Models for nitrate reductases and related enzymes

Duquesne University, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): Pterin containing molybdenum enzymes are found in all forms of life, they catalyze numerous reactions that provide vitality in life processes. At the catalytic heart of these enzymes resides a remarkable molecule called molybdopterin that harbors multiple redox active components, and binds molybdenum. In humans, absence of this cofactor due to genetic disposition results in severe physiological disorders including death. The long- term objective of our research program is to understand enzymatic function in order to improve the quality of human health and the environment. While over fifty years of continued research on molybdenum enzymes has made strides, there exist significant gaps in our understanding of the relationship between the structure and the function of molybdopterin enzymes. The specific goals of this research are: to examine what controls the substrate binding and catalytic efficiency in periplasmic nitrate reductase in pathogenic Campylobacter jejuni; to understand how redox states of the dithiolene can influence the spectroscopic properties and electronic description of the molybdenum center; and to develop synthetic strategies for preparing the complete molybdenum cofactor. The proposed research is noteworthy because it will help develop a significantly superior understanding of the chemical properties of a vital biomolecule that is a key component in many life processes. In addition, the proposed research also investigates an important enzyme from a pathogenic organism that infects nearly half a billion people yearly with an estimated cost of $8 billion dollars. The proposed research is related to public health because, a) in Campylobacter jejuni periplasmic nitrate reductase is potentially involved in pathogenicity, and the result generated from the proposed research may allow developing future therapeutics; b) developing the synthetic procedures for molybdenum cofactor may lead to therapy of the genetic disorder due to molybdenum cofactor deficiency; and c) new important knowledge will be generated about the structure-function of an important class of enzyme which in turn can help improve human health. Therefore, the proposed research is relevant to the NIH's mission as it pertains to the pursuit of fundamental knowledge regarding the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of ailment.