Revisiting trypanosomatid nucleoside diphosphate kinases

Abstract

BACKGROUND An increasing amount of research has led to the positioning of nucleoside diphosphate kinases (NDPK/NDK) as key metabolic enzymes among all organisms. They contribute to the maintenance the intracellular di-and tri-phosphate nucleoside homeostasis, but they also are involved in widely diverse processes such as gene regulation, apoptosis, signal transduction and many other regulatory roles.OBJETIVE Examine in depth the NDPKs of trypanosomatid parasites responsible for devastating human diseases (e.g., Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp.) which deserve special attention.METHODS The earliest and latest advances in the topic were explored, focusing on trypanosomatid NDPK features, multifunctionality and suitability as molecular drug targets.FINDINGS Trypanosomatid NDPKs appear to play functions different from their host counterparts. Evidences indicate that they would perform key roles in the parasite metabolism such as nucleotide homeostasis, drug resistance, DNA damage responses and gene regulation, as well as host-parasite interactions, infection, virulence and immune evasion, placing them as attractive pharmacological targets.MAIN CONCLUSIONS NDPKs are very interesting multifunctional enzymes. In the present review, the potential of trypanosomatid NDPKs was highlighted, raising awareness of their value not only with respect to parasite biology but also as molecular targets.

Targeting the nucleotide metabolism of Trypanosoma brucei and other trypanosomatids

“…The NDP kinases are also compartmentalized, and studies from T. cruzi show specific isoenzymes for the flagellum/microtubules (NDPK2), glycosome (NDPK3), and cytosol/nucleus (NDPK1) (Miranda et al 2022 ). Surprisingly, NDPK1 can also be excreted and it has been proposed that its extracellular activity might have an immunoregulatory role important for virulence (Miranda et al 2022 ). From a drug development perspective, it is unclear if it is enough to inhibit specific NDP kinases or NMP kinases in order to kill T. brucei or other trypansomatids.…”

Experimental structure based drug design (SBDD) applications for anti‐leishmanial drugs: A paradigm shift?

“…For pyrimidine nucleotides, leishmanial dUTPases are also essential enzymes that convert dUTP to dUMP which is the substrate of thymidylate synthase (TS) for producing dTMP, thus increasing the dTTP:dUTP ratio during DNA synthesis and reducing dUMP misincorporations and DNA repair occurrences that might ultimately result in DNA fragmentation and cell death. 52 Leishmania must salvage folate and pterin cofactors for DNA synthesis and other functions from both the insect and the mammalian hosts. 53 Uptake mainly in folate and biopterin form by active transporters such as FT1 and BT1…”

“…The fourth enzyme in the pathway, dihydroorotate dehydrogenase (DHODH) differs in mechanism from the human enzyme and therefore provides an interesting point for drug discovery. For pyrimidine nucleotides, leishmanial dUTPases are also essential enzymes that convert dUTP to dUMP which is the substrate of thymidylate synthase (TS) for producing dTMP, thus increasing the dTTP:dUTP ratio during DNA synthesis and reducing dUMP misincorporations and DNA repair occurrences that might ultimately result in DNA fragmentation and cell death 52 …”