Image of Crystals photographed in the HM Holden lab

Virtually every living process, whether it is programmed cell death, mitosis, HIV infection, or embryonic development involves proteins. Indeed, the term protein is derived from the Greek word proteois, which means “first.” My laboratory has had a long-standing interest in protein structure and function where we utilize a combination of biophysical and biochemical techniques to address important mechanistic questions.

We are presently studying a variety of fascinating enzymes that are involved in the biosynthesis of di-, tri-, and tetradeoxysugars. These unusual carbohydrates control or alter the behavior of a wide range of biological molecules. They are found, for example, on the O-antigens of Gram-negative bacteria, and indeed there is growing evidence that O-antigens play important physiological roles including, but not limited to, virulence, effective colonization of host tissues, protection from phagocytosis and serum-mediated killing, and resistance to antimicrobial peptides. As such, the enzymes involved in the productions of these unusual sugars may serve as important drug targets.

In addition to being found on O-antigens, many of these unusual sugars have been observed on various antibiotics, antifungal agents, and chemotherapeutics. Importantly, it has been demonstrated that these carbohydrates provide or enhance the pharmacological properties of the macromolecules to which they are attached. By understanding the structures and functions of the enzymes involved in the biosynthesis of unusual sugars, it will be possible to enzymatically produce novel “designer” carbohydrates with new biological properties that extend far beyond their current function. We are limited only by our imagination once we understand how complex biomolecules are synthesized and how new compounds can be generated.

Research in the laboratory is funded by the NIH.