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Polyamine metabolism in Leishmania: from arginine to trypanothione

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Abstract

Polyamines (PAs) are essential metabolites in eukaryotes, participating in a variety of proliferative processes, and in trypanosomatid protozoa play an additional role in the synthesis of the critical thiol trypanothione. The PAs are synthesized by a metabolic process which involves arginase (ARG), which catalyzes the enzymatic hydrolysis of l-arginine (l-Arg) to l-ornithine and urea, and ornithine decarboxylase (ODC), which catalyzes the enzymatic decarboxylation of l-ornithine in putrescine. The S-adenosylmethionine decarboxylase (AdoMetDC) catalyzes the irreversible decarboxylation of S-adenosylmethionine (AdoMet), generating the decarboxylated S-adenosylmethionine (dAdoMet), which is a substrate, together with putrescine, for spermidine synthase (SpdS). Leishmania parasites and all the other members of the trypanosomatid family depend on spermidine for growth and survival. They can synthesize PAs and polyamine precursors, and also scavenge them from the microenvironment, using specific transporters. In addition, Trypanosomatids have a unique thiol-based metabolism, in which trypanothione (N1-N8-bis(glutathionyl)spermidine, T(SH)2) and trypanothione reductase (TR) replace many of the antioxidant and metabolic functions of the glutathione/glutathione reductase (GR) and thioredoxin/thioredoxin reductase (TrxR) systems present in the host. Trypanothione synthetase (TryS) and TR are necessary for the protozoa survival. Consequently, enzymes involved in spermidine synthesis and its utilization, i.e. ARG, ODC, AdoMetDC, SpdS and, in particular, TryS and TR, are promising targets for drug development.

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Abbreviations

AdoMet:

S-Adenosylmethionine

AdoMetDC:

S-Adenosylmethionine decarboxylase

APA:

3-Aminooxy-1-aminopropane

APC:

Amino acid-polyamine-organocation

APX:

Ascorbate peroxidase

ARG:

Arginase

CAT:

Cationic amino acid transporter

dAdoMet:

Decarboxylated S-adenosylmethionine

DFMO:

α-Difluoromethylornithine

eEF1B:

Eukaryotic translation elongation factor 1B

GR:

Glutathione reductase

GspS:

Glutathionyl-spermidine synthetase

l-Arg:

l-Arginine

MCF:

Mitochondrial carrier family

NO:

Nitric oxide

NOS:

Nitric oxide synthase

nsGPX:

Non selenium glutathione peroxidase-like enzyme

ODC:

Ornithine decarboxylase

PA:

Polyamine

PAO:

Polyamine oxidase

PLP:

Pyridoxal 5′-phosphate

PV:

Parasitophorous vacuole

ROS:

Reactive oxygen species

RNOS:

Reactive nitric oxide species

RR:

Ribonucleotide reductase

Spd:

Spermidine

SpdS:

Spermidine synthase

Spm:

Spermine

TDPX:

Tryparedoxin peroxidase

TR:

Trypanothione reductase

TrxR:

Thioredoxin reductase

TryS:

Trypanothione synthetase

T(SH)2 :

Trypanothione, or N1, N8-bis(glutathionyl)spermidine

TXN:

Tryparedoxin

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  1. Institute of Biology and Molecular Pathology, CNR, c/o Department of Biochemical Sciences, University “Sapienza”, P.le A. Moro 5, 00185, Rome, Italy

    Gianni Colotti & Andrea Ilari

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  1. Gianni Colotti
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  2. Andrea Ilari
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Correspondence to Gianni Colotti or Andrea Ilari.

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G. Colotti and A. Ilari contributed equally to the work.

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Colotti, G., Ilari, A. Polyamine metabolism in Leishmania: from arginine to trypanothione. Amino Acids 40, 269–285 (2011). https://doi.org/10.1007/s00726-010-0630-3

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