Critical Insight into Plausible Acquired Tocopherol Pathway in Neglected Human Trypanosomatids

Abstract

Despite global therapeutic advancements, tropical parasitic infections like trypanosomiasis and leishmaniasis continue to be a major health concern in developing countries. These two tropical infectious diseases lead to enormous economic loss, significant disability, and morbidity, accounting for over one million deaths per year worldwide. The causative parasites, which shuttle between an insect vector and a mammalian host, thrive either in the bloodstream or in the intramacrophage environments. Essentially, the parasites live in an environment of oxidative stress and therefore require metabolic pathways to counterbalance the host immune response and survive the adverse conditions. Apart from the trypanothione pathway elucidated in the parasites, there exists a tocopherol pathway that functions to scavenge the reactive chemical species. This pathway, unique to photosynthetic organisms, is essential for the parasite's survival, though the enzymes involved remain largely uncharacterized. Consequently, an understanding of the origin of the pathway and where and how the interconnected tocopherol pathway functions may result in the identification of promising and potential therapeutic interventions to combat these deadly diseases. Recent works underline the presence of the tocopherol pathway in trypanosomatids and hypothesize that trypanosomatids may be tocopherol prototrophs. This review focuses on the biosynthesis of tocopherols in Trypanosoma and Leishmania in light of the current evidence.

Oxidants and Antioxidants in the Redox Biochemistry of Human Red Blood Cells

“…Interestingly, it has been seen that intracellular parasites, including the RBC-infecting Plasmodium falciparum , are capable of synthesizing tocopherol as a defense mechanism against oxidative stress. − …”

An anti‐leishmanial compound 4′,7‐dihydroxyflavone elicits ROS‐mediated apoptosis‐like death in Leishmania parasite

“…CPB can also modulate host immune responses like the Th1 immune response [46]. TAT enzyme is a known target of TI 4 and is involved in the tocopherol pathway and methionine‐related pathways [17,47]. CPA and CPB expression were three‐ to four‐fold higher, whereas TAT had an upregulation of eight‐fold.…”

“…From earlier studies, TI 4 has been suggested to target TAT, which is an important enzyme for stress responses [64]. In addition, the tocopherols, which are important ROS scavengers in several organisms [47], were reduced drastically upon TI 4 treatment. Based on this information, we evaluated the ROS accumulation inside the parasite.…”

“…From our previous studies, we had characterized that the compounds are capable of targeting the TAT enzyme and also found that TAT could be an enzyme in the tocopherol metabolism pathway [33,47]. The K i values for TI 1, TI 3, TI 4 and TI 5 were recorded to be 24.41, 0.91, 0.3 and 40.39 μ m , respectively [33].…”