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Catalytic mechanism and properties of pyridoxal 5'-phosphate independent racemases: how enzymes alter mismatched acidity and basicity.
- Source :
-
Natural product reports [Nat Prod Rep] 2019 Dec 11; Vol. 36 (12), pp. 1687-1705. - Publication Year :
- 2019
-
Abstract
- Covering: up to March 2019 Amino acid racemases and epimerases are key enzymes that invert the configuration of common amino acids and supply many corresponding d-isomers in living organisms. Some d-amino acids are inherently bioactive, whereas others are building blocks for important biomolecules, for example lipid II, the bacterial cell wall precursor. Peptides containing them have enhanced proteolytic stability and can act as important recognition elements in mammalian systems. Selective inhibition of certain amino acid racemases (e.g. glutamate racemase) is believed to offer a promising target for new antibacterial drugs effective against pathogens resistant to current antibiotics. Many amino acid racemases employ imine formation with pyridoxal phosphate (PLP) as a cofactor to accelerate the abstraction of the alpha proton. However, the group reviewed herein achieves racemization of free amino acids without the use of cofactors or metals, and uses a thiol/thiolate pair for deprotonation and reprotonation. All bacteria and higher plants contain such enzymes, for example diaminopimelate epimerase, which is required for lysine biosynthesis in these organisms. This process cannot be accomplished without an enzyme catalyst as the acidities of a thiol and the substrate α-hydrogen are inherently mismatched by at least 10 orders of magnitude. This review describes the structural and mechanistic studies on PLP-independent racemases and the evolving view of key enzymatic machinery that accomplishes these remarkable transformations.
- Subjects :
- Amino Acid Isomerases antagonists & inhibitors
Amino Acid Isomerases chemistry
Amino Acid Isomerases metabolism
Enzyme Inhibitors chemistry
Protein Conformation
Racemases and Epimerases antagonists & inhibitors
Sulfhydryl Compounds metabolism
Enzyme Inhibitors pharmacology
Pyridoxal Phosphate metabolism
Racemases and Epimerases chemistry
Racemases and Epimerases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-4752
- Volume :
- 36
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Natural product reports
- Publication Type :
- Academic Journal
- Accession number :
- 30994146
- Full Text :
- https://doi.org/10.1039/c9np00017h