Living systems chirality

It is estimated that approximately one-half of all drugs worldwide exist as stereoisomers. However, only one-half of stereoisomeric drugs are marketed as the individual stereoisomer and most of the latter are of natural or semi-synthetic origin. There is increasing awareness of the clinical importance of drug stereoselectivity because differences in the behavior of isomers in the chiral living system can result in significant differences in clinical outcomes. Table 1 presents a number of examples of these difference. 

Section 7 8 Both enantiomers of the same substance are identical m most of then-physical properties The most prominent differences are biological ones such as taste and odor m which the substance interacts with a chiral receptor site m a living system Enantiomers also have important conse quences m medicine m which the two enantiomeric forms of a drug can have much different effects on a patient... 

Although scientists have known since the time of Louis Pasteur (1) that optical isomers can behave differentiy in a chiral environment (eg, in the presence of polarized light), it has only been since about 1980 that there has been a growing awareness of the implications arising from the fact that many dmgs are chiral and that living systems constitute chiral environments. Hence, the optical isomers of chiral dmgs may exhibit different bioactivities and/or biotoxicities. 

Almost 140 years ago Pasteur showed how a racemic mixture could be separated into its chiral constituents. Ever since, theories such as the three possibilities above have been proposed to explain an abiotic origin for molecular chirality in living systems. At the present time, however, no agreement exists about which explanation is best. In each ofthese scenarios, we can imagine production of some initial enantiomeric excess (e.e.). 

Here is an important point almost all chiral amino acids that occur naturally in proteins throughout all of nature have L-stereochemistry. Why has nature uniquely selected L-amino acids for the construction of proteins No one knows for sure. In passing, we note that D-amino acids do occur in some living systems. The cell walls of bacteria possess both d- and L-amino acids, for example. However, these are introduced in a manner distinct from that employed to synthesize proteins. 

It is remarkable that virtually all amino acid residues in proteins are L stereoisomers. When chiral compounds are formed by ordinary chemical reactions, the result is a racemic mixture of d and l isomers, which are difficult for a chemist to distinguish and separate. But to a living system, D and L isomers are as different as the right hand and the left. The formation of stable, repeating substructures in proteins (Chapter 4) generally requires that their constituent amino acids be of one stereochemical series. Cells are able to specifically synthesize the l isomers of amino acids because the active sites of enzymes are asymmetric, causing the reactions they catalyze to be stereospecific. 

All living organisms are chemical factories, and virtually every chemical reaction that occurs in a living system is catalyzed by special proteins called enzymes. All enzymes are globular proteins. Folding the peptide chains into a compact structure creates a chiral pocket. This is called the active site of the enzyme. The extraordinary specificity that enzymes show for their given substrate molecules is because the active site exactly matches the dimension and shape of the molecules upon which the enzyme acts. One reason enzymes speed reaction rates is that enzymes capture reacting molecules and hold them in place next to each other. Furthermore, key amino acid side chains are located in the active site of each enzyme. For example, if a reaction is catalyzed by acid, then an acidic side chain will be located in the active site, exactly where it is needed to catalyze the reaction. 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

Enzymes in living systems are chiral, and they are capable of distinguishing between enantiomers. Usually, only one enantiomer of a pair fits properly into the chiral active site of an enzyme. For example, the levorotatory form of epinephrine is one of the principal hormones secreted by the adrenal medulla. When synthetic epinephrine is given to a patient, the (—) form has the same stimulating effect as the natural hormone. The ( + ) form lacks this effect and is mildly toxic. Figure 5-15 shows a simplified picture of how only the ( —) enantiomer fits into the enzyme s active site. 

Most of the molecules we find in nature are chiral—a complicated molecule is much more likely not to have a plane of symmetry than to have one. Nearly all of these chiral molecules in living systems are found not as racemic mixtures, but as single enantiomers. This fact has profound implications, for example, in the chemistry of drug design, and we will come back to it later. 

Cintas P (2002) Chirality of living systems a helping hand from crystals and oligopeptides. Angew Chem Int Ed 41 1139-1145... 

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