Early History of the Recognition of Molecular Biochirality

Abstract

This opening chapter recalls the history of the discoveries that led to the appreciation of the nature and importance of molecular chirality in biology, as well as the development of stereochemistry as an interdisciplinary field connecting chemistry and biology. The discoveries described cover roughly the period of ca. 1840-1940, although certain relevant events of earlier or later times are also addressed. A large number of chiral substances occur in nature in unichiral (i.e., single-enantiomer) form, and for centuries many such substances were used in crude extracts for relief from diseases. For the science of biochirality, the first milestone was the discovery of molecular chirality by Louis Pasteur in 1848. Thereafter, fundamental advances were made, beginning in 1857 with Pasteur's discovery of biological enantioselectivity, in the metabolism of (±)-tartaric acid. With the advances in organic chemistry during the second half of the nineteenth century, the structures of many organic molecules were elucidated and new chiral compounds synthesized, and by the turn of the twentieth century studies of stereoselectivity in the biological activity or enzymatic transformations of natural or synthetic substances were proliferating, and chiroselectivity was often found. Among the names associated with important discoveries in biochirality appear Pasteur, Piutti, Fischer, Cushny, Easson and Stedman, and others. The findings soon prompted attempts to explain the phenomenon of enantioselectivity in biological action, beginning with Pasteur's proposal to account for enantioselectivity in the metabolism of tartaric acid. In 1894 Fischer announced his "lock-and-key" metaphor to explain enantioselectivity in enzyme-substrate interactions and in 1933 Easson and Stedman advanced the first chemical-structure-based model, the three-point-attachment paradigm, to rationalize enantioselectivity at adrenergic receptors. This model has been generalized as the simplest basis for enantioselectivity in biological activity. Today molecular chirality is widely recognized as an important modulator of the effects of chiral substances in a variety of branches of biology and medicine.

Chemical Basis of Biological Homochirality during the Abiotic Evolution Stages on Earth

“…The origin of biological homochirality (BH) [1][2][3][4] is often described as a scientific mystery [5] and the lack of a scientific explanation of the BH phenomenon is often used as proof against the theory of evolution [6]. However, it is possible nowadays to give a rigorous basic physico-chemical justification for the origin of BH.…”

“…The advances made in asymmetric induction during the 20 th Century dominate the mainstream opinion on chiral methods in chemistry. Consequently, historically the emergence of homochirality has been justified mainly on the basis of the asymmetric induction of enantioselective reactions by physical chiral forces [2,27,28], in conjunction with non-linear asymmetric inductions leading to chiral amplifications [29][30][31] and the kinetic trapping of the final chiral species. To assume this as the basis for BH implies that during the evolutionary stages (see Figure 1) corresponding to the condensation reactions leading to the homochiral functional polymers and chiral replicators, homochirality is achieved by starting from enantiopure pools of homochiral building blocks (amino acids and carbohydrates).…”

Channels with Helical Modulation Display Stereospecific Sensitivity for Chiral Superstructures

“…Another topological property of molecules that has posed long-standing challenges to its control is molecular chirality. Even after more than 150 years after the discovery of biomolecular chirality [24], the common methods for obtaining well-defined representatives of chiral pairs-enantiomers-are by leading synthesis in a certain way, what happens well in vivo; however, it brings a price of increased costs of synthesis in organic chemistry or by recrystallization which is not always feasible if the enantiomers do not form crystal units. The challenges of controlling the chirality are virtually identical with those connected to obtaining well-defined molecular knots [25,26].…”

Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis

“…The structural characterization of the end-products indicates there is regio- and enantioselectivity in the non-enzymatic reaction—the stereogenic center C1 generated in the dimerization exclusively favors the R -configuration ( Figure 1 ). This observation is very unusual, because the stereochemical C–C couplings in biosynthesis are usually related to chirality generating enzymes such as aldolases [ 14 , 15 , 16 ], ketolases [ 17 , 18 ], Diels–Alderases [ 19 , 20 , 21 , 22 , 23 ], and others [ 24 ]. Previously, FlsQ1 was hypothetically annotated as the master in the fluostatin’s conjugate reaction due to its homology with a known dimerase in the NmrA protein family of actinorhodin biosynthesis) [ 25 , 26 ].…”