early life researcher at George Mason University. Another popular theory posits that polarized light emitted from a rapidly spinning star in our early galaxy destroyed more right-handed amino acids in some selective way and thereby improved the left-handed amino acids' chances of serving as the building blocks of life. Both forms are also referred to as L-amino acids and D-amino acids. The marking comes from the Latin words laevus (left) and dexter(right).

Since this selection was made, it encouraged evolution to perpetuate the dominant amino acids, explains Gerald Joyce, a researcher of the beginning of life at the Scripps Research Institute in La Iola, California, "in a similar way to the way in which the greeting of peace accepted in Western culture was created by shaking the right hand." The greeting would work in a similar way if we all agreed to shake the left hand, but without it being an accepted way many awkward encounters would have occurred. And so most of the mechanisms of living cells, starting with the enzymes that produce amino acids and ending with the complicated structures known as ribosomes - which string together amino acids and form proteins - are adapted to operate with left-handed amino acids and not with their right-handed partners.

In fact, this early decision of life to favor left-handed amino acids also affected the chirality of another series of organic compounds: the carbohydrates. In the last ten years, many research groups have conducted experiments with solutions simulating the "primordial soup", which may have existed on Earth about four billion years ago. They discovered that if there is an excess of some simple left-handed amino acids in these solutions, they cause, for complicated chemical reasons, a preference for the formation of right-handed carbohydrates, a chiral preference that is indeed valid throughout the biological world.

The molecules that violate the rule of left-handed amino acids in nature received more widespread attention only in the 90s, after Schneider showed that some right-handed compounds serve as neurotransmitters in the human brain. In 20, chemist Philip Kuchel from the University of Sydney determined that duck venom has right-handed amino acids. In 2002, researchers at Harvard and the Howard Hughes Medical Institute reported that several right-handed amino acids have unknown and unexpected roles in the bacterial cell wall. In 2009, researchers discovered that complex colonies of bacteria that spread out in thin layers on surfaces, from hot springs to medical equipment, apparently use right-handed amino acids as a signal that heralds the retirement of the biological layer.

In humans, it was found that the amino acid D-aspartate serves as a neurotransmitter involved in the normal development of the brain. In addition, the amino acid D-serine works with the left-handed amino acid L-glutamate to activate nerve molecules that are essential for a process that neuroscientists call synaptic plasticity, which in turn is essential for learning and creating memories. Right serine also seems to play an important role in the multifaceted mental disorder schizophrenia. Sufferers of this disease have too little D-serine in the brain, a finding that has prompted several pharmaceutical companies to look for ways to increase the levels of D-serine. However, an excess of right serine may cause problems in other circumstances. Too high a concentration can cause increased brain damage after a stroke. Researchers are therefore trying to develop drugs that will lower the right serine levels to mitigate the harmful effects of the stroke.

Our cellular factories produce only left-handed amino acids. How then, in the end, do our bodies also have right-handed amino acids, the researchers wondered. Schneider discovered that brain cells do not build right-hand serine molecules from scratch. In fact, they produce an enzyme that changes the chirality of the amino acid serine from the L-form to the D-form. This is a clever way to take advantage of the high levels of left-handed amino acids already present in the cell.

Biology also uses the same method when the right-handed amino acids are part of a peptide, a short chain of amino acids, such as that found in duck venom. In such cases, the reliable mechanism of the ribosome builds the peptide as usual, from left-handed amino acids. Then an enzyme activates the structure of one of the amino acids in the peptide and changes it from the L form to the D form. Nature "catch a ride" on the mechanism for producing left-handed amino acids and connecting them to each other, so it is not required to develop a complete system of biosynthetic enzymes, which it needed It was necessary to build the right-handed molecules from the ground up, explains Gunter Kreil, a chemist at the Austrian Academy of Sciences in Vienna, who discovered in 2005 the enzyme that creates right-handed amino acids found in the venom of poisonous tree frogs in South America.

Crail became interested in the subject after he first heard about the native inhabitants of Peru, called Matses, who use powerful hallucinogenic drugs in their hunting rituals. The drugs contain peptides found in the skin of tree frogs Phyllomedusa bicolor which include right-handed amino acids. The Matses burn the skin of their chests and then apply the frog skin extract to the burns. The drug immediately causes them diarrhea and heart palpitations and then makes them faint. They wake up with very sharp senses and a feeling that they have superhuman strength. The peptide produced by the frogs is composed almost entirely of left-handed amino acids, but without the only right-handed amino acid it contains, the drug does not induce hallucinations at all, Kreil says.

The world of shadows

Although right-handed amino acids appear in toxins in a wide variety of living things, there are also some in which these molecules have a more peaceful purpose. Crayfish, for example, use right-handed amino acids to stimulate their sex life and to maintain normal salt levels in their bodies.

And yet, the heaviest users of right-handed amino acids are still single-celled organisms, and here too researchers are discovering new roles for these molecules. Most bacteria build their cell wall from a substance that combines sugars and proteins called peptidoglycan and contains D-alanine and other right-handed amino acids. In 2009, Matthew Waldor from Harvard University and the Howard Hughes Medical Center discovered that the bacteria strengthen the peptidoglycan using a "cement" containing D-methionine and D-leucine. These right-handed amino acids can also change the structure of peptidoglycan in neighboring bacteria, and even from different species. The discovery suggests that the bacteria may be able to use these molecules to coordinate multicellular activities such as turning on fluorescence and building a bacterial plaque, Waldor says. Understanding the way in which the bacteria communicate with each other through right-handed amino acids attracts the attention of those interested in developing drugs or products that break down bacterial layers on our teeth, in the lungs of cystic fibrosis patients, in fuel pipes and in medical equipment such as catheters.

One of the reasons that bacteria and venomous animals use right-handed amino acids is that the presence of such acids in a peptide, or larger protein, makes it difficult for the host's or enemy's enzymes to break it down. All animals have enzymes, called proteases, whose job it is to quickly break down proteins built from left-handed - but not right-handed - amino acids. In fact, drug developers tried to add right-handed amino acids to medical proteins and peptides in order to evade the sweeping actions of the proteases and survive longer in the body.

Now, as researchers explore the strange new world of right-handed amino acids, they're looking for other roles these molecules might play. Losik and others assume, for example, that at least some of the right-handed amino acids produced by the trillions of bacterial cells found on our skin, in our intestines and in other areas of the body, may have an important effect on our well-being, our health and perhaps even our behavior.

One of the big questions currently preoccupying right-handed amino acid researchers is whether, apart from the brain, there is another organ that actively produces these molecules. The initial results suggest that this is the case. Yoko Nagata's research group from Nihon University in Tokyo reported right-handed amino acids in human saliva. Researchers led by Kenji Hamase from Kyushu University in Japan observed high concentrations of D-alanine in insulin-secreting beta cells in the pancreas of rats. In addition to this, in preliminary experiments recently conducted in Kuchel's laboratory in Australia, he found in the hearts of mice and humans enzymes that convert left-handed amino acids into right-handed ones, similar to the enzymes found in duck venom.

However, the exact role played by such enzymes in human physiology is "a complete mystery", according to Kuchel. But at least the very idea that they play important roles no longer seems ridiculous.

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in brief

Amino acids, the building blocks of proteins, have two forms, which, like the palms of our hands, are mirror images of each other. When life began on Earth, they preferred the "left-handed" amino acids to the "right-handed" ones to carry out the activities in the cells.

For a long time the only exceptions were found in bacteria. However, in recent years, more and more examples of this have also been found in terrestrial animals, including humans.

Biomedical researchers are looking for applications for these exotic amino acids to treat diseases such as schizophrenia, cystic fibrosis and retinal degeneration.

on the notebook

Sarah Everts, born in Montreal, is the Berlin correspondent for the weekly magazine for news in chemistry and engineering. She also runs a blog about art and science called Artful Science.

Credit: Jen Christiansen

And more on the subject

The New Ambidextrous Universe: Symmetry and Asymmetry from Mirror Reflections to Superstrings. Third revised edition. Martin Gardner. Dover, 2005.

High Dose D-Serine in the Treatment of Schizophrenia. Joshua Kantrowitz et al. in Schizophrenia Research, Vol. 121, no. 1, pages 125-130; August 2010.

D-Amino Acids in Chemistry, Life Sciences, and Biotechnology. Edited by Hans Brückner and Noriko Fujii. Wiley, 2011.

Emerging Knowledge of Regulatory Roles of D-Amino Acids in Bacteria. Felipe Cava et al. in Cellular and Molecular Life Sciences, Vol. 68, no. 5, pages 817–831; March 2011. www.ncbi.nlm.nih.gov/pmc/articles/PMC3037491

More of the topic in Hayadan:

• What are you doing there at the university - chapter 9 dealing with chiralism
• A new approach to drug development
• Does the asymmetry of biological molecules originate in space?