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. We have 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 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. 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. Molecular modeling confirms the similarity of the cyclic hemiketal form of 2,2-difluoro-2-deoxyascorbic acid also the cyclic hemiketal form of dehydroascrobic acid. Transport properties of these analogues, as well as their effects on glutarodoxin, the enzyme that reduces deoxyascorbic acid to ascorbic acid, are being investigated. 6-Halo-6-deoxy-L-ascorbic analolgs, when oxidized, are unable to form a similar cyclic hemiacetal. If the cyclic structure is the form that is transported by the dehydroasorbate transporter, the oxidiazed 6-halo analogs should not be translocated. Studies to examine this question are in progress. Approaches to [18-F]-6-deoxy-6-fluoro-L-ascorbic acid are being investigated based on nucleophilic fluoride substitution of a triflate precursor.
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| 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 |
