Journal
CHEMICAL SCIENCE
Volume 5, Issue 6, Pages 2191-2199Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3sc53009d
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Funding
- National Science Foundation (NSF)
- Engineering and Physical Sciences Research Council (EPSRC) [NSF 0822536, EPSRC EP/G002843/1, EP/J014301/1, EP/G007705/01]
- Engineering and Physical Sciences Research Council [EP/J001430/1, EP/J010588/1, EP/G002843/1, EP/G007705/1] Funding Source: researchfish
- EPSRC [EP/G002843/1, EP/J001430/1, EP/J010588/1] Funding Source: UKRI
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Combined quantum mechanics/molecular mechanics (QM/MM) simulations of the reaction catalysed by phosphite dehydrogenase (PTDH) identify Met53 as important for catalysis. This catalytic role is verified by experiments (including replacement by norleucine and selenomethionine), which show that mutation of this residue significantly affects k(cat), without changing K-M for phosphite. QM/MM and ab initio QM calculations show that the catalytic effect is electrostatic in nature. The side chain of Met53 specifically stabilizes the transition state for the hydride transfer step of the reaction catalysed by PTDH, forming a 'face-on' interaction with His292. To our knowledge, a defined catalytic role for methionine in an enzyme (as opposed to a steric or binding effect, or interaction with a metal ion) has not previously been identified. Analyses of the Protein Data Bank and Cambridge Structural Database indicate that this type of interaction may be relatively widespread, with implications for enzyme-catalysed reaction mechanisms and protein structure.
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