Auxiliary Proteins and Allosteric Control of the Mitochondrial Branch of B12 Trafficking, Assembly, and Reactivity.

[摘要] The presence of cofactors in enzymes broadens the range of chemical transformations catalyzed in Nature. Adenosylcobalamin (AdoCbl) or coenzyme-B12, is a biologically active derivative of vitamin B12 and an organometallic enzyme cofactor that is rare and reactive by virtue of having a labile organocobalt bond. To cope with the low cellular abundance and high reactivity of active B12 derivatives, Nature uses auxiliary proteins that support absorption, assimilation, trafficking and targeting of B12 precursors to B12-dependent enzymes. In humans, methylmalonyl-CoA mutase (MCM) is a mitochondrial protein and the only known AdoCbl-dependent enzyme. Genetic disruption of the gene encoding MCM, or to genes encoding the auxiliary proteins, lead to a rare genetic disorder known as methylmalonic acidemia. In humans, two mitochondrial proteins, an adenosyltransferase (ATR) and a GTPase (G-protein) chaperone of MCM, CblA, perform the final steps in AdoCbl synthesis and delivery to the MCM active site. ATR is a bifunctional enzyme with ATP-dependent cob(I)alamin adenosyltranserase and ATP-dependent AdoCbl transfer activities. Much of our understanding of the mammalian mitochondrial B12-trafficking pathway is derived from clinical genetic studies on patients with cobalamin disorders and detailed enzymological studies of closely related bacterial orthologs particularly from Methylbacterium extorquens. The findings reported in this dissertation demonstrate the critical role of allosteric communication in mediating the AdoCbl trafficking from its point of synthesis on ATR to its delivery to MCM.

[发布机构] University of Michigan

[效力级别] Allostery

[关键词] B12 Trafficking Proteins;Allostery;Biological Chemistry;Science;Biological Chemistry