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Nicola E. Brasch

Associate Professor

Ph.D. University of Otago (New Zealand), 1994

Vitamin B12 Chemistry

 

The structure of vitamin B12 (cyanocobalamin, CNCbl) is shown in Figure 1 (X = CN-). Cobalamins (= vitamin B12 derivatives) are cobalt-containing macrocyclic complexes which vary in the ligand occupying the upper axial site (= X, Fig. 1). Cobalamins are synthesized by microorganisms found in soil, water and the intestine of some animals; however humans cannot synthesize cobalamins and instead obtain their daily requirement (1- 6 µg) from animal products. The MeCbl and AdoCbl forms of vitamin B12 (X = Me or Ado, Fig. 1) are cofactors for approximately 15 known enzyme reactions. A deficiency in vitamin B12 can lead to anaemia ("pernicious anaemia") and/or neurological disorders. Of the 15 or so vitamin B12-dependent enzyme reactions known, two of these reactions, involving methionine synthase and methylmalonyl-CoA mutase, occur in humans. In the former reaction, the vitamin B12 derivative methylcobalamin is an intermediate in the methylation of homocysteine by methyl-tetrahydrofolate. A current "hot topic" in the medical literature is the recently demonstrated relationship between high serum levels of homocysteine and a greatly increased risk of strokes or heart attacks. In addition, it is now well established that individuals with high serum levels of homocysteine are more likely to develop neurological disorders. It has recently been estimated that 15-20% of the US population over the age of 65 years are B12 deficient.

 Structure of vitamin B12 and its derivatives. X = CN, Me, Ado, OH2, GS, NO etc.

Structure of vitamin B12 and its derivatives.
X = CN, Me, Ado, H2O, GS, NO etc

Vitamin B12-Small Molecule Interactions

We are interested in vitamin B12-small molecule interactions of biological relevance. To illustrate, in collaboration with the lab of Dr. Donald Jacobsen, Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic, we have recently shown that the glutathione derivative of B12, glutathionylcobalamin (X = GS, Fig. 1) is naturally occurring in mammalian cells. It was also recently proposed by Dr. Andrew McCaddon and co-workers that thiolatocobalamins may be more potent therapeutics than the currently available pharmaceutical forms of B12. We have developed procedures for synthesizing thiolatocobalamins and are interested in the chemical and biological properties of these complexes. In 2007 the US pharmaceutical company Pamlab licensed out a patent concerning N-acetyl-L-cysteinylcobalamin from Kent State University.

Vitamin B12 Bioconjugates and Therapeutics

Other areas of interest include the synthesis and properties of vitamin B12 bioconjugates. In addition to synthesizing B12 bioconjugates, studies designed at probing the stability of the complexes under physiological conditions will also be carried out. Collaborations will also be established with other groups to examine the in vitro and/or in vivo properties of the more promising complexes.

The ability of vitamins to act as drug carriers (or vectors) for transporting orally administered pharmaceuticals to cells has been recognized for some time. Only small, neutral, water-soluble molecules can pass across biological membranes to any degree by passive diffusion. Due to the large size of vitamins, these important biomolecules are therefore typically associated with active transport mechanisms for absorption and cellular uptake. This is especially important for vitamin B12, given the very small amounts that are present in most foods. Utilizing vitamin B12 bioconjugates for the transportation of drugs has been shown to have applications in the uptake of peptides, proteins, imaging agents and chemotherapeutics.

Vanadium compounds mimic and/or enhance nearly all of the known metabolic actions of insulin; however they are poorly absorbed. Recently we have prepared the first vitamin B12 bioconjugate which could potentially be an active, orally administered pharmaceutical for the treatment of diabetes (R. Mukherjee et al, Chem. Commun., 2008, 3783). This work was featured in C&E News (Science & Technology Concentrate, 2008, June 30 issue).

The Coordination Chemistry of Vanadium(III)

The +3 oxidation state of vanadium is of interest for several reasons. V(III) clusters spontaneously form in solution with interesting structures, spectroscopic properties, and magnetic properties. Furthermore, V(III) clusters can exhibit spin frustration and behave as single molecule magnets, and therefore have potential applications in data storage. V(III) complexes are also of interest with respect to their electron transfer properties and their potential to act as catalysts in industrially relevant processes and by mimicking the active sites of metalloproteins.

The importance of vanadium in biology first attracted attention through the work of Martin Henze and co-workers, who discovered high concentrations of vanadium(III) in the blood cells of sea squirts. Ascidians of the suborder Phlebobranchia are small marine animals that sequester vanadium(V) from seawater and reduce it to vanadium(III). How or why these creatures accumulate this metal ion is unknown.

The chemistry of vanadium(III) itself, especially in aqueous systems, is poorly defined compared with that of vanadium in the more stable oxidation states of +4 and +5. Our studies of vanadium(III) complexes have commenced with simple ligands such as amino acids, or ligands which model amino acids. Although it was proposed a number of years ago that V(III) clusters with nuclearity greater than two exist is aqueous solution, there is practically no structural data to substantiate this claim. Recently we structurally characterized and studied the aqueous solution chemistry of a series of trimeric and tetrameric V(III) complexes of acetate and related ligands (R. Mukherjee et al, Inorg. Chem. 2007, 46, 1575). 1H NMR spectroscopy and ES-MS measurements demonstrated that the polynuclear complexes are not purely solid state phenomena, but retain their structural integrity in solution.

Further details on our research can be obtained at our Research Group Website.



Scholarly, Creative & Professional Activities
  1. Hassanin, H. A.; Hannibal, L.; Jacobsen, D. W.; El-Shahat, M. F.; Hamza, M. S. A. and Brasch, N. E.* Mechanistic Studies on the Reaction between R2N-NONOates and Aquacobalamin: Evidence for Direct Transfer of a Nitroxyl (NO-) Group from R2N-NONOates to Cobalt(III) Centers, Angew. Chemie Int. Ed., 2009, 48(47), 8909.
  2. Suarez-Moreira, E.; Yun, J.; Birch, C. S.; Williams, J. H. H.; McCaddon, A.; Brasch, N. E.* Vitamin B12 and Redox Homeostasis: Cob(II)alamin Reacts with Superoxide at Rates Approaching Superoxide Dismutase (SOD). J. Am. Chem. Soc., 2009, 131(42), 15078.
  3. Mukherjee, R.; McCaddon, A.; Smith, C. A.; Brasch, N. E.* Synthesis, Synchrotron X-ray Diffraction and Kinetic Studies on the Formation of a Novel Thiolatocobalamin of Captopril: Evidence for cis-trans isomerization in the b-axial Ligand, Inorg. Chem., 2009, 48(19), 9526.  
  4. Hannibal, L.; Smith, C. A.; Smith, J. A.; Axhemi, A.; Miller, A.; Wang, S.; Brasch, N. E. and Jacobsen, D. W.* High Resolution Crystal Structure Determination of the Methylcobalamin Analogs Ethylcobalamin and Butylcobalamin by X-ray Synchrotron Diffraction, Inorg. Chem., 2009, 48(14), 6615.
  5. Birch, C. S.; Brasch, N. E.; McCaddon, A. and Williams, J. H. H.* A Novel Role for Vitamin B12: Cobalamins are Potent Intracellular Antioxidants, Free Rad. Biol. Med., 2009, 47(2), 184.
  6. Hannibal, L.; Kim, J.; Brasch, N. E.; Wange, S.; Rosenblatt, D. S.; Banerjee, R.; Jacobsen, D. W.* Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product, Mol. Gen. Metab., 2009, 97, 260.
  7. Hassanin, H. A.; Hannibal, L.; Jacobsen, D. W.;  Brown, K. L.; Marques, H. L.* and Brasch, N. E.* NMR Spectroscopy and Molecular Modelling Studies of Nitrosylcobalamin: Further Evidence that the Deprotonated, Base-off Conformation is an Important Conformation of Nitrosylcobalamin in Solution, Dalton Trans. 2009, 424 (selected for the journal cover and selected as a "Hot article").
  8. Hannibal, L.; Axhemi, A.; Glushchenko, A. V.; Suarez-Moreira, E.; Brasch, N. E.*; Jacobsen, D. W.*, Accurate Assessment and Identification of Naturally Occurring Cellular Cobalamins, Clin. Chem. Lab. Med. 2008, 46, 1739.
  9. Mukherjee, R.; Donnay, E. G.; Radomski, M. A.; Miller, C.; Redfern, D. A.; Gericke, A.; Damron, D. S.; Brasch, N. E.* Vanadium-Vitamin B12 Bioconjugates as Potential Therapeutics for Treating Diabetes, Chem. Commun. 2008, 3783. This article was also selected for inclusion in the Royal Society of Chemistry's Chemical Biology Research Articles virtual journal.

Patents

  1. Brasch, N. E.; Birch, C. S.; Williams, J. H. H. Pharmaceutical compositions and therapeutic applications for the use of a novel vitamin B12 derivative, N-acetyl-L-cysteinylcobalamin. U.S. Patent Application 20080076733, 2008.
  2. Brasch, N. E.; Xia, L. Method of Synthesis of β-thiolato Cobalamin Nucleoside Compounds, U.S. Patent Application 20040054128, 2004.
Nicola E. Brasch
OFFICE
Department of Chemistry
OFFICE HOURS


GROUP WEBSITE

http://www.brasch-group.com

CONTACT INFO
nbrasch@kent.edu