Victor S Lamzin, Zbigniew Dauter and Keith S Wilson
European Molecular Biology Laboratory, Hamburg, Germany and University of York, York, UK
All natural proteins are composed of L-amino acids and are inherently chiral. The properties of both L- and chemically synthesized D-amino acids are identical except in optically asymmetric interactions. Structuralstudies of D-L racemic mixtures of crystallographic interest are discussed. The review also gives some recent examples of stereospecificity: how L-proteins deal with L- or D-substrates and how enzymes can function as racemases. Two particular examples of stereoselectivity are then discussed. Current Opinion in Structural Biology 1995, 5:830-836
"Chirality is a property of anygeometrical figure if its image in a plane mirror, ideally realised, cannot be brought to coincide with itself" (Lord Kelvin, 1893) . The word 'chiral' is derived from the Greek word 'cheir', meaning hand . It is well known from geometric principles that any three points always lie in a plane. If the number of points is increased to four, they no longer need to lie in a plane and therefore becomecandidates to serve as a chiral geometric structure. In organic substances, by definition containing carbon atoms, a tetrahedral sp 3 hybridized carbon with four different substituents will always be a chiral centre. A substrate carbon atom is not chiral if two out of four of its substituent groups are equivalent. It may however be 'prochiral' if a subsequent enzymatic reaction, resulting in a product,affects one of these two groups  . The same is true of a substrate which has an SP2 carbon which becomes sP3 in the product . Therefore a protein-ligand interaction is stereospecific if either the substrate or product has a chiral centre. A widely used nomenclature defines a chiral carbon atom as being R (derived from the Latin rectus for right) or S (sinister for left) . The carbon isviewed from the direction opposite to the substituent atom of lowest atomic mass. If the atomic mass of the remaining three substituents decreases in a clockwise direction, the configuration of the chiral carbon is R, otherwise it is S. Another nomenclature uses D for right- and L for left-handed chiral centres (Fig. 1). Both nomenclatures are used in this article. However, RI S enantiomers aredefined on the basis of a chiral centre, whereas nIL were originally based on optical rotation . Chirality, as an inherent property of organic compounds which are products of biological processes, was first described by Louis Pasteur . A further breakthrough
Fig. 1. The D- and L-configuration of amino acids, the building blocks ofproteins. Only the L-enantiomer is found in natural proteins and this is the source of chirality in biological molecules.
was made by Emil Fischer , who suggested that biological macromolecules were composed of chiral L-amino acids and D-sugars. Natural substrates or ligands can have either an L- or a D-configuration for those centres where the reaction takes place. The cornerstone ofprotein-ligand chiral recognition is multi-point attachment theory  which states that at least three of the four substituents on the chiral carbon atom should interact with the protein. Indeed, if only two of the groups interact, interchange of the other two may not affect the protein-ligand interaction. Every major category of biological molecules is chiral, including proteins, nucleic acids,polysaccharides, lipids and steroids. If polymers, they are built up of units possessing chiral centres and the resulting three-dimensional fold is chiral. Indeed, any polymer chain folded into a three-dimensional structure will generally adopt one of two mirror images: for proteins where the individual units are chiral, only one of the two images is energetically feasible. Only one of these mirror...