How did the preference for 'single-handedness' in biological molecules arise? Amplification of the trace imbalance in a mixture of handed molecules bolsters the case for chance being the answer.
Some molecules are chiral — they exist in two forms that are mirror images of each other, right-handed and left-handed. Thus it seems reasonable that reactions that form chiral molecules from purely achiral precursors should produce equal amounts of each handed form to preserve achiral symmetry. So how did biological processes develop a preference for one or the other, such as left-handed amino acids, and right-handed sugars? In the Journal of the American Chemical Society, Singleton and Vo1 report that, starting from two achiral compounds, they have prepared a chiral product in which one handed form dominates over the other. Have they demonstrated a fundamental principle that explains the mystery surrounding the predominance of a particular handedness in biomolecules?
The superstition surrounding the immutability of the achiral state has led to a reverence for molecular phenomena that break such reaction symmetry. However, for many years it has been known that such symmetry breaking can occur randomly through a variety of different mechanisms2: for example, during the crystallization of a solution in which both hands are in equilibrium3, or in the spontaneous formation of chiral liquid-crystal domains4. In such cases, a small deviation from the achiral state is coupled to a process that is self-perpetuating and exponentially self-amplifying — that is, autocatalytic. As yet, spontaneous achiral symmetry breaking has not been observed for a reaction that occurs completely in homogeneous solution, and that is what Singleton and Vo were hoping to test.
The authors were following up the work of the Japanese chemist Kenso Soai, who reported an autocatalytic reaction in which a slight excess of one hand in the product suffices to direct any future product to that same handed form5,6. The reaction scheme involved batchwise additions of diisopropyl zinc to 2-methylpyrimidine-5-carboxaldehyde, recycling the product as the catalyst for the next batch. The selectivity (that is, the fraction of handed product formed) was determined as a function of batch number. In Soai's experiments, numerous alcohols were claimed to influence the course of the reaction and adding as little as 1% chiral alcohol sealed the fate of the product.
Singleton and Vo1 simply asked whether the nonlinearity of this reaction was sensitive enough to amplify the random, statistical imbalance that occurs naturally in a 'balanced' mixture of handed molecules. To their surprise, the products were formed in imbalanced proportions, but from reaction to reaction the amount of chiral product did not vary in a statistical way, indicating a systematic cause for the selectivity. Oddly enough, Soai had patented the same reaction, assuming random behaviour7.
Through a series of careful control and doping experiments, Singleton and Vo1 deduced that chiral impurities in the reaction solvent — at the level of parts per billion and too small to be detected directly — were at the root of the phenomenon. Their results corroborate Soai's report of the effect of minor amounts of chiral additives on this reaction and emphasize the extreme sensitivity of the autocatalytic reaction. The high degree of selectivity and the apparent ability of so many different additives to instigate this selectivity demonstrate the need for additional experimentation and a complete kinetic analysis8.
The work highlights a caveat in the study of the origin of biological homochirality: the need to reconcile studies of a reaction that has a highly nonlinear response to deviations from the achiral state with the inherent presence of chiral impurities after a billion years of life on the planet. In contrast to the worries of biological contamination in a modern context, there remain issues of degradation or re-equilibration of the handed forms in a prebiotic context, which Singleton and Vo address.
Indeed, one problem associated with trying to explain the prebiotic origin of achiral symmetry breaking as being due to crystallization is that the system would re-equilibrate when crystals dissolved or degraded. But coupling chirality in crystals with chemistry as selective as the diisopropyl zinc/pyrimidine carboxaldehyde system means that symmetry breaking during crystallization could be propagated from one type of compound to another. Clearly, any process capable of shifting the balance in one setting need only leave a trace imbalance to influence the outcome of an autocatalytic reaction such as the one investigated by Soai.
Many proposals for the origin of biological homochirality have been predicated on the idea that a deterministic mechanism is necessary3 — that is, that the handedness we see in biomolecules must inherently be determined in the laws of physics, like the loss of parity. Singleton and Vo's study, in conjunction with Soai's work, supports the idea that abiological autocatalysis could be the process by which a randomly generated trace chiral influence was amplified. If so, then in the prebiotic world examples of dominant molecular handedness were already likely to have been abundant. Thus, biomolecular handedness is an imperative of the evolutionary process downstream from molecular handedness, and smart money still bets on chance over determinism9.
Singleton, D. A. & Vo, L. K. J. Am. Chem. Soc. 124, 10010–10011 (2002).
Siegel, J. S. Chirality 10, 24–27 (1998).
Havinga, E. Chem. Weekblad 38, 642–645 (1941).
Link, D. R. et al. Science 278, 1924–1927 (1997).
Soai, K., Shibata, T., Morioka, H. & Choi, K. Nature 378, 767–768 (1995).
Sato, I., Kadowaki, K. & Soai, K. Angew. Chem. Int. Edn 39, 1510–1512 (2000).
Soai, K., Shibata, T. & Kowata, Y. Japan Kokai Tokkyo Koh o (1997) 9-268179 (application date: 1 February 1996 and 18 April 1996).
Blackmond, D. G., McMillan, C. R., Ramdeehul, S., Schorm, A. & Brown, J. M. J. Am. Chem. Soc. 123, 10103–10104 (2001).
Berger, R., Quack, M. & Tschumper, G. S. Helv. Chim. Acta 83, 1919–1950 (2000).
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