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Personendaten zu Dr. Marcel Frese

  Dr. Marcel Frese
Dr. Marcel Frese
Raum: F2-129
Telefon: 0521 106 2048

Halogenating enzymes in the field of bioorganic chemistry

Halogenated products are widely distributed in nature. Some of these metabolites show potent biological activities, e.g. as antibiotic and antitumor agents like chloramphenicol, vancomycin and cryptophycin. In most cases, the incorporation of the halogen substituent is an essential structural key feature for biological activity. Since chemical halogenation often requires rough reaction conditions and results in unwanted byproduct formation, enzymatic halogenation often leads to specific substrates with both regio- and stereoselectivity. Therefore, the characterization of naturally occurring enzymatic halogenation mechanisms has become an active area of research. A proposed mechanism for FADH2-depedent halogenases is shown in fig. 1.

Fig. Proposed mechanism of FADH2-dependent halogenases (Wagner et al., 2008).

A reductase provides FADH2, which directly reacts with O2. Afterwards, HOCl as the chlorinating agent is formed and tunneled intraenzymatically to a lysine residue, where chlorine is activated to react with the substrate, in this case L-tryptophan. An additional glutamic acid residue is involved in stabilization and deprotonation of the intermediate. Processes, which proceed inside the halogenase are shaded grey.

The FADH2-dependent halogenase CrpH (GenBank accession no. ABM21576) takes part in the biosynthetic formation of cryptophycin, a potent tubulin-destabilizing depsipeptide, in the cyanobacteria Nostoc sp. ATCC 53789. Although the biosynthesis of cryptophycins in Nostoc has already been described (Magarvey et al., 2008), the direct precursor for chlorination with CrpH is not known. Since most enzymes in cryptophycin biosynthesis show low substrate specificity, CrpH might use several potential precursors for halogenation. Therefore, halogenases like CrpH can be used to halogenate synthetically prepared or PKS/NRPS derived substrates, which could lead to the development of novel compounds with enhanced biological activity. In addition, these halogenated products can be converted chemically for further modification.

Wagner, C., El Omari, M., König, G.M., J. Nat. Prod.2009, 72, 540-553.
Magarvey, N. A., Beck, Z. Q., Golakoti, T., Ding, Y., Huber, U., Hemscheidt, T. K., Abelson, D., Moore, R. E., Sherman, D.H., ACS Chem Biol.20061(12), 766-779.


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