Tryptophan chlorination

Figure 1.59 Formation of hypochlorous acid from FAD-4o -OOH (a) mechanism of tryptophan chlorination (b) catalyzed by tryptophan 7-halogenase and (c) catalyzed by halogenating enzyme RebH.

Dong, C., Flecks, S., Unversucht, S. et al. (2005) Tryptophan 7-halogenase (PrnA) structure suggests a mechanism for regioselective chlorination. Science, 309, 2216-2219. 

A remarkable, intriguing rearrangement that possibly eould be framed in the context of this ehapter is the one observed in the biosynthesis of the chlorinated fungicide pyrrolnitrin. This compound is produced from the amino aeid tryptophan 179 by the baeterial cells of Pseudomonas pyrrocinia [85BBA181 91MI2 92MI1 94MI3]. A proposal for the biosynthesis... 

The most potent precursors of mutagenicity were methionine, tyrosine, phenylalanine, and the group of heterocyclic amino acids. Tryptophan, histidine, proline, and hydroxyproline were subsequently chlorinated individually. Of these four, tryptophan and proline were the most significant precursors of mutagenic activity, although some activity was also observed in the extract of chlorinated histidine. 

Chlorination of individual amino acids showed that methionine, tyrosine, phenylalanine, tryptophan, and proline produce highly mutagenic extracts. GC-MS analysis of these extracts indicated the presence of only one known mutagen, dichloroacetonitrile, but this mutagen was not present at a level that would be likely to account for the mutagenic activity. 

The anticancer indolocarbazole alkaloid rebeccamycin has been the subject of several biosynthetic studies (1439-1441, 2416), which is also proposed to involve the chlorination of tryptophan (Scheme 4.9). 

Dong C, Flecks S, Unversucht S, Haupt C, van Pee K-H, Naismith JH (2005) Tryptophan 7-Halogenase (PmA) Structure Suggests a Mechanism for Regioselective Chlorination. Science 309 2216... 

Fu X, Wang Y, Kao J, Irwin A, d Avignon A, Mecham RP, Parks WC, Heinecke JW (2006) Specific Sequence Motifs Direct the Oxygenation and Chlorination of Tryptophan by Myeloperoxidase. Biochemistry 45 3961... 

Weber LW, Lebofsky M, Stahl BU, et al. 1992b. Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. Part III Structure-activity relationship with increased plasma tryptophan levels, but no relationship to hepatic ethoxyresorufin o-deethylase activity. Arch Toxicol 66(7) 484-488. 

The introduction of chlorine into tryptophan at C-7 is proposed as the initial step in the biosynthesis of rebeccamydn (126), the powerful indolocarbazole antitumor antibiotic from Lechevalieria aerocolonigenes [117-119]. The proposed overall biosynthesis of rebeccamydn is shown in Scheme 19.4 [119]. 

That chlorination occurs early in the biosynthesis of rebeccamycin is shown by the identification of two genes in the biosynthetic duster and their ability to chlorinate tryptophan at C-7 as shown in Scheme 19.5 [117]. 

Modification by performic acid oxidation Treatment of proteins with performic acid leads to the oxidation of cysteine and cystine residues to cysteic acid residues (Sanger 1949). Methionine residues are quantitatively converted to the sulfone (Hirs 1956), and tryptophan undergoes oxidative destruction (Toennies and Homiller 1942 Benassi et al. 1965). Other amino acids are not modified, provided that precautions are taken to avoid chlorination (Thompson 1954 Hirs 1956), or bromination (Sanger and Thompson 1963) of tyrosine residues. Cleavage of peptide bonds does not occur on performic acid oxidation at low temperature. 

Among the numerous discoveries that we owe to the botanists and the pharmacognosts, the precocious interest for tryptophan metabolites has to be evoked, especially the interest for indolylacetic acid. This compound acts as growth hormone in plants. Para-chlorinated phenoxyacetic... 

Figure 16.9-3. Substrates accepted by tryptophan 7-halogenase (a) indole derivatives, (b) phenylpyrrole derivatives the positions of chlorination are indicated by arrows 431.

The recently detected FADH2-dependent halogenases are substrate specific. Tryptophan 7-halogenase catalyzes the chlorination and bromination of d- and L-trypto-phan to 7-chloro- or 7-bromotryptophan, respectively1201. This enzyme also accepts a number of other indole derivatives such as tryptamine, indole-3-acetonitrile, 3-me-thylindole and 5-methylindole as substrates (Fig. 16.9-3a) 43L In addition to indoles, aminophenylpyrrole derivatives are also chlorinated by tryptophan 7-halogenase (Fig. 16.9-3b) 43L... 

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