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Toward an Improved Understanding of the Glutamate Mutase System

Sandala, Gregory M.; Smith, David M.; Marsh E. Neil G.; Radom, Leo
Toward an Improved Understanding of the Glutamate Mutase System // Journal of the American Chemical Society, 129 (2007), 6; 1623-1633 (međunarodna recenzija, članak, znanstveni)

Toward an Improved Understanding of the Glutamate Mutase System

Sandala, Gregory M. ; Smith, David M. ; Marsh E. Neil G. ; Radom, Leo

Journal of the American Chemical Society (0002-7863) 129 (2007), 6; 1623-1633

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Glutamate mutase; ab initio; coenzyme B12

High-level quantum chemistry calculations have been used to examine the catalytic reactions of adenosylcobalamin-dependent glutamate mutase (GM) with the natural substrate (S)-glutamic acid. We have also examined the rearrangement of (S)-2-hydroxyglutaric acid, (S)-2-thiolglutaric acid, and 2-ketoglutaric acid, all of which have previously been shown to react as substrates or inhibitors of the enzyme. Our calculations support the notion that the 100-fold difference in kcat between glutamate and 2-hydroxyglutarate is associated with the relatively high energy of the glycolyl radical intermediate compared with the glycyl radical. More generally, calculations of radical stabilization energies for a variety of substituted glycyl radical analogues indicate that modifications at the radical center can profoundly affect the relative stability of the resulting radical, leading to important mechanistic consequences. We find that the formationof a thioglycolyl radical, derived from (S)-2-thiolglutaric acid, is highly dependent on the protonation state of sulfur. The neutral radical is found to be of stability similar to that of the glycolyl radical, whereas the Sform of the thioglycolyl radical is much more stable, thus providing a rationalization for the inhibition of the enzyme by the substrate analogue 2-thiolglutarate. Two possible rearrangement pathways have been examined for the reaction of GM with 2-ketoglutaric acid, for which previous experiments had suggested no rearrangement took place. The fragmentation-recombination pathway is associated with a fragmentation step that is very endothermic (by 102.2 kJ mol-1). In contrast, the addition-elimination pathway has significantly lower energy requirements. An alternative possibility, namely, that 2-ketoglutaric acid is bound in its hydrated form, 2, 2-dihydroxyglutaric acid, also leads to a pathway with relatively low energy requirements, suggesting that some rearrangement might be expected under such circumstances.

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Projekt / tema
098-0982933-2937 - Računalno proučavanje strukture i funkcije proteina (David Matthew Smith, )

Institut "Ruđer Bošković", Zagreb

Autor s matičnim brojem:
David Matthew Smith, (260506)

Časopis indeksira:

  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI