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Structural Mechanisms of Slow-Onset, Two-Step Enzyme Inhibition

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Whereas the ability to recognize and measure the kinetics of slow-onset enzyme inhibition is fully developed, our understanding of the structural mechanisms is still evolving. This literature review focuses on the two-step process in which a rapid-equilibrium enzyme/ inhibitor (EI) complex isomerizes slowly and reversibly to a tighter EI* complex. Although structural details are still mostly lacking, some generalities have been realized. The most central finding is that protein conformational changes are often subtle and sometimes even difficult to identify. Most interactions occur in the initial complex formation and the isomerization represents critical but minor adjustments. When available, energetic estimates based on these structural refinements match the differences in free energy of interaction calculated from equilibrium constants for EI and EI* and thus are sufficient to explain the kinetics. Less often described and defined for two-step slow inhibition, larger polypeptide movement induced by inhibitor binding such as loop or flap rearrangements has been observed or hypothesized. Separately, ionization of inhibitor has been critical in several systems and implies poor solvent accessibility of bound inhibitor. Finally, as described for the two cyclooxygenase isozymes, movement of inhibitor into and through the protein matrix can give rise to slow-onset kinetics.

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Document Type: Research Article

Publication date: January 1, 2010

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  • Current Chemical Biology aims to publish full-length and mini reviews on exciting new developments at the chemistry-biology interface, covering topics relating to Chemical Synthesis, Science at Chemistry-Biology Interface and Chemical Mechanisms of Biological Systems.

    Current Chemical Biology covers the following areas: Chemical Synthesis (Syntheses of biologically important macromolecules including proteins, polypeptides, oligonucleotides, oligosaccharides etc.; Asymmetric synthesis; Combinatorial synthesis; Diversity-oriented synthesis; Template-directed synthesis; Biomimetic synthesis; Solid phase biomolecular synthesis; Synthesis of small biomolecules: amino acids, peptides, lipids, carbohydrates and nucleosides; and Natural product synthesis).

    Science at Chemistry-Biology Interface (Chemical informatics; Macromolecular catalysts and receptors; Enzymatic synthesis; Biosynthetic engineering; Combinatorial biosynthesis; Plant cell based chemistry; Bacterial and viral cell based chemistry; Chemistry of cellular processes in plants/animals; Receptor chemistry; Cell signaling chemistry; Drug design through understanding of disease processes; Synthetic biology; New high throughput screening techniques; Small molecular array fabrication; Chemical genomics; Chemical and biological approaches to carbohydrates proteins and nucleic acids design; Chemical and biological regulation of biosynthetic pathways; and Unnatural biomolecular analogs).
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