Tryptophan oxygenation: mechanistic considerations

Abstract

From a protein structural viewpoint, tryptophan is often considered an inert structural amino acid, playing a role as a hydrophobic anchor in membrane proteins or as part of the hydrophobic core of soluble proteins. However, tryptophan is the only polyaromatic amino acid and, from a chemical viewpoint, possesses unique reactivity owing to the electron-richness of the indole system. This reactivity is seen in the area of natural products and metabolites which have exquisite modifications of the indole ring system. Enzymes have evolved multiple strategies to break or modify the indole ring; one particular class is the IDO/TDO (indoleamine/tryptophan dioxygenase) superfamily. A new member of this family, PrnB, on the surface catalyses a very different reaction, but actually shares much of the early chemistry with the tryptophan dioxygenases. Studies on PrnB have contributed to our understanding of the wider superfamily. In the present mini-review, recent developments in our understanding of how the TDO class of enzymes use activated molecular oxygen to break the indole ring are discussed.

Systemic tryptophan and kynurenine catabolite levels relate to severity of rhinovirus-induced asthma exacerbation: a prospective study with a parallel-group design

“…Tryptophan 2,3-dioxgenase (TDO), IDO1 and IDO2 are known to enhance the degradation of tryptophan into N-formyl-kynurenine, which is rapidly converted into kynurenine27 28 and further degraded into 3-hydroxy-kynurenine, anthranilic acid, 3-hydroxy-anthranilic acid and quinolinic acid. TDO is constitutively and specifically expressed in the liver and maintains circulating tryptophan levels within a physiological range 29.…”

Benzofuranquinones as inhibitors of indoleamine 2,3-dioxygenase (IDO). Synthesis and biological evaluation

“…Incorporation of electron withdrawing ester or acid substituents at C-3 is detrimental to biological activity (entries 1, 2, 4-7), although the morpholino amide (entry 3) retains some activity. The fusion of an additional benzene ring at C-5/C-6 (entries 4, 10, 14) results in less potent compounds, as does the substitution of the 5-methoxy group by amino groups (entries [15][16][17][18]. For comparison, the hydroquinones 10a and 10b corresponding to 3a and 3b were assayed, and found to be ineffective IDO inhibitors with 80-90% enzyme activity remaining at 10 μM inhibitor concentrations.…”

“…11 It is a monomeric catalytic haem-containing enzyme with a known structure wherein the active site is composed of two subsites with the haem pocket accommodating the indole ring of the natural substrate tryptophan, 12 and whose mechanism has been widely studied. [13][14][15][16] There are a number of known inhibitors of IDO, encompassing many structural types as outlined in recent reviews. 17,18 The most widely studied are based on 1-methyltryptophan (1-MT), a competitive inhibitor with the natural substrate, but generally only poorly active (K i = 62 µM).…”