Tryptophan reaction with oxygen

Catabolism of tyrosine and tryptophan begins with oxygen-requiring steps. The tyrosine catabolic pathway, shown at the end of this chapter, results in the formation of fumaric acid and acetoaceticacid, Iryptophan catabolism commences with the reaction catalyzed by tryptophan-2,3-dioxygenase. This enzyme catalyzes conversion of the amino acid to N-formyl-kynurenine The enzyme requires iron and copper and thus is a metalloenzyme. The final products of the pathway are acetoacetyl-CoA, acetyl-Co A, formic add, four molecules of carbon dioxide, and two ammonium ions One of the intermediates of tryptophan catabolism, a-amino-P-carboxyrnuconic-6-semialdchydc, can be diverted from complete oxidation, and used for the synthesis of NAD (see Niacin in Chapter 9). 

Elucidating all the fascinating details of this reaction will require further mechanistic, structural, and model studies. Finally, the discovery of self-processing redox enzymes (see Section 6 see Metal-mediated Protein Modification) may be relevant to understanding aspects of the evolution of enzymes. Metal-ion mediated redox chemistry with oxygen can modify several amino acids, especially tyrosine, tryptophan, cysteine, and histidine. This may have provided a path to generate new redox cofactors prior to the advent of the complex biosynthetic pathways. 

Histidine is susceptible to oxidation in the presence of metals, primarily by reaction with singlet oxygen, and this constitutes a major cause of enzyme degradation. Both histidine and tryptophan are highly susceptible to photooxidation. 

Reaction Mechanism. The following reaction mechanism is compatible with the above data. Tryptophan first combines with ferrous enzyme and activates the heme in the enzyme. The activated enzyme then reacts with oxygen to form an intermediary ternary complex. Both substrates, tryptophan and oxygen, are activated in the complex and interact, yielding formylkynurenine as product. 

The main products of tryptophan oxidation with singlet oxygen are a dioxethane derivative, formed via 1,4-cycloaddition and a hydroperoxide at C-3. Subsequent decomposition of these intermediates yields N-formylkynurenine, whereas their ring closure leads to cis- and trans-isomers of 3a-hydroxypyrroloindoles, that is, 3a-hydroxy-l,2,3,3,8,8a-hexahydropyrrolo[2,3-fo]indole-2-carboxylic acids and 3a,8a-dihydroxypyrroloindoles. The simplified reaction sequences are given in Figure 2.38. 

The discovery that formylkynurenine is formed by an oxygenation reaction, with the introduction of two atoms of oi gen into tryptophan eliminates the posrability or need of an oxidation product contaming only one atom of oigrgen. Hie Ot must be introduced in a single step into the tryptophan giving a product which immediately rearranges to formyl-kynurenine. This makes a hydroxy intermediate improbable and unnecessary. 

Kostic el al. discovered that Pd11 complexes, when attached to tryptophan residues, can rapidly cleave peptides in acetone solutions to which a stoichiometric amount of water is added, for hydrolysis.436 The indole tautomer in which a hydrogen has moved from the nitrogen to C(3) is named indolenine. Its palladium(II) complexes that are coordinated via the nitrogen atom have been characterized by X-ray crystallography and spectroscopic methods.451 Binuclear dimeric complexes between palladium(II) and indole-3-acetate involve cyclopalladation.452 Bidentate coordination to palladium(II) through the N(l) and the C(2) atoms occurs in binuclear complexes.453 Reactions of palladium(II) complexes with indole-3-acetamide and its derivatives produced new complexes of unusual structure. Various NMR, UV, IR, and mass spectral analyses have revealed bidentate coordination via the indole carbon C(3) and the amide oxygen.437... 

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