Research
Interests
The Biosynthesis of (5R)-Carbapenem
In collaboration with
Mr. Greg Sandala and Prof. Leo Radom (
Dr. Chris Easton (
Prof. Christopher
Schofield (
Carbapenems are a particularly important
class of antibiotics as their stability towards serine b-lactamases provides
superior resistance over alternatives, such as penicillins
and cephalosporins [1]. Studies of carbapenem biosynthesis are of significant interest as they
may assist in devising efficient pathways to produce medicinally useful
compounds. Of the three enzymes involved in the biosynthesis of the simplest carbapenem ((5R)-carbapenem, (5R)-2),
the hexameric carbapenem synthase (CarC) is particularly
interesting. It has been proposed [2] that the role of this
2-oxoglutarate-dependent (2OG) nonheme iron oxygenase is to catalyze C2/C3 desaturation
and the C5 epimerization of (3S,5S)-carbapenam
((3S,5S)-1). In addition, the
saturated but epimerized product ((3S,5R)-1
is also generated during the transformation [3] :
The crystal
structure of this enzyme has only recently been solved [4]. Along with very
recent experimental investigations [5], this structure is helping scientists
unravel the mechanism of this transformation. However, the unprecedented
epimerization at C5 is, at present, poorly understood. Due to the highly
reactive nature of the tentative reaction intermediates, such a question is
very difficult to answer experimentally. Computational investigations, on the
other hand, are not hindered by this fact and therefore have the potential to
make a significant contribution to this problem.
At
present, by using a combination of quantum, classical and coupled
quantum-classical approaches, I am working on characterizing possible
intermediates in this reaction. In addition, I am completing a comparison of
several mechanistic alternatives in an effort to better understand the unusual
but important CarC-catalyzed production of (5R)-carbapenem.
[1] (a) Livermore, D. M.;
Woodford, N. Curr. Opin. Microbiol. 2000, 3, 489–495. (b) McGowan, S. J.; Bycroft, B. W.; Salmond, G. P. C.
Trends Microbiol.
1998, 6, 203.
[2] (a) McGowan, S. J.;
Holden, M. T. G.; Bycroft, B. W.; Salmond,
G. P. C. Anton. Leeuw.
Int. J. G. 1999, 75, 135–141. (b) Bycroft,
B. W.; Chabra, S. R. J. Chem. Soc., Chem. Commun. 1989, 2325.
[3] Stapon,
A.; Li, R.; Townsend, C. A. J. Am. Chem.
Soc. 2003, 125, 8486.
[4] Clifton, I. J.; Doan,
L. X.; Sleeman, M. C.; Topf,
M.; Suzuki, H.; Wilmouth, R. C.; Schofield, C. J. J. Biol. Chem. 2003, 278, 20843.
[5] Stapon,
A.; Li, R.; Townsend, C. A. J. Am. Chem.
Soc. 2003, 125, 15746.
.