All organisms produce a host of compounds that are generally not required in primary metabolic processes, but play important regulatory functions. These secondary metabolites have been exploited by every civilization to enhance life and cure human diseases. We know these as hormones, antibiotics, antitumor agents, and antivirals. Since these metabolites can harm cells if produced in excess, or if present when a need for them does not exist, their production is often strictly regulated. An understanding of how cells synthesize and regulate the production of secondary metabolites is essential if one is to be able to exploit them as human therapeutic agents. Deazapurines are secondary metabolites that are derived from purines. This proposal outlines studies on the biosynthesis of deazapurine-containing secondary metabolites by bacterIa. Our goal is to bring to fore the tools of genomics, molecular biology and enzymology to form the framework of how these metabolites are synthesized, and to exploring the chemical transformations that underlies the biosynthesis of these molecules.

Public Health Relevance

Deazapurine-containing compounds are widely distributed in nature and have diverse biological roles. Our goal is to understand the chemical transformations that underlie biosynthesis of these compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM072623-10S1
Application #
8914744
Study Section
Special Emphasis Panel (ZRG1-BCMB-D (02))
Program Officer
Anderson, Vernon
Project Start
2005-01-17
Project End
2018-03-31
Budget Start
2014-08-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
Total Cost
$50,000
Indirect Cost
Name
University of Arizona
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Bruender, Nathan A; Grell, Tsehai A J; Dowling, Daniel P et al. (2017) 7-Carboxy-7-deazaguanine Synthase: A Radical S-Adenosyl-l-methionine Enzyme with Polar Tendencies. J Am Chem Soc 139:1912-1920
Nelp, Micah T; Young, Anthony P; Stepanski, Branden M et al. (2017) Human Viperin Causes Radical SAM-Dependent Elongation of Escherichia coli, Hinting at Its Physiological Role. Biochemistry 56:3874-3876
Bruender, Nathan A; Bandarian, Vahe (2017) The Creatininase Homolog MftE from Mycobacterium smegmatis Catalyzes a Peptide Cleavage Reaction in the Biosynthesis of a Novel Ribosomally Synthesized Post-translationally Modified Peptide (RiPP). J Biol Chem 292:4371-4381
Bruender, Nathan A; Bandarian, Vahe (2016) The Radical S-Adenosyl-l-methionine Enzyme MftC Catalyzes an Oxidative Decarboxylation of the C-Terminus of the MftA Peptide. Biochemistry 55:2813-6
Bruender, Nathan A; Wilcoxen, Jarett; Britt, R David et al. (2016) Biochemical and Spectroscopic Characterization of a Radical S-Adenosyl-L-methionine Enzyme Involved in the Formation of a Peptide Thioether Cross-Link. Biochemistry 55:2122-34
Dowling, Daniel P; Miles, Zachary D; Köhrer, Caroline et al. (2016) Molecular basis of cobalamin-dependent RNA modification. Nucleic Acids Res 44:9965-9976
Bruender, Nathan A; Bandarian, Vahe (2016) SkfB Abstracts a Hydrogen Atom from C? on SkfA To Initiate Thioether Cross-Link Formation. Biochemistry 55:4131-4
Nelp, Micah T; Song, Yang; Wysocki, Vicki H et al. (2016) A Protein-derived Oxygen Is the Source of the Amide Oxygen of Nitrile Hydratases. J Biol Chem 291:7822-9
Skinner, Owen S; Havugimana, Pierre C; Haverland, Nicole A et al. (2016) An informatic framework for decoding protein complexes by top-down mass spectrometry. Nat Methods 13:237-40
Miles, Zachary D; Myers, William K; Kincannon, William M et al. (2015) Biochemical and Spectroscopic Studies of Epoxyqueuosine Reductase: A Novel Iron-Sulfur Cluster- and Cobalamin-Containing Protein Involved in the Biosynthesis of Queuosine. Biochemistry 54:4927-35

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