2005 Ohio Student Research Forum

Abstract

Synthesis and Characterization of the Vitamin B12 Derivatives Thiolatocobalamins
Roberto Chavez
Kent State University, Department of Chemistry
Mentor: Dr. Nicola Brasch

The adenosyl and methyl forms of vitamin B¹² are cofactors for two B12-dependent enzyme reactions in humans. The thiol derivatives of vitamin B₁₂, thiolatocobalamins, are also of interest for a number of reasons. Glutathionylcobalamin (GSCbl) is a naturally occurring intracellular form of vitamin B₁₂ found in mammalian cells⁵. It has been proposed that GSCbl is an intermediate in the formation of the two coenzyme forms of vitamin B₁₂, adenosylcobalamin and methylcobalamin^4,5. Glutathione plays an important role in biosynthesis, metabolism, transport, and the protection against possibly harmful free radicals^1,2. Aquacobalamin is another naturally occurring intracellular form of vitamin B₁₂, and recent studies by our group have shown that glutathionylcobalamin is rapidly formed from aquacobalamin and glutathione at the high intracellular concentrations of glutathione (1-10 mM) present in biological systems⁴. McCaddon et al. have also suggested that thiolatocobalamins could be useful in the treatment of cognitive disorders stemming from B₁₂ deficiencies^6,7. Learning more about the stability of thiolatocobalamins would prove to be extremely useful if these compounds were to be used as therapeutics.

Previous studies have shown that the Co-S bond of cysteinylcobalamin is very unstable and spontaneously cleaves in aqueous solution, whereas there is no discernible decomposition of glutathionylcobalamin over a period of 24 hr. The aim of this study is to examine how the structure of the thiol affects the stability of the cobalt-sulfur bond of thiolatocobalamins. We have synthesized a series of thiolatocobalamins with the thiols glutathione, homocysteine, N-acetylcysteine, glutamylcysteine, N-acetylhomocysteine, and cysteine. Future experiments will focus on determining rate constants for the cleavage of the Co-S bond in these vitamin B₁₂ derivatives.

References
(1) Taniguchi, N.; Higashi, T.; Sakamoto, Y.; Meister, A.; Eds. Glutathione Centennial: Molecular Perspectives and Clinical Implications, Academic Press, San Diego, 1989.
(2) Parkinson, A., in Casarett and Doull’s Toxicology - The Basic Science of Poisons, 5th edtn; Klaassen, C. D., Ed.; McGraw-Hill, New York, 1996, p 1111.
(3) Brasch, N. E. and Finke, R. G. J. Inorg. Biochem. 1999, 73, 215-219.
(4) Brasch N. E.; Xia, L.; Cregan, A.. G. and Berben L. A. Inorg. Chem. 2004, 43, 6848-6857.
(5) Brasch N. E.; Suto, R. K.; Anderson, O. P.; Finke, R. G. Inorg. Chem. 2001, 40, 2686-2692.
(6) McCaddon, A. (2003) World Patent Appl. WO2002087593.
(7) McCaddon, A.; Regland, B.; Hudson, P. and Davis, G. Neurology, 2002, 58, 1395-99.