Ascorbic acid (vitamin C), a dietary requirement for human health, is an electron donor for several enzymatic actions, functions as an antioxidant, and is implicated in host defense mechanisms, endocrine function and the visual process (lens). Recent renewed interest in the biochemistry of ascorbic acid has been prompted by the realization that relatively little is known concerning the concentrations of the vitamin required for optimum functioning of these several roles. In the case of enzymatic reactions, optimal rate of a process is defined as that concentration that allows the reaction to reach Vmax without toxicity. As part of a program to determine these concentrations, in situ kinetic measurements have been carried out for certain vitamin C-linked reactions. In addition to examination of functional roles of vitamin C, recent characterization of efficient transport mechanisms that translocate vitamin C across cellular membranes has emphasized the importance of the vitamin to biological processes. In previous work, we synthesized radiolabelled 6-deoxy-6-iodoascorbic acid as a tool for studying additional details of the ascorbic acid transport system. Transport studies indicate this will be a useful tool in attempts to isolate the ascorbic acid transport protein. To investigate the importance of the 2-hydroxyl group on ascorbic acid activity, we also previously prepared 2-deoxy-ascorbic acid, and 2-deoxy-2-halo ascorbic acids, including 2-deoxy-2-fluoroascorbic acid, an isosteric and isopolar, non-oxidizable, analogue. In addition, the cyclic hemiketal form of 2,2-difluoro-2-deoxyascorbic acid also was prepared, a structure that corresponds to the cyclic hemiketal form of dehydroascrobic acid. Experiments with 6-bromo-6-deoxyascorbic acid have revealed that the oxidized form (6-bromo-deoxyascorbic acid) is not transported by the glucose trasporter that translocates deoxyascorbic acid itself. On the other hand, we had shown previously that 6-bromo-6-ascorbic acid is transported by the ascorbic acid transport protein. A working hypothesis is that it is the cyclic ketal form of dehydroascorbic acid that is recognized by the trasmprot protein. It is impossible for oxidized 6-bromo-6-deoxyascorbic acid to form such a cyclic ketal. In a new approach to the study of ascorbic acid glucose transport, we are preparing new flavonoid analogues to study sturtural parameters of these inhibitors of ascorbate and glucose transport. Inculded will be potential affinity labels for the transport protein(s). Effects of fluorine substitution biolgical begavior of the flavonoids also will be examined. A series of fluorinated chalcones have been prepared and will be cyclized under conditions that produce the flavonoid structures.
| Chen, Qi; Espey, Michael Graham; Sun, Andrew Y et al. (2008) Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 105:11105-9 |
| Corpe, Christopher P; Lee, Je-Hyuk; Kwon, Oran et al. (2005) 6-Bromo-6-deoxy-L-ascorbic acid: an ascorbate analog specific for Na+-dependent vitamin C transporter but not glucose transporter pathways. J Biol Chem 280:5211-20 |
| Rumsey, S C; Welch, R W; Garraffo, H M et al. (1999) Specificity of ascorbate analogs for ascorbate transport. Synthesis and detection of [(125)I]6-deoxy-6-iodo-L-ascorbic acid and characterization of its ascorbate-specific transport properties. J Biol Chem 274:23215-22 |
