Structure biotin

Very recently two series of ureylenebenzene and ureylenecpctohexane derivatives related to the biotin structure (see formulae) have been found to possess specifically anti-biotin effects (82a) and thus provide further examples of deliberately modelled anti-metabolites. 

Miyamoto S and P A Kollman 1993a. Absolute and Relative Binding Tree Energy Calculations of the Interaction of Biotin and its Analogues with Streptavidin Using Molecular Dynamics/Free Energy Perturbation Approaches. Proteins Structure, Function and Genetics 16 226-245. 

The structure of biotin was determined in the early 1940s by Kogl in Europe and by dn Vigneand and coworkers in the United States. Interestingly, the biotin molecule contains three asymmetric carbon atoms, and biotin could thus exist as eight different stereoisomers. Only one of these shows biological activity. 

Lipoic acid exists as a mixture of two structures a closed-ring disulfide form and an open-chain reduced form (Figure 18.33). Oxidation-reduction cycles interconvert these two species. As is the case for biotin, lipoic acid does not often occur free in nature, but rather is covalently attached in amide linkage with lysine residues on enzymes. The enzyme that catalyzes the formation of the lipoamide nk.2Lg c requires ATP and produces lipoamide-enzyme conjugates, AMP, and pyrophosphate as products of the reaction. 

The chemical structure of biotin (hexahydro-2-oxo-IH-thieno [3,4-d] imidazol-4-valeric acid) is shown in Fig. 1. Of the eight stereoisomers, only d-(+)-biotin occurs naturally and is biologically active. 

Fig- 7.3 Biotin in the conformation bound to streptavidin (PDB INQM) compared to a small-molecule X-ray stmcture from CSD (BIOTINIO), a single 3D structure generated... 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

Figure 3.3. Structure of the ICAT reagent. The reagent contains a biotin affinity tag that is used to isolate ICAT-labeled peptides. The reagent also contains a linker that exists in a heavy (where X= deuterium) or light form (X= hydrogen) and a reactive group with specificity towards the thiol groups of cysteine residues. Figure adapted from Gygi et al. (1999).

Weber, P. C. Ohlendorf, D. H. Wendoloski, J. J. Salemme, F. R., Structural origins of high-affinity biotin binding to Streptavidin, Science 1989, 243, 85-88. 

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