Lysine transporters in human trypanosomatid pathogens

Inbar, Ehud; Canepa, Gaspar E.; Carrillo, Carolina; Glaser, Fabian; Grotemeyer, Marianne Suter; Rentsch, Doris; Zilberstein, Dan; Pereira, Claudio A.

doi:10.1007/s00726-010-0812-z

Cited by 36 publications

(41 citation statements)

References 63 publications

(79 reference statements)

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“…In ST parasites, aside from the dramatic drop in Arg, the levels of many free amino acids were modified; only L-tyrosine underwent a small increase, whereas others amino acids experienced moderate (alanine (Ala), valine (Val), Pro, phenylalanine (Phe), tryptophan (Trp), glutamic acid (Glu)) to important decrease (glutamine (Gln)). In other words, a scenario resembling amino acid -resistant *Mass error is related to differences between the equipments (LC-MS and CE-MS) and the public database search starvation was created by MT; despite the strong capability of amino acid inter conversion in Leishmania afforded by the tricarboxylic acid cycle (TCA) and aminotransferases, this amino acid shortage may impair the rate of protein synthesis, however if so, it is puzzling that other essential amino acids such as lysine [75] or the aforementioned methionine [76], did not undergo variation. Importantly, none of the Ser (serine)/ Gly/Cys triad, also connected to methionine biosynthesis through homocysteine underwent significant variation.…”

Section: Resultsmentioning

confidence: 99%

Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania

et al. 2014

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Miltefosine (MT) (hexadecylphosphocholine) was implemented to cope with resistance against antimonials, the classical treatment in Leishmaniasis. Given the scarcity of anti- Leishmania (L) drugs and the increasing appearance of resistance, there is an obvious need for understanding the mechanism of action and development of such resistance. Metabolomics is an increasingly popular tool in the life sciences due to it being a relatively fast and accurate technique that can be applied either with a particular focus or in a global manner to reveal new knowledge about biological systems. Three analytical platforms, gas chromatography (GC), liquid chromatography (LC) and capillary electrophoresis (CE) have been coupled to mass spectrometry (MS) to obtain a broad picture of metabolic changes in the parasite. Impairment of the polyamine metabolism from arginine (Arg) to trypanothione in susceptible parasites treated with MT was in some way expected, considering the reactive oxygen species (ROS) production described for MT. Importantly, in resistant parasites an increase in the levels of amino acids was the most outstanding feature, probably related to the adaptation of the resistant strain for its survival inside the parasitophorous vacuole.

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Section: Resultsmentioning

confidence: 99%

Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania

et al. 2014

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“…L. donovani and T. cruzi also have dedicated plasma membrane transporters for the selective uptake of arginine (LdAAP3 and TcAAP411) and lysine (LdAAP7 and TcAAP7) (Shaked-Mishan et al, 2006; Inbar et al, 2012). The reason for separating lysine and arginine transport in these parasites is unclear (mammalian transporters typically transport both amino acids) but it may be related to the fluctuating metabolic demands of these parasites during their life cycle, which may require differential regulation of lysine and arginine salvage.…”

Section: Parasite Amino Acid Transporters—the Aaap Familymentioning

confidence: 99%

Transport proteins of parasitic protists and their role in nutrient salvage

et al. 2014

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The loss of key biosynthetic pathways is a common feature of important parasitic protists, making them heavily dependent on scavenging nutrients from their hosts. This is often mediated by specialized transporter proteins that ensure the nutritional requirements of the parasite are met. Over the past decade, the completion of several parasite genome projects has facilitated the identification of parasite transporter proteins. This has been complemented by functional characterization of individual transporters along with investigations into their importance for parasite survival. In this review, we summarize the current knowledge on transporters from parasitic protists and highlight commonalities and differences in the transporter repertoires of different parasitic species, with particular focus on characterized transporters that act at the host-pathogen interface.

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“…Placing a bromoacetamide group onto the 2-O position of D-glucose or the 6-O position of D-fructose resulted in high-affinity competitive inhibitors of glucose uptake by BF trypanosomes (7). These compounds had 50% lethal dose (LD 50 ) values for BF trypanosomes in culture that were in the low micromolar range, indicating that inhibition of the parasite hexose transporter was lethal to mammalian-stage parasites and confirming the potential for TbHT1 as a possible drug target. To date, no localization experiments have been performed for either TbHT1 or TbHT2, nor have genetic approaches been undertaken to confirm the essential nature of TbHT1 in BF trypanosomes.…”

Section: Hexose Transportersmentioning

confidence: 86%

“…However, the mechanism whereby these parasites sense arginine and modulate the levels of LdAAP3 mRNAs remains to be deciphered. Recently, a lysine transporter gene from L. donovani (LdAAP7) and its ortholog from T. cruzi (TcAAP7) were cloned and functionally expressed (50). The inability to knock out the LdAAP7 gene suggests that this is the sole lysine transporter in L. donovani and that this permease is essential to promote the uptake of this required amino acid.…”

Section: Amino Acid Transportersmentioning

confidence: 99%

Nutrient Transport and Pathogenesis in Selected Parasitic Protozoa

Landfear

2011

Eukaryot Cell

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Parasitic protozoa, such as malaria parasites, trypanosomes, and Leishmania, acquire a plethora of nutrients from their hosts, employing transport proteins located in the plasma membrane of the parasite. Application of molecular genetic approaches and the completion of genome projects have allowed the identification and functional characterization of a cohort of transporters and their genes in these parasites. This review focuses on a subset of these permeases that have been studied in some detail, that import critical nutrients, and that provide examples of approaches being undertaken broadly with these and other parasite transporters. Permeases reviewed include those for hexoses, purines, iron, polyamines, carboxylates, and amino acids. Topics of special emphasis include structure-function approaches, critical roles for transporters in parasite viability and physiology, regulation of transporter expression, and subcellular targeting. Investigations of parasite transporters impact a broad spectrum of basic biological problems in these protozoa.Parasitic protozoa are responsible for a host of devastating diseases worldwide, including malaria, African trypanosomiasis, Chagas' disease, leishmaniases, toxoplasmosis, and many others. While all organisms must acquire nutrients from their environment, the parasitic mode of life has a number of consequences regarding nutrient uptake. First, the parasite must compete with its insect and vertebrate hosts for acquisition of many essential compounds and thus must evolve efficient uptake mechanisms. Second, the typical parasitic life cycle entails at least two hosts, one of which is often an invertebrate vector and the other a vertebrate host. Thus, the microbe cycles between multiple physiologically distinct milieus that may present pronounced differences in available nutrients, pH, temperature, ionic composition, etc. The parasite must express nutrient uptake systems that accommodate these profound alterations in environment and may employ regulatory mechanisms to alter the level of uptake according to nutrient availability and/or life cycle stage. The capacity of a parasite to import critical nutrients is central to its ability to be transmitted, to infect a host, and to cause disease and hence is an important component of pathogenesis. Figure 1 illustrates the interaction with the mammalian host of 3 parasites discussed in this review, Plasmodium, Trypanosoma brucei, and Leishmania, and reveals how the unique niche in the host dictates the mode of nutrient acquisition. African trypanosomes are extracellular parasites that live in the blood and interstitial spaces of the host and thus salvage nutrients directly from these extracellular fluids. In contrast, both Plasmodium and Leishmania live within parasitophorous vacuoles inside the red blood cell and macrophage, respectively. Intracellular parasitism provides constraints and opportunities regarding nutrient acquisition, specifically the need to import nutrients across 3 membrane systems and potentially the opportunity ...

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Lysine transporters in human trypanosomatid pathogens

Cited by 36 publications

References 63 publications

Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania

Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania

Transport proteins of parasitic protists and their role in nutrient salvage

Nutrient Transport and Pathogenesis in Selected Parasitic Protozoa

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