Our research aims at a detailed understanding
of the catalytic mechanism of pharmaceutically
relevant enzymes. To reach these goals, we are
using a variety of enzymological techniques but
also chemical, biophysical and molecular biological
tools.
NAD + Metabolism
NAD + is the cofactor of choice of enzymes
that catalyze many oxidation-reduction reactions
in both prokaryotes and eukaryotes, but its vital
role in cellular metabolism goes beyond its use
as a cofactor. The tight dependence between cellular
metabolism and a properly functional and regulated
NAD + biosynthesis has recently triggered a renewed
interest in enzymes of NAD + metabolism as targets
for antibiotics against pathogenic bacteria.
In this respect, a detailed understanding of
the structure and mechanism of these enzymes
is necessary, but as of now very few enzymes
of NAD + metabolism have been the subjects of
mechanistic investigation. My research group
will initially focus on the study of the mechanism
of the reactions catalyzed by NAD + synthetase,
nicotinamidase/pyrazinamidase and NMN amidohydrolase.
Biosynthesis of Pyrrolo[1,4]benzodiazepines
The pyrrolo[1,4]benzodiazepines (PBDs) are
a class of potent antitumor antibiotics found
in streptomyces defined by a common pyrrolo[1,4]benzodiazepine
ring system. Because of their ability to interact
and covalently modify specific sequences of DNA,
PBDs have drawn interest as potential anticancer
and gene-targeting agents. Considerable efforts
have been reported on the chemical synthesis
and design of new PBDs and their structure-activity
relationships but very little attention has been
devoted to the study of the biosynthesis of the
structurally unique PBDs. My research program
aims at establishing the biosynthetic pathway
of three naturally produced PBDs- anthramycin,
sibiromycin, and tomaymycin.
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Barbara Gerratana, Samantha O.
Arnett, Anthony Stapon,
and Craig A. Townsend
(2004) "Carboxymethylproline
Synthase from Pectobacterium
carotorova: a Multi-faceted Member of the Crotonase Superfamily"
Biochemistry 43, 15936-15945.
Barbara
Gerratana, Anthony Stapon,
and Craig A.
Townsend (2003) “Inhibition and Alternate Substrate
Studies on the Mechanism of Carbapenam Synthetase
from Erwinia carotovora”, Biochemistry
43, 7836-7847.
Barbara
Gerratana, W.
W. Cleland, and Perry
A. Frey (2001) “Mechanistic Roles of Thr134,
Tyr160 and Lys164
in the Reaction Catalyzed by dTDP-Glucose 4,6-Dehydratase”,
Biochemistry 40, 9187-9195.
Barbara Gerratana,
Perry
A. Frey, and W. W. Cleland
(2001) “Characterization
of the Transition-State Structure of the Reaction of Kanamycin Nucleotidyltransferase
by Heavy-Atom Kinetic Isotope Effects”, Biochemistry 40, 2972-2977.
Barbara
Gerratana, W. W. Cleland, and Laurie A. Reinhardt (2001) “Regiospecificity
Assignment for the Reaction of Kanamycin Nucleotidyltransferase from
Staphylococcus aureus”, Biochemistry 40, 2964-2971.
Barbara
Gerratana, Gwendolyn A. Sowa, and W. W. Cleland
(2000) “Characterization
of the Transition-State Structures and Mechanisms for the Isomerization
and Cleavage Reactions of Uridine 3’-m-Nitrobenzyl
Phosphate”, J. Am.
Chem. Soc. 122, 12615-12621. |
