Tryptophan (TRY) is an amino acid participating in biosynthesis of proteins and methoxyindoles (serotonin and melatonin). TRY 2,3-dioxygenase 2 (TDO) is a ratelimiting enzyme of the major non-protein route of TRY metabolism: the cleavage of indole ring of TRY with the formation of formyl-kynurenine, and subsequently, kynurenine (KYN). Since TDO is intracellular enzyme, TRY must enter cell to be available as a substrate for KYN formation. Cellular uptake of TRY is facilitated by ATP-binding cassette (ABC) transporter. Thus, besides TDO, ABC transporter is a rate-limiting factor of TRY conversion into KYN.
Animal and human studies suggested that aging is associated with upregulation of TRY-KYN metabolism. Thus, plasma KYN/ TRY ratio (marker of activity of KYN formation from TRY) is increased with aging. Increased formation of KYN derivative, kynurenic acid, was observed in aged rat brain and in human serum.
One of the mechanisms of aging-associated upregulation of TRY-KYN metabolism might be the increased production of cortisol, the inducer of TDO. Association between TRY-KYN metabolism and aging might be further supported by the observations of the increased rate of TRY conversion into KYN in obesity, diabetes, atherosclerosis, menopause, major depression and other aging-associated medical and psychiatric disorders (including metabolic syndrome). TRY-KYN pathway and related genes were described in Drosophila melanogaster. The end product of TRY-KYN pathway in Drosophila is brown eye pigment.
TDO is the rate-limiting enzyme of KYN formation from TRY in Drosophila, as in the other species. Life spans of TDO-deficient (vermilion) and of ABC transport impaired (white) eye mutants of Drosophila melanogaster were longer than of wild type flies.
This data are in line with the observation of high mortality in humans with increased plasma KYN/TRY ratio at the entry of the 10-year prospective study of nonagenarians. Therefore, it could be true that prolongation of life span might be associated with the slow rate of KYN formation from TRY.
To further evaluate this hypothesis scientists studied the effect of TDO inhibitor, alpha-methyl tryptophan (aMT) and of ABC transporter inhibitor, 5-methyltryptophan (5MT), on the life span of wild type Oregon flies. Results have shown that aMT and 5MT prolonged mean and maximum life span (by 27 % and 43 %, and 21 % and 23 %, resp.) of fruit flies.
In conclusion, prolongation of life span was observed in wild stock flies treated by the inhibitors of TDO and of ABC transporter. Both treatments supposed to limit TRY conversion into KYN. This data are in agreement with previously observed extension of life span in Drosophila mutants with deficient TDO or impaired ABC transporter, and with neuroprotective effect of genetic inhibition of TDO. Importantly, in difference with genetic mutations, pharmacological interventions increased not only mean survival time but maximum life span as well. Inhibition of TRY conversion into KYN might be a target for anti-aging intervention.
Source: Innovita Research Foundation.