Tryptophan 2,3-dioxygenase (TDO2) is a heme-containing enzyme that plays a crucial role in the metabolism of the essential amino acid tryptophan. This enzyme catalyzes the first and rate-limiting step in the kynurenine pathway, which is the oxidative cleavage of the indole ring of tryptophan to form N-formylkynurenine .
The TDO2 gene is located on chromosome 4q32.1 in humans . The gene encodes a protein that forms a homo-tetrameric structure, with each monomer having a molecular weight of approximately 48 kDa . The active enzyme complex is around 190 kDa in size . The enzyme contains a heme prosthetic group, which is essential for its catalytic activity .
TDO2 is primarily expressed in the liver, but it is also found in other tissues such as the brain and placenta . The enzyme’s primary function is to regulate systemic tryptophan levels by catalyzing its degradation along the kynurenine pathway . This pathway is significant for the production of several bioactive metabolites, including kynurenine, which can be further metabolized into nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in cellular metabolism .
The reaction catalyzed by TDO2 involves the incorporation of molecular oxygen into tryptophan, resulting in the formation of N-formylkynurenine. This reaction is the first and rate-limiting step in the kynurenine pathway .
TDO2 has been implicated in various physiological and pathological processes. Increased activity of TDO2 and subsequent production of kynurenine have been associated with immune suppression in cancer . This is because kynurenine and its metabolites can modulate immune responses, potentially aiding tumor cells in evading immune surveillance .
Additionally, single nucleotide polymorphisms (SNPs) in the TDO2 gene have been linked to disorders such as autism and hypertryptophanemia . The enzyme’s role in tryptophan metabolism also makes it a potential target for therapeutic interventions in diseases where tryptophan catabolism is dysregulated .
Recombinant human TDO2 is produced using genetic engineering techniques, where the TDO2 gene is cloned and expressed in suitable host cells. This allows for the production of large quantities of the enzyme for research and therapeutic purposes . Recombinant TDO2 retains the same structural and functional properties as the native enzyme, making it a valuable tool for studying tryptophan metabolism and developing potential therapeutic agents .