Buffers

Redox

Chirality

Entropy

or whether a complex polysaccharide can serve as a food for humans (starch) or is indigestible (wood).

Since biological chemistry is based upon organic materials, the shapes that we are concerned with are ultimately dictated primarily by the orientation of substituents around carbon atoms. Our knowledge of the importance of handedness in chemical systems has true biological underpinnings, going back to the very earliest work of Pasteur in the 1840s. Pasteur was studying the properties of salts of tartaric acid — products of grape fermentation. He was the first to achieve the resolution of a mixture of isomers, doing so on the basis of the physical characteristics of the salt crystals and picking out the differing crystal types by hand.

Following the pioneering work of Pasteur, vant' Hoff and Le Bel independently recognized in the 1870s that when four different groups are attached to a carbon atom, arrayed as at the corners of a tetrahedron, then the arrangements can be in two different forms, as depicted schematically below.

These two versions of the molecule are not occupying the same three-dimensional space, even though they contain the same basic set of atoms. In fact, their mirror images are not superimposable.

so too can nature recognize alternate arrays of substituents around carbon atoms. This is readily seen from models of two forms of lactic acid.

In order to rationally describe and discuss asymmetric molecules such as these, one needs some rules and some convenient ways to depict such molecules on the printed page. It was proposed by M.A. Rosonoff in the early part of the twentieth century, building on the earlier work of Emil Fischer, that the isomers of glyceraldehyde be adopted as standards for stereochemistry. The model shown on the left is designated as L-glyceraldehyde, while that on the right is D-glyceraldehyde.

You should also manipulate the two forms of the molecule by clicking on the Chime buttons below to get an appreciation of how they look in three-dimensional space.

One can also depict these molecules and related ones, such as the simple amino acid, serine, in the following manner:

We can even draw them in simpler fashion, where the horizontal lines represent bonds coming forward from the plane of the page, and the vertical bonds represent those bonds going behind the plane of the page. It is important to note that the nomenclature referred to here and in the following discussion relates to the absolute configuration in space around the asymmetric carbon atoms, and not to any optical properties of the compound in question.

While the D,L nomenclature serves well for simple systems with only a single asymmetric carbon atom, ambiguities can arise for more complex molecules. A more rigorous nomenclature termed the "R,S system" was introduced by Cahn, Ingold, and Prelog, which allows for the unambiguous description of molecules with multiple chiral centers. The rules for this system are, in brief, as follows: (See also pp. 96-99 in Garrett and Grisham, Second Edition.) The four substituents around a chiral carbon atom are rank ordered, with atoms of a higher atomic number being ranked above those with a lower atomic number. If two of the bound atoms are identical, the functional groups are rank ordered in the following priority:

One then views the molecule from the chiral center to the atom with the lowest priority. If, in this view, the other atoms decrease in priority in a counterclockwise direction, then that chiral center is designated as "S." If the atoms decrease in priority in a clockwise direction, then that chiral center is designated as "R." The use of this nomenclature system for the different forms of glyceraldehyde and for the amino acid alanine is shown below.

Many of the molecules used by biological systems have multiple chiral centers, and thus have many possible geometric configurations in space. For example, the amino acid isoleucine has two asymmetric carbon atoms, resulting in four potential isomers (2S,3S; 2S,3R; 2R,3R; 2R,3S).

Almost invariably, only one such geometric isomer is in fact used by biological systems (the 2S,3S version in the case of isoleucine). This is because these molecules do not exist in isolation, but have to fit exactly into complementary positions on other molecules. It is because of this interactivity between molecules that even compounds that, after a superficial examination, have no obvious asymmetry can behave in a highly asymmetric fashion in biochemical reactions. Consider, for example, the simple molecule ethanol (CH3CH2OH). One could depict the molecule as

and expect that either H atom would react in identical fashion. But, if one views the ethanol from the perspective of an enzyme trying to dock with the ethanol, then the two ends of the molecule can look very different. If one looks at the molecule down the axis of the blue hydrogen atom, with the other hydrogen arrayed at the top, then the hydroxyl group is arrayed to the right and the CH3 group to the left.

By contrast, if one examines the molecule down the axis of the other (red) hydrogen atom figure, then the CH3 group is to the right and the OH to the left.

If there are complementary areas on the enzyme surface on which to bind the H, HO, and CH3 substituents, then these two views of the ethanol molecule are certainly not equivalent. Such molecules are said to have "prochiral" centers.

As an analogy, one could consider the landing of a spaceship with three different docking legs onto the landing site of an alien planet. Each of the legs has to match up with a specific docking module. Only one of the spaceships shown below will make it to a safe landing because of the mating requirements of the objects in three-dimensional space.

Exactly this sort of discrimination occurs in real-world biological systems. One example of how an enzyme can deal selectively with apparently equivalent groups comes from the action of the enzyme aconitase on its substrate (reactant) citrate. This enzyme, which is a catalyst in a major metabolic pathway called the tricarboxylic acid cycle, is able to selectively remove just one of four chemically equivalent hydrogen atoms from citrate to form cis-aconitate.

An examination of the three-dimensional structure of aconitase, obtained through X-ray crystallography, has clearly demonstrated that this selectivity in hydrogen removal comes precisely from the manner in which the prochiral center is bound by the enzyme. You can explore the three-dimensional structure of aconitase by clicking on the Chime button below. If you are not familiar with how to use Chime, we suggest that you first visit the Serum Albumin Structure module on this site to gain proficiency. You can use the commands "select," "hetero," and "ligand" to highlight the bound substrate. If you then display this part of the molecule in ball and stick mode and leave the remainder as wireframe, it is possible to zoom in and fully explore the relationship of the substrate to the groups on the enzyme. In addition to the substrate, you should also see highlighted the sulfur atoms, which play a vital role, as part of an Fe/S center, in the catalytic activity of the enzyme.

One of the challenging questions of chemical evolution is why one set of chemical isomers became the dominant forms in nature, such as the L-amino acids rather than the D-amino acids. Most of the experiments that seek to emulate prebiotic conditions for synthesis of organic materials certainly do not produce any marked excess of one set of chiral molecules.

The term "hand in glove" aptly describes how the parts of biological systems operate in conjunction with one another. The chirality of small molecules described above is just a small manifestation of a whole world of complementary interactions in biological chemistry, not the least of which are the interactions governing the replication of nucleic acids through which we pass genetic information from one generation to the next.