Sulfur-containing metabolites play significant roles in many important processes that define healthy cellular activity. To make sulfur precursor molecules available for subsequent metabolism, and for DNA and RNA metabolism and various protein posttranslational modifications, prokaryotic and eukaryotic cells have developed salvage or sparing pathways. When such pathways become compromised, there are many health-related effects that are noted. For example, disruption or reduced functioning of the methionine salvage pathway has consequences relative to cancer cell growth and liver cirrhosis. In addition, intermediates of this pathway have been shown to influence apoptotic processes, while analogs of these intermediates are promising therapeutic agents that selectively disrupt the life cycle of malarial and trypanosome parasites. Despite the importance of such pathways, the strategies by which microorganisms and higher organisms control their ability to salvage sulfur-containing metabolites is not well understood, nor is there good understanding of the variety of ways in which these metabolites may be produced. In this investigation, the overall goal is to better understand the mechanism and regulation of newly discovered and wide-spread novel sulfur salvage pathways. Based on recent studies, it is apparent that an important and surprising strategy taken by diverse organisms is to employ ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) or the RubisCO-like protein (RLP), or both RubisCO and RLP, as key reactions that anchor sulfur salvage pathways in the cell. Both enzymes catalyze absolutely essential reactions that are needed for the metabolism and salvage of sulfur-containing metabolites in the cell. Using a model organism (Rhodospirillum rubrum) that is amenable to genetic and biochemical manipulation, and employs both aerobic (RLP-anchored) and anaerobic (RubisCO-anchored) methionine/sulfur salvage pathways, we will seek to: (a) elucidate the involvement of novel reactions required for new pathways of sulfur salvage;(b) determine how the aerobic and anaerobic pathways are differentially controlled;and (c) establish how the active site region of RubisCO accommodates and enables catalysis of reactions crucial to both sulfur and carbon metabolism. The latter aim presents an unprecedented opportunity to provide new paradigms for integrating protein structure/function relationships to key and diverse physiological processes.

Public Health Relevance

For healthy metabolism, all organisms must make provision to supply cells with adequate levels of key sulfur-containing compounds. When this ability is compromised, a number of pathologies results in both humans and lower organisms. This study seeks to understand the underlying mechanisms by which cells control newly discovered metabolic routes for the production of essential sulfur compounds.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM095742-04
Application #
8690909
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Reddy, Michael K
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210