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1. Cracan, Valentin F. Structure, Function and Metabolic Roles of IcmF-a Fusion Between the Radical B12 Enzyme and its G-protein Chaperone.

Degree: PhD, Biological Chemistry, 2012, University of Michigan

Coenzyme B12 is a biologically active form of vitamin B12 and used in Nature as a radical reservoir to catalyze chemically challenging transformations. The loading of B12-enzymes with the correct cofactor form is critically important for their function and is gated by chaperones that use the chemical energy of GTP hydrolysis to ensure the fidelity of the process. Two highly similar coenzyme B12-dependent enzymes that catalyze carbon skeleton rearrangements, methylmalonyl-CoA mutase (MCM) and isobutyryl-CoA mutase (ICM), are widely distributed in bacteria. MCM catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA while ICM catalyzes the reversible interconversion of isobutyryl-CoA and n-butyryl-CoA. Curiously, a variant, IcmF, is found in >80 bacterial species. Although IcmF was misannotated as an MCM variant in the database, I have demonstrated by expressing four bacterial IcmFs that it is an active ICM, fused to its chaperone. This discovery expands the known distribution of ICM activity well beyond the genus Streptomyces where it is involved in polyketide biosynthesis. Subsequently we have discovered that IcmF catalyzes a novel coenzyme B12-dependent 1,2-rearrangement of isovaleryl-CoA and pivalyl-CoA (2,2-dimethylpropionyl-CoA). Biochemical experiments demonstrate that in an IcmF in which the base specificity loop motif, NKxD is modified to NKxE, catalyzes the hydrolysis of both GTP and ATP. IcmF is susceptible to rapid inactivation during turnover and GTP confers protection, but only during utilization of isovaleryl-CoA as substrate. I have characterized the mutase and GTPase activities in intact and truncated versions of IcmF lacking the B12- or the substrate-binding domains to investigate interactions between the domains. I have demonstrated that adenosyltransferase (ATR), which synthesizes coenzyme B12, also transfers the cofactor to IcmF. To gain insights into the metabolic role of IcmF, we have disrupted the icmF gene in Myxococcus xanthus in collaboration with Dr. Montserrat Elias-Arnanz (Universidad de Murcia, Spain) and in Ralstonia eutropha H16 in collaboration with Dr. Antony Sinskey (MIT) and currently are testing the resulting phenotypes under different growth conditions. Advisors/Committee Members: Banerjee, Ruma (committee member), Palfey, Bruce A. (committee member), Ragsdale, Stephen W. (committee member), Sherman, David H. (committee member), Smith, Janet (committee member).

Subjects/Keywords: IcmF Is a Fusion Between a Coenzyme B12-dependent Isobutyryl-CoA/N-butyryl-CoA Isomerase and a G-protein Chaperone.; AdoCbl, 5'-Deoxy-5'-Adenosylcobalamin; IcmF Also Isomerizes Isovaleryl-CoA to Pivalyl-CoA.; Biological Chemistry; Science

…and related ATPases is the presence of the mononucleotide-binding fold (called the G or… …HypB (hydrogenase pleiotropic B) is a metal-binding G protein that mediates and… …the G protein chaperone for MCM (57), it is necessary to expand the suggested… …into the Function of the G-protein Domain ..111 4.1 Introduction… …ASTRACT Coenzyme B12 is a biologically active form of vitamin B12 and used in Nature as a… 

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APA (6th Edition):

Cracan, V. F. (2012). Structure, Function and Metabolic Roles of IcmF-a Fusion Between the Radical B12 Enzyme and its G-protein Chaperone. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/91597

Chicago Manual of Style (16th Edition):

Cracan, Valentin F. “Structure, Function and Metabolic Roles of IcmF-a Fusion Between the Radical B12 Enzyme and its G-protein Chaperone.” 2012. Doctoral Dissertation, University of Michigan. Accessed June 26, 2019. http://hdl.handle.net/2027.42/91597.

MLA Handbook (7th Edition):

Cracan, Valentin F. “Structure, Function and Metabolic Roles of IcmF-a Fusion Between the Radical B12 Enzyme and its G-protein Chaperone.” 2012. Web. 26 Jun 2019.

Vancouver:

Cracan VF. Structure, Function and Metabolic Roles of IcmF-a Fusion Between the Radical B12 Enzyme and its G-protein Chaperone. [Internet] [Doctoral dissertation]. University of Michigan; 2012. [cited 2019 Jun 26]. Available from: http://hdl.handle.net/2027.42/91597.

Council of Science Editors:

Cracan VF. Structure, Function and Metabolic Roles of IcmF-a Fusion Between the Radical B12 Enzyme and its G-protein Chaperone. [Doctoral Dissertation]. University of Michigan; 2012. Available from: http://hdl.handle.net/2027.42/91597

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