Research article summary (published 23 Apr 2009):

PTR1-dependent synthesis of tetrahydrobiopterin contributes to oxidant susceptibility in the trypanosomatid protozoan parasite Leishmania major.

Full Abstract

Leishmania must survive oxidative stress, but lack many classical antioxidant enzymes and rely heavily on trypanothione-dependent pathways. We used forward genetic screens to recover loci mediating oxidant resistance via overexpression in Leishmania major, which identified pteridine reductase 1 (PTR1). Comparisons of isogenic lines showed ptr1 (-) null mutants were 18-fold more sensitive to H(2)O(2) than PTR1-overproducing lines, and significant three- to fivefold differences were seen with a broad panel of oxidant-inducing agents. The toxicities of simple nitric oxide generators and other drug classes (except antifolates) were unaffected by PTR1 levels. H(2)O(2) susceptibility could be modulated by exogenous biopterin but not folate, in a PTR1- but not dihydrofolate reductase-dependent manner, implicating H(4)B metabolism specifically. Neither H(2)O(2) consumption nor the level of intracellular oxidative stress was affected by PTR1 levels. Coupled with the fact that reduced pteridines are at least 100-fold less abundant than cellular thiols, these data argue strongly that reduced pteridines act through a mechanism other than scavenging. The ability of unconjugated pteridines to counter oxidative stress has implications to infectivity and response to chemotherapy. Since the intracellular pteridine levels of Leishmania can be readily manipulated, these organisms offer a powerful setting for the dissection of pteridine-dependent oxidant susceptibility in higher eukaryotes.

Author information

Author/s: Nare, Bakela (B); Garraway, Levi A (LA); Vickers, Tim J (TJ); Beverley, Stephen M (SM);

Affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Grants: AI21903 (Agency:NIAID NIH HHS) ; R01 AI021903-25A1 (Agency:NIAID NIH HHS) ; R01 AI029646-18 (Agency:NIAID NIH HHS) ; R01 AI029646-19 (Agency:NIAID NIH HHS) ; R01 AI031078-17 (Agency:NIAID NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Current genetics (Curr Genet), published in United States. (Language: eng)

Reference: 2009-Jun; vol 55 (issue 3) : pp 287-99

Dates: Created 2009/06/08; Completed 2009/09/28; Revised 2009/10/12;

PMID: 19396443, status: MEDLINE (last retrieved date: 10/13/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

External Links for this article
(including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.

MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals Biopterin - analogs & derivatives; biosynthesis; pharmacology Drug Resistance - genetics Folic Acid - metabolism Hydrogen Peroxide - pharmacology Leishmania major - drug effects; genetics; metabolism Methylnitronitrosoguanidine - pharmacology Molsidomine - analogs & derivatives; pharmacology Multienzyme Complexes - metabolism

Mutation Nitric Oxide Donors - pharmacology Nitroso Compounds - pharmacology Oxidants - pharmacology Oxidoreductases - genetics; metabolism Protozoan Proteins - genetics; metabolism Pteridines - metabolism Tetrahydrofolate Dehydrogenase - metabolism Thymidylate Synthase - metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Multienzyme Complexes (0) ; Nitric Oxide Donors (0) ; Nitroso Compounds (0) ; Oxidants (0) ; Protozoan Proteins (0) ; Pteridines (0) ; thymidylate synthase-dihydrofolate reductase (0) ; 5,6,7,8-tetrahydrobiopterin (17528-72-2) ; Biopterin (22150-76-1) ; Molsidomine (25717-80-0) ; 3-morpholino-sydnonimine (33876-97-0) ; Folic Acid (59-30-3) ; Methylnitronitrosoguanidine (70-25-7) ; S-nitrosopenicillamine (73466-15-6) ; Hydrogen Peroxide (7722-84-1) ; Oxidoreductases (EC 1.-) ; pteridine reductase (EC 1.1.1.253) ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Thymidylate Synthase (EC 2.1.1.45)

Related articles

These are the most related articles currently in our database:

• The roles of pteridine reductase 1 and dihydrofolate reductase-thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major. 21 May 1997
• Characterization of quinonoid-dihydropteridine reductase (QDPR) from the lower eukaryote Leishmania major. 29 Jul 2002
• Pteridine salvage throughout the Leishmania infectious cycle: implications for antifolate chemotherapy. 4 Apr 2001
• Explaining an unusually fast parasitic enzyme: folate tail-binding residues dictate substrate positioning and catalysis in Cryptosporidium hominis thymidylate synthase. 31 Jul 2008
• Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major. 29 Aug 2003
• Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. 30 Aug 1999
• Phenolic acids protect low density lipoproteins from peroxynitrite-mediated modification in vitro. 30 Dec 1999
• Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. 16 Jul 2008
• PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. 20 Nov 1994
• Nitric oxide activation of TrkB through peroxynitrite. 7 Nov 2000

See 100+ related articles.

Related Article Map

Legend: - FREE Full text Article. - Abstract only. - Title only. More help.

See a larger map of 100+ related articles.