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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Prokaryotic Cell and Molecular Biology Study Section (PCMB)
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Hagan, Ann A
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Ohio State University
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Satagopan, Sriram; Sun, Yuan; Parquette, Jon R et al. (2017) Synthetic CO2-fixation enzyme cascades immobilized on self-assembled nanostructures that enhance CO2/O2 selectivity of RubisCO. Biotechnol Biofuels 10:175
North, Justin A; Miller, Anthony R; Wildenthal, John A et al. (2017) Microbial pathway for anaerobic 5'-methylthioadenosine metabolism coupled to ethylene formation. Proc Natl Acad Sci U S A 114:E10455-E10464
Varaljay, Vanessa A; Satagopan, Sriram; North, Justin A et al. (2016) Functional metagenomic selection of ribulose 1, 5-bisphosphate carboxylase/oxygenase from uncultivated bacteria. Environ Microbiol 18:1187-99
Satagopan, Sriram; Tabita, F Robert (2016) RubisCO selection using the vigorously aerobic and metabolically versatile bacterium Ralstonia eutropha. FEBS J 283:2869-80
North, Justin A; Sriram, Jaya; Chourey, Karuna et al. (2016) Metabolic Regulation as a Consequence of Anaerobic 5-Methylthioadenosine Recycling in Rhodospirillum rubrum. MBio 7:
Wrighton, Kelly C; Castelle, Cindy J; Varaljay, Vanessa A et al. (2016) RubisCO of a nucleoside pathway known from Archaea is found in diverse uncultivated phyla in bacteria. ISME J 10:2702-2714
Dey, Swati; North, Justin A; Sriram, Jaya et al. (2015) In Vivo Studies in Rhodospirillum rubrum Indicate That Ribulose-1,5-bisphosphate Carboxylase/Oxygenase (Rubisco) Catalyzes Two Obligatorily Required and Physiologically Significant Reactions for Distinct Carbon and Sulfur Metabolic Pathways. J Biol Chem 290:30658-68
Satagopan, Sriram; Chan, Sum; Perry, L Jeanne et al. (2014) Structure-function studies with the unique hexameric form II ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) from Rhodopseudomonas palustris. J Biol Chem 289:21433-50
Erb, Tobias J; Evans, Bradley S; Cho, Kyuil et al. (2012) A RubisCO-like protein links SAM metabolism with isoprenoid biosynthesis. Nat Chem Biol 8:926-32
Warlick, Benjamin P E; Imker, Heidi J; Sriram, Jaya et al. (2012) Mechanistic diversity in the RuBisCO superfamily: RuBisCO from Rhodospirillum rubrum is not promiscuous for reactions catalyzed by RuBisCO-like proteins. Biochemistry 51:9470-9

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