Enzyme Chirality and Stereochemistry
Enzymes themselves are inherently levo (L-) structures because they are composed exclusively of L-amino acids, making the enzyme proteins themselves left-handed chiral molecules. 1, 2
Structural Basis of Enzyme Chirality
All naturally occurring proteins, including enzymes, are built almost exclusively from L-amino acids, which creates an inherent left-handed chirality in the polypeptide backbone and three-dimensional structure 1
The stereochemical configuration of enzymes reflects the L-amino acid composition, with the three-dimensional folding of the polypeptide backbone and orientation of amino acid side chains determining the overall chiral structure 3
This L-amino acid composition creates right-handed helices as the predominant secondary structure in proteins, though rare left-handed helices (occurring in only 31 verified cases among 7,284 proteins) can exist and are typically functionally significant 1
Functional Implications of Enzyme Chirality
The enantioselectivity of enzymes—their ability to recognize and metabolize only one enantiomer of chiral substrates—directly results from the chiral L-amino acid structure of the enzyme itself 3
Despite the theoretical requirement for strict enantioselectivity, some viral and human enzymes demonstrate a lack of stereospecificity, which occurs because in biological systems containing only D-nucleosides and L-amino acids, there is no evolutionary pressure for absolute stereoselectivity 3
Amino acids function as cofactors in many enzymes and play crucial roles in stereochemistry, as demonstrated by chiral nanozymes where L-phenylalanine modifications show higher catalytic ability for D-substrates, while D-phenylalanine modifications are more effective toward L-substrates 4
Clinical Relevance of Enzyme Stereoselectivity
Enzymes exhibit stereospecific substrate recognition in drug metabolism, exemplified by verapamil where L-verapamil demonstrates 10-18 times greater potency than D-verapamil in affecting AV conduction (EC50: L-verapamil 17.7 ng/ml vs D-verapamil 188.9 ng/ml) 5
D-amino acid oxidase and D-aspartate oxidase represent important examples of enzymes with stereoselectivity that have implications for human health, disease states, and serve as potential drug targets 2
The presence of both L- and D-amino acid enantiomers in biological systems necessitates enzymes with stereoselectivity, including amino acid racemases that catalyze interconversion and oxidases that perform oxidative deamination of specific enantiomers 2