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Amino Acids

, Volume 40, Issue 2, pp 269–285 | Cite as

Polyamine metabolism in Leishmania: from arginine to trypanothione

  • Gianni ColottiEmail author
  • Andrea IlariEmail author
Review Article

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.

Keywords

Polyamines Leishmania Arginine Trypanothione Redox metabolism Drug targets 

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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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Institute of Biology and Molecular Pathology, CNR, c/o Department of Biochemical SciencesUniversity “Sapienza”RomeItaly

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