In the previous two articles, we examined enantiomers, which are mirror-image isomers that appear to be twins due to slight differences in their three-dimensional arrangements around a central carbon atom (or substituents) connected to four different atoms. Although these structures cannot be superimposed, they visually resemble each other. We also explored how these two mirror-image forms have historically been distinguished and named, as well as the concept of racemic mixtures, where the characteristics of each enantiomer cancel each other out when present in equal proportions. Now, let’s investigate what significance these mirror-image isomers hold in our biological activities.
Life's Choice: Homochirality
To understand the significance of chirality in living organisms, perhaps the most important concept is homochirality. As we learned from Pasteur's experiments, a racemic mixture refers to the presence of two forms of enantiomers in equal proportions. Homochirality describes the tendency to exclusively prefer one specific form of these two mirror-image isomers, which is also referred to as enantiomeric purity or single chirality. To avoid confusion with similar concepts such as "enantiopure," which refers to a drug made from only one enantiomer, this article will use the term "homochirality."
The importance of homochirality lies in the fact that living systems consistently exhibit the same (homo-) chirality. Molecules within living organisms selectively utilize specific enantiomers, resulting in a uniform display of chirality that distinguishes them from racemic mixtures, which are randomly composed of equal parts of both forms. It is also crucial to note that when molecules are artificially synthesized in the laboratory, any chiral molecules produced will necessarily be in racemic form. This aspect will be particularly important to consider in the upcoming discussion on pharmacology.
Homochirality is distinctly observed in nature, particularly within biological systems. All life forms on Earth—mammals, vertebrates, plants, the smallest microorganisms, and even atoms and their particles and subparticles—exhibit chirality. This phenomenon of chirality permeates all areas of modern science, from fundamental particle physics to astronomy and biochemistry, allowing living organisms to replicate and evolve based on chiral molecules, while also transmitting information about themselves.
What is particularly noteworthy is that within living organisms, molecules exclusively utilize one of the two possible mirror-image isomer pairs for metabolic processes, or only one form exists altogether. The human body operates in an environment where amino acids, carbohydrates, lipids, and nucleic acids selectively distinguish between one side of the enantiomers. For example, carbohydrates in the body are primarily in the D-form, while amino acids are in the L-form. RNA and DNA contain D-ribose and D-deoxyribose, respectively, as their building blocks.
RNA and DNA, which are responsible for copying and storing genetic information, having homochirality carries significant implications. If the sugars and bases that make up the nucleic acids are not aligned in the correct sequence, the hydrogen bonding between them may not be optimized, preventing the formation of the smooth and stable helical structure we recognize. If both D-form and L-form sugars were intermixed within the structure, it could distort the overall helical configuration. Would it be possible to maintain the current form under such circumstances? If any part of the structure were to become distorted, enzymes like DNA polymerase might struggle to accurately replicate genetic information, and the DNA repair mechanisms could also be affected, leading to a failure to recognize damaged areas.
If the chemical replication mechanisms do not function smoothly, it could result in a higher error rate during the polymerization process, thereby increasing the rate of genetic mutations. This is a rather unsettling scenario to imagine. The most prudent decision and selection made by living organisms to maintain an optimal self-replicating system and ensure safety in survival and reproduction could indeed be the establishment of homochirality.
There still seems to be no clear explanation as to why nature exhibits a tendency toward a single chirality. In discussions about the origin of life, the question of why organisms formed based on a single form of homochirality, and why the opposite enantiomer did not emerge, remains an old mystery. One wonders whether both left-handed and right-handed forms coexisted prior to the emergence of life, with one form gradually disappearing, or if there was already a convergence toward a single chirality before the appearance of life.
Additionally, there are questions about whether handedness existed even at the birth of the universe. From a molecular perspective, it is intriguing that biopolymers such as proteins, glycolipids, and polynucleotides are based on D-form sugars and L-form amino acids. Theoretically, there is no reason they could not have formed from the opposite enantiomers, so why was there a selection for D-form sugars and L-form amino acids? Could life have arisen from L-form sugars and D-form amino acids instead?
Moreover, can life emerge from racemic mixtures, or is homochirality a prerequisite for the development of life? These questions remain unanswered enigmas in the scientific community, prompting ongoing research and speculation about the fundamental nature of life and its origins.
Hypothesis on the origin of homochirality: Parity violation
There are several hypotheses aimed at explaining the origin of homochirality, where the symmetry between enantiomers is broken, leading to the dominance of one form. One such hypothesis is parity violation.
Physics explains natural phenomena through four fundamental interactions: gravity, electromagnetic force, weak nuclear force, and strong nuclear force. Parity refers to the concept of symmetry regarding whether these interactions remain the same in a reflected environment. While parity is conserved in gravitational, electromagnetic, and strong nuclear interactions, it was discovered in the mid-20th century that parity symmetry is violated in weak nuclear interactions.[1]
Experiments showed that when coordinates (x, y, z) are reflected across a mirror to (-x, -y, -z), the expectation that all physical laws would apply equally to the original and its twin mirror image is literally broken. As a result of this "parity violation," it is possible that there exists a very slight but definite energy difference between the ground states of two mirror-image enantiomers, which were expected to exhibit identical energy levels. This difference implies that one of the enantiomers could be more energetically stable.
The subtle asymmetry arising from this energy difference may have ultimately favored one chiral form over the other, providing a potential explanation for the origin of homochirality. However, while much research is ongoing in this area, no definitive evidence has yet been found. There is also a strong viewpoint that a minor energetic advantage for one enantiomer may not be sufficient to push biological molecules in a single direction.[2]
Does the Universe Prefer Left-Handedness?
Parity violation is related not only to homochirality but also to the left-handed properties of the universe. In atomic nuclei, protons, which are of the same charge, repel each other vigorously. In this scenario, neutrons, which have no charge, don't contribute much help. It is the strong nuclear force that holds all these particles tightly together to maintain the integrity of the nucleus.
When we look at the numbers of neutrons and protons that make up the nucleus, they generally maintain a proper ratio. However, if this ratio deviates beyond a certain range, the nucleus becomes unstable and undergoes radioactive decay, such as beta decay, to transition back to a stable state. In other words, there is a natural process of releasing energy through beta decay, allowing the nucleus to revert from an unstable state to a stable, lower-energy state, governed by the weak nuclear force.
Beta Decay
When there are too many neutrons, β⁻ (beta minus) decay occurs, converting a neutron into a proton. Conversely, if there are too many protons, β⁺ (beta plus) decay takes place, transforming a proton into a neutron. To delve deeper into the background of these transformations, it's important to note that both neutrons and protons are particles composed of quarks, but they have different configurations of up quarks and down quarks. By changing the number of these quarks, it becomes possible to convert between neutrons and protons.
In the case of a neutron converting into a proton, this process emits an electron and an antineutrino. Conversely, when a proton is converted into a neutron, a positron and a neutrino are released. These quark transformations are mediated by elementary particles known as W/Z bosons.
An interesting fact is that neutrinos, which only interact via the weak force, appear as left-handed particles because they always rotate clockwise toward the observer. Experiments have shown that during beta decay, neutrinos are emitted asymmetrically in a specific direction, indicating that the weak nuclear force exhibits left-handed bias and demonstrating a slight violation of parity symmetry. This observation leads to the hypothesis that only subatomic particles with left-handed spin decay, suggesting that the universe itself may possess a left-handed bias. Reports from experiments conducted at CERN's Large Hadron Collider have indicated that only down quarks with left-handed spin decay into up quarks.[3]
In the early Earth environment, one form may have been more stable or easier to form, leading it to be favored over its opposite type. Additionally, parity violation could have contributed to the dominance of one form over the other. While various hypotheses exist, one fact we can all agree upon when observing the mechanisms of life is that nature avoids unnecessary energy consumption. Nature does not waste energy. Biological processes must be energy-efficient, and using both forms side by side would create competing pathways, necessitating choices that could introduce unnecessary complexity into metabolic pathways, increasing energy expenditure and reducing reaction accuracy.
By adopting a single form, biological reactions can be simplified and made more efficient, optimizing function. Imagine a scenario where multiple amino acids come together to synthesize a complex and large protein known as an enzyme. If all those amino acids are consistently in the L-form, the folding of the protein will proceed smoothly and seamlessly without interference.
Tipping point
I recall an interesting book I read long ago titled "Tipping Point," which discussed the intense competition between VHS and Betamax for video tape standards. When VHS achieved a 51% market share, even though it was just a 1% initial difference, it triggered a self-amplifying feedback loop or network effect. This ultimately led VHS to gain overwhelming consumer preference and dominate the market, eclipsing its competitor.
Could it be that a similar process contributed to the formation of homochirality, where one type ultimately prevailed? Consider the numerous enzymes that play crucial roles at every stage of biological processes. These enzymes can only function effectively when they precisely fit their specific substrates. Similarly, receptors, which serve as gateways for cellular signaling, must bind only to their compatible ligands.
This requirement for high precision highlights the characteristic of stereoselectivity, emphasizing that biological systems favor specific chiral forms for optimal functioning. Just as the slight initial advantage of VHS snowballed into a dominant market position, perhaps a minor preference for one chiral form over the other led to the eventual establishment of homochirality in biological systems
Stereospecificity
For glucose to participate in metabolic processes within the body, various enzymes and receptors must recognize it. As we know, the glucose found in the human body, which is involved in metabolism, is D-glucose. Enzymes and receptors, which are large proteins, also possess specific three-dimensional structures. For them to recognize, bind to, and react with glucose, their spatial configurations must align perfectly.
To catalyze chemical reactions, enzymes must accurately identify and bind to specific molecules among a vast array of biomolecules. One of the conditions that enable this specificity is the stereochemical binding site, which is referred to as the enzyme's stereospecificity. The active site of an enzyme has a particular directional and three-dimensional structure designed to select substrate molecules that have the correct stereochemical arrangement for catalysis.
Receptors also play a crucial role in binding signal molecules (ligands) to transmit biological signals into cells. Similar to enzymes, receptors have binding sites with three-dimensional structures that allow for tailored binding. This specificity means that receptors can only bind to particular ligands. For example, a specific receptor must exclusively bind to a certain hormone to ensure accurate signal transduction. Thus, receptors recognize the stereochemical structure of ligands with remarkable precision, allowing them to bind only to those ligands that share the correct spatial configuration. While passive processes like diffusion across membranes may not involve intricate interactions between large molecules and may have less impact on stereospecificity, it is crucial for molecules that require specific interactions, such as enzymes or drugs, to have stereospecificity.
In conclusion, the numerous enzymes and receptors within biological systems select only one form out of two enantiomers. If they had to choose between two forms at any given moment, it would lead to unnecessary overload in metabolic processes, ultimately degrading accuracy, stability, and reaction rates.
Naturally occurring two enantiomers: Two Scents
Not all chiral molecules in living organisms exhibit homochirality. Occasionally, both mirror-image enantiomers of a chemical compound can be found within an organism, and these enantiomers can display significantly different characteristics, such as taste and smell.
Carvone is a compound from the terpenoid family. Like many other isoprene-based natural substances, it is primarily produced as a metabolic byproduct in response to environmental factors. Carvone exists as a pair of enantiomers, each possessing distinct aromas. More specifically, the two enantiomers bind to different olfactory receptors, allowing them to be perceived as having different scents. The S-form of carvone emits a strong, spicy aroma reminiscent of caraway seeds, which belong to the Apiaceae family, while the R-form has a sweet, minty fragrance similar to spearmint. Despite having identical boiling points, densities, and appearances, the fact that these two forms produce entirely different scents is quite fascinating.
For further details on isoprene, please refer to previous article.
From isoprene to cholesterol: terpenes, terpenoids, and isoprenoid
Why do natural molecules generate both enantiomers instead of homochirality?
Natural molecules do not always exhibit homochirality; sometimes, both enantiomers of a chemical compound are produced. When we examine isoprenoids or terpenoids, which are assembled from isoprene units, we find that they are primarily known as defensive molecules that protect the organism.
Rather than selectively expressing a single chiral molecule, producing multiple enantiomers may allow for various ecological functions and roles that aid in self-defense and reproduction. For instance, the unpleasant aroma of caraway can repel insects and herbivores, while the fragrant scent of spearmint can attract pollinators that assist in reproduction. This dual functionality represents a clever evolutionary adaptation. It seems that nature is quite resourceful.
Another example is limonene, a monoterpene where the R-form has an orange scent, while the S-form emits a lemon or pine scent. Even though nature generates both mirror-image enantiomers, our biological systems have no problem recognizing them. This is because the receptors that bind to each enantiomer have matching binding sites that allow for specific recognition.
Thus, whether it involves homochirality or twin chirality, there is no need for special concern. Nature likely has its reasons for such diversity, and in its natural state, it appears to maintain harmony without any confusion.
In fact, not all amino acids in living organisms are L-forms. D-amino acids have already been found in the cell walls of certain bacteria, and they have also been detected in human tissues such as the brain, teeth, lens, plasma, urine, saliva, amniotic fluid, skin, and bones. There are even claims that as we age, the increase in D-amino acids can lead to physiological changes, potentially contributing to age-related diseases such as cataracts, atherosclerosis, and Alzheimer's disease.
There is also an interesting perspective that the advancement of certain food processing technologies has led to the inclusion of amino acids converted from L-forms to D-forms in processed foods. This could add one more reason to avoid processed foods, right? 😊
The Nightmare of Mirror-Image Isomers
The most terrifying scenario I've encountered related to homochirality involves the hypothetical situation where some scientists artificially synthesize the mirror-image enantiomers that do not exist in nature. What would happen to humanity if mirror-image enantiomers of cyanobacteria or certain bacteria and viruses were synthesized and widely spread?
First, if phytoplankton that feed on cyanobacteria find it difficult to consume the mirror-image cyanobacteria's products, the entire ecological food chain based on them could collapse. Additionally, predators of cyanobacteria may be unable to digest or recognize these mirror-image forms, allowing them to proliferate at an extraordinary rate without any control. Ultimately, they could outcompete the existing cyanobacteria, leading to the collapse of the current ecosystem.
Just as cyanobacteria introduced oxygen into Earth's atmosphere, aiding the evolution of life, these mirror-image cyanobacteria could also alter the atmosphere. What if a new oxygen revolution occurred, transforming the atmosphere into a harmful and highly reactive form? That single bacterium could trigger truly horrific consequences, drastically changing the balance of the ecosystem and the trajectory of evolution. While this is a scientifically intriguing imaginary scenario, it serves to reinforce our understanding of the significance of homochirality.
Could life in the universe also be homochiral?
Homochirality is considered a unique bio-marker that enables molecular consistency, a distinctive characteristic of living organisms, and a sign of life. It may also be a prerequisite for the origin of life or early evolutionary processes. Therefore, in the search for extraterrestrial life, efforts are being made to find traces of chiral substances and homochirality as strong indicators of existing or extinct life forms.
Research continues to explore whether there are or were molecules in the universe with a predominance of one enantiomer. As part of these efforts, NASA's exploring equipment design includes optical purity analysis. For instance, NASA’s Mars rover Curiosity and the European Space Agency's (ESA) comet lander Philae have attempted to collect organic materials and measure the predominant chiral phenomena (optical purity). Although definitive results have yet to be found, follow-up missions are expected to continue these experiments, contributing to our understanding of homochirality in the cosmos.
[References]
[1] The Origin of Biological Homochirality
https://cshperspectives.cshlp.org/content/11/3/a032540.full
[2] Chirality and the Origin of Life
https://www.mdpi.com/2073-8994/13/12/2277
[3] Only left-handed particles decay
https://www.nature.com/articles/524008b.pdf
[4] The Search for Chiral Asymmetry as a Potential Biosignature in Samples from Mars
https://ntrs.nasa.gov/citations/2021002648
