Professor
Structure determination of macromolecules of biological interest
Crystallization of proteins and x-ray crystallography
Energy-conformation analysis of protein ligand interactions
Molecular structure is a major determinant in the expression
of biochemical and physical properties of macromolecules. Quite often
the three dimensional arrangement of atoms of a molecule of biological
consequence provides a basis for hypothetical mechanisms of catalysis,
regulation of catalysis, and the self-assembly of multisubunit proteins.
Results from x-ray diffraction have contributed immensely to the understanding
of hemoglobins, of allosteric enzymes such as aspartate carbamoyltransferase,
of DNA, and of viral agents such as the influenza virus.
Research in Dr. Honzatko's group focuses on the structure-function relationships
of the enzymes adenylosuccinate synthetase and glucoamylase. As an enzyme
governing the first commited step in AMP biosynthesis from inosine-5'-monophosphate,
adenylosuccinate synthetase plays a crucial role in the metabolism of
all living systems. Adenylosuccinate synthetase is important to the
study of purine metabolism, to the design of drugs for chemotherapies
of cancer and Chagas' disease and to the study of fundamental aspects
of chemical catalysis of reactions involving three substrates. Known
inhibitors of the enzyme have potential pharmacological value. Hadacidin,
for instance, has antitumor activity, selectively inhibiting denylosuccinate
synthetase. L-Alanosine is converted into a metabolite, which is the
most potent known inhibitor of the synthetase; that metabolite is effective
also as an antitumor agent. The differences in substrate specificity
of the synthetases from mammals and the synthetases from parasites responsible
for Chagas' disease (the South American sleeping sickness which afflicts
some 20 million people) is a basis for the development of new drugs.
Glucoamylase from the fungus Aspergillus is perhaps the most heavily
used enzyme in a commerical process. The enzyme is involved in the conversion
of cornstarch to high-fructose sweeteners. The recent structure determination
of glucoamylase in Dr. Honzatko's group has provided essential information
to investigators who wish to engineer an enzyme with properties better
suited to its commercial application. The investigation of glucoamylase-inhibitor
complexes, anticipated for the near future, should provide a wealth
of information pertaining to the catalytic mechanism by which the enzyme
converts starch into glucose.
