Interference of the exclusive purine scavenge pathway of Leishmania

Unlike mammalian cells, all protozoan parasites studied to date are unable to synthesize the purine ring de novo.111,112 Instead, a unique purine salvage strategy is evolved by the parasites, which is critical for its survival. The first step of the salvage process of Leishmania donovani is the translocation of preformed purines, mediated by two high-affinity nucleoside transporters, LdNT1 and LdNT2, located on the parasites' surface membrane.113,114

The uptake of a trivalent arsenical drug (an analogue of antimony) is regulated by a P2 nucleoside transporter in Trypanosoma brucei and resistance to the melarsen drugs (organoarsenic drugs for the treatment of sleeping sickness - melarsen oxide, p-(4,6-diamino-s-triazin-2-yl)aminophenylarsenoxide) is related to alterations in P2 transporter.115 As other anti-leishmanial agents such as the purine analogues allopurinol riboside were also manipulated by this specific transporter,116 a selective interference with this novel salvage pathway, which is the fundamental biochemical difference between parasite and host, may be one of the mechanisms of action of SbV drugs. Direct interactions of SbV with nucleosides under acidic conditions (pH ~5) have been reported117 and the uptake of the drug may be mediated by nucleosides.

Guanosine diphosphate-mannose is the key monosaccharide for protein and lipid glycoconjugation in mannose-activated pathway. A large amount of unusual mannose-rich cell surface associated and secreted glycoconjugates is produced in Leishmania, including lipophosphoglycan (LPG), proteophospho-glycans (PPGs) and glucoinositolphospholipids (GIPLs), depending on the availability of GDP-mannose. GDP-mannose pyrophosphorylase (GDPMP)

Table 23.3 Biological features and therapeutic aspects of As, Sb and Bi15

Arsenic

Antimony

Bismuth

Treatment for

Sleeping sickness,

Parasite infection

Ulcer, Helicobacter

Leukemia

(Leishmania)

pylori infection

Human

AsV (60%), As111

SbV (5%), Sb111

RBC (0.5%)

absorption

(~80-100%)

(5%)

Metabolism

AsV ! As111 !

SbV ! Sb111 !

Bi111 ! thiol

MMA

thiol conjugate

conjugate

Excretion

Urine

80-95% urine

95% via urine

with within 6 h

Biological

Arsenate

T(SH)2? Arsc?

/

reductant

reductase (ArsC)

Extent of

>60%

~5-10%

/

reduction

Cellular uptake

AsV, phosphate

SbV? Sb111, GlpF

Transferrin,

inorganic

citrate

transporter (PiT)

As111, GlpF

Cellular excretion

As111, ArsAB

Sb111, ArsAB

MT?

ATPase pump,

ATPase pump,

MT?

MT?

Thiol affinity

AsV, low As111,

SbV, low Sb111,

Bi111, High

medium

medium high

Toxicity

AsV (high)

SbV (low)

Bi111 (low)

As111 (high)

Sb111 (medium)

is the central enzyme in the formation of GDP-mannose.118 Disruption of the mannose-activated glycoconjugate synthesis by deletion of the corresponding GDPMP gene in L. mexicana resulted in the loss of the ability to infect macrophages.119 The virulence character demonstrated that targeting the GDP-mannose biosynthesis pathway might be an effective way to control Leishmania infection. The possible mechanisms and resistance of antimony agents in Leishmania are summarized in Table 23.3 and Figure 23.6.

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