Distinct overexpression of cytosolic and mitochondrial tryparedoxin peroxidases results in preferential detoxification of different oxidants in arsenite-resistant Leishmania amazonensis with and without DNA amplification

Lin, Yi‐Chun; Hsu, Ju-Yu; Chiang, Su-Chi; Lee, Sho Tone

doi:10.1016/j.molbiopara.2005.03.009

Cited by 50 publications

(37 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4 and 5A). This result correlates with the report by Lin et al that overexpression of tryparedoxin peroxidase is linked with resistance against oxidative stress (36). Low-molecular-mass thiol also plays an important role in the defense against oxidative damage caused by oxidants (42,47).…”

Section: Discussionsupporting

confidence: 89%

“…This pathway consists of a cascade of low-molecular-weight, thiol-specific oxidoreductases acting in an NADPH-dependent manner to detoxify peroxides in the following order: trypanothione reductase (TR) ¡ trypanothione (TSH) ¡ tryparedoxin ¡ tryparedoxin peroxidase (11,55). In antimonial resistance, it was shown that overexpression of tryparedoxin peroxidase is linked with resistance against oxidative stress (36). In trypanosomatids, a reduced form of trypanothione is involved in the maintenance of the intracellular reducing environment, substituting for the glutathione (GSH) found in most other organisms (18).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Purkait¹,

Kumar²,

Nandi

et al. 2012

Antimicrob Agents Chemother

273

251

View full text Add to dashboard Cite

The clinical value of amphotericin B, the mainstay therapy for visceral leishmaniasis in sodium antimony gluconatenonresponsive zones of Bihar, India, is now threatened by the emergence of acquired drug resistance, and a comprehensive understanding of the underlying mechanisms is the need of the hour. We have selected an amphotericin B-resistant clinical isolate which demonstrated 8-fold-higher 50% lethal doses (LD 50 ) than an amphotericin B-sensitive strain to explore the mechanism of amphotericin B resistance. Fluorimetric analysis demonstrated lower anisotropy in the motion of the diphenylhexatriene fluorescent probe in the resistant strain, which indicated a higher fluidity of the membrane for the resistant strain than for the sensitive strain. The expression patterns of the two transcripts of S-adenosyl-L-methionine:C-24-⌬-sterol methyltransferase and the absence of ergosterol, replaced by cholesta-5,7,24-trien-3␤-ol in the membrane of the resistant parasite, indicate a decreased amphotericin B affinity, which is evidenced by decreased amphotericin B uptake. The expression level of MDR1 is found to be higher in the resistant strain, suggesting a higher rate of efflux of amphotericin B. The resistant parasite also possesses an upregulated tryparedoxin cascade and a more-reduced intracellular thiol level, which helps in better scavenging of reactive oxygen species produced by amphotericin B. The resistance to amphotericin B was partially reverted by the thiol metabolic pathway and ABC transporter inhibitors. Thus, it can be concluded that altered membrane composition, ATP-binding cassette transporters, and an upregulated thiol metabolic pathway have a role in conferring amphotericin B resistance in clinical isolates of Leishmania donovani. L eishmaniasis, or kala azar, is a group of diseases caused by a protozoan parasite of the genus Leishmania. Kala azar is a symptomatic infection of liver, spleen, and bone marrow. The global estimates for the incidence and prevalence of kala azar cases per year are 0.5 and 2.5 million, respectively (57). In India, visceral leishmaniasis (VL) has been reported in parts of West Bengal, Uttar Pradesh, and Bihar. It poses a major health problem in the state of Bihar, which accounts for nearly 90% of the total cases in India (51). Chemotherapy has proven to be the only effective way of controlling infections and is highly dependent upon antimonycontaining drugs, such as sodium stibogluconate (Pentostam). Amphotericin B (AmB) is used as the drug of choice when acquired drug resistance emerges for traditional antimony therapy, and nearly 64% of cases in regions of Bihar where VL is hyperendemic are now resistant to antimonials (28). Hexadecylphosphocholine (miltefosine) is the first orally administered drug for VL and the latest to enter the market. The dosing scheme of hexadecylphosphocholine is 100 mg/kg of body weight/day for 28 days in adults weighing Ն50 kg, 50 mg/kg/day in adults weighing Ͻ50 kg, and 2.5 mg/kg/day in children (maximum dose, 100 mg/day). Major concerns abou...

show abstract

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Purkait¹,

Kumar²,

Nandi

et al. 2012

Antimicrob Agents Chemother

273

251

View full text Add to dashboard Cite

show abstract

“…The data presented here establish for the first time that overexpression of an active TryP directly contributes to the multifactorial Sb(III) resistance mechanisms in Leishmania tarentolae. Our observations with Sb(III)-resistant L. tarentolae are broadly supported by the recent studies of Hsu and colleagues, who reported the overexpression of several components of both the cytosolic and mitochondrial tryparedoxin pathways in laboratory-generated, arsenite-resistant Leishmania amazonensis (17,21). TryPs form the backbone of parasite antioxidant defenses.…”

Section: Discussionsupporting

confidence: 87%

“…Interestingly, Southern analysis of genomic DNA isolated from wild-type, revertant, and resistant cells confirmed that in- An association between TryP and heavy metal resistance has previously been established. In recent studies, Lin and colleagues described the concomitant overexpression of cytosolic and mitochondrial TryP in laboratory-generated, arsenite-resistant Leishmania amazonensis (17,21). Arsenite-resistant Leishmania parasites are often found to be cross-resistant to Sb(III), and the mechanisms of resistance to both metalloids are believed to share many common features (12,14).…”

mentioning

confidence: 99%

Roles of Trypanothione S -Transferase and Tryparedoxin Peroxidase in Resistance to Antimonials

Wyllie

Vickers

Fairlamb

2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The clinical value of antimonial drugs, the mainstay therapy for leishmaniasis, is now threatened by the emergence of acquired drug resistance, and a comprehensive understanding of the underlying mechanisms is required. Using the model organism Leishmania tarentolae, we have examined the role of trypanothione S-transferase (TST) in trivalent antimony [Sb(III)] resistance. TST has S-transferase activity with substrates such as chlorodinitrobenzene as well as peroxidase activity with alkyl and aryl hydroperoxides but not with hydrogen peroxide. Although S-transferase activity and TST protein levels were unchanged in Sb(III)-sensitive and -resistant lines, rates of metabolism of hydrogen peroxide, t-butyl hydroperoxide, and cumene hydroperoxide were significantly increased. Elevated peroxidase activities were shown to be both trypanothione and tryparedoxin dependent and were associated with the overexpression of classical tryparedoxin peroxidase (TryP) in the cytosol of L. tarentolae. The role of TryP in Sb(III) resistance was verified by overexpression of the recombinant Leishmania major protein in Sb(III)-sensitive promastigotes. An approximate twofold increase in the level of TryP activity in this transgenic cell line was accompanied by a significant decrease in sensitivity to Sb(III) (twofold; P < 0.001). Overexpression of an enzymatically inactive TryP failed to result in Sb(III) resistance. This indicates that TryP-dependent resistance is not due to sequestration of Sb(III) and suggests that enhanced antioxidant defenses may well be a key feature of mechanisms of clinical resistance to antimonial drugs.

show abstract

“…Another group of highly abundant redox proteins, tryparedoxins, have diverse cell functions, such as peroxide metabolism, synthesis of deoxynucleotides, and regulation of mitochondrial DNA replication (19,40). The results from studies with peroxiredoxin-overexpressing Leishmania and Trypanosoma cruzi cells and double-stranded RNA interference studies with T. brucei show that peroxiredoxins have an important role in eliminating hydroperoxides and peroxynitrite (8,33,55). In eukaryotes, peroxiredoxins are considered to act as a regulator of H 2 O 2 -mediated intracellular signaling processes and not as general antioxidant devices.…”

mentioning

confidence: 99%

Overexpression of MitochondrialLeishmania majorAscorbate Peroxidase Enhances Tolerance to Oxidative Stress-Induced Programmed Cell Death and Protein Damage

et al. 2009

View full text Add to dashboard Cite

Distinct overexpression of cytosolic and mitochondrial tryparedoxin peroxidases results in preferential detoxification of different oxidants in arsenite-resistant Leishmania amazonensis with and without DNA amplification

Cited by 50 publications

References 40 publications

Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

Roles of Trypanothione S -Transferase and Tryparedoxin Peroxidase in Resistance to Antimonials

Overexpression of MitochondrialLeishmania majorAscorbate Peroxidase Enhances Tolerance to Oxidative Stress-Induced Programmed Cell Death and Protein Damage

Contact Info

Product

Resources

About