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
Wilcoxen, Jarett; Bruender, Nathan A; Bandarian, Vahe et al. (2018) A Radical Intermediate in Bacillus subtilis QueE during Turnover with the Substrate Analogue 6-Carboxypterin. J Am Chem Soc 140:1753-1759
Young, Anthony P; Bandarian, Vahe (2018) TYW1: A Radical SAM Enzyme Involved in the Biosynthesis of Wybutosine Bases. Methods Enzymol 606:119-153
Bandarian, Vahe (2018) Preface. Methods Enzymol 606:xv-xvi
Grell, Tsehai A J; Kincannon, William M; Bruender, Nathan A et al. (2018) Structural and spectroscopic analyses of the sporulation killing factor biosynthetic enzyme SkfB, a bacterial AdoMet radical sactisynthase. J Biol Chem 293:17349-17361
Grell, Tsehai A J; Young, Anthony P; Drennan, Catherine L et al. (2018) Biochemical and Structural Characterization of a Schiff Base in the Radical-Mediated Biosynthesis of 4-Demethylwyosine by TYW1. J Am Chem Soc 140:6842-6852
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; 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
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
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

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