Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 104, Issue 12, Pages 1267-1275Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2010.08.008
Keywords
KDO8PS; Metalloenzymes; Mechanism; QM/MM; Potential energy surface; Evolution
Funding
- PHS [GM69840]
- NSF [CHE0512144]
- Wayne State University Research Enhancement Program in Computational Biology
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The three-dimensional structures of metal and non-metal enzymes that catalyze the same reaction are often quite different, a clear indication of convergent evolution. However, there are interesting cases in which the same scaffold supports both a metal and a non-metal catalyzed reaction. One of these is 3-deoxy-D-mannooctulosonate 8-phosphate (KDO8P) synthase (KDO8PS), a bacterial enzyme that catalyzes the synthesis of KDO8P and inorganic phosphate (P-i) from phosphoenolpyruvate (PEP), arabinose 5-phosphate (A5P), and water. This reaction is one of the key steps in the biosynthesis of bacterial endotoxins. The evolutionary tree of KDO8PS is evenly divided between metal and non-metal forms, both having essentially identical structures. Mutagenesis and crystallographic studies suggest that one or two residues at most determine whether or not KDO8PS requires a metal for function, a clear example of minimalist evolution. Quantum mechanical/molecular mechanical (QM/MM) simulations of both the enzymatic and non-enzymatic synthesis of KDO8P have revealed the mechanism underlying the switch between metal and non-metal dependent catalysis. The principle emerging from these studies is that this conversion is possible in KDO8PS because the metal is not involved in an activation process, but primarily contributes to orienting properly the reactants to lower the activation energy, an action easily mimicked by amino acid side-chains. (C) 2010 Elsevier Inc. All rights reserved.
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