title: A role for adenine nucleotides in the sensing mechanism to purine starvation in Leishmania donovani.
abstract: Purine salvage by Leishmania is an obligatory nutritional process that impacts both cell viability and growth. Previously, we have demonstrated that the removal of purines in culture provokes significant metabolic changes that enable Leishmania to survive prolonged periods of purine starvation. In order to understand how Leishmania sense and respond to changes in their purine environment, we have exploited several purine pathway mutants, some in which adenine and guanine nucleotide metabolism is uncoupled. While wild type parasites grow in any one of a variety of naturally occurring purines, the proliferation of these purine pathway mutants requires specific types or combinations of exogenous purines. By culturing purine pathway mutants in high levels of extracellular purines that are either permissive or non-permissive for growth and monitoring for previously defined markers of the adaptive response to purine starvation, we determined that adaptation arises from a surveillance of intracellular purine nucleotide pools rather than from a direct sensing of the extracellular purine content of the environment. Specifically, our data suggest that perturbation of intracellular adenine-containing nucleotide pools provides a crucial signal for inducing the metabolic changes necessary for the long-term survival of Leishmania in a purine-scarce environment.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
authors.forename: Jessica L
authors.identifier: 0000-0003-4989-3869
authors.initials: JL
authors.lastname: Martin
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Yates
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Boitz
authors.affiliation: Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Koop
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
authors.forename: Audrey L
authors.initials: AL
authors.lastname: Fulwiler
authors.affiliation: Department of Biochemistry and Virginia Tech Center for Drug Discovery, M/C 0308, Virginia, Tech, Blacksburg, VA, 24061, USA.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Cassera
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
authors.forename: Buddy
authors.initials: B
authors.lastname: Ullman
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Carter
mesh_terms: D000225:Adenine / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism*; D006147:Guanine / Q000378:metabolism; D006150:Guanine Nucleotides / Q000378:metabolism; D007893:Leishmania donovani / Q000378:metabolism*; D011685:Purine Nucleotides / Q000378:metabolism; D011687:Purines / Q000737:chemistry / Q000378:metabolism*; D013217:Starvation
chemical_list: D000227:Adenine Nucleotides; D006150:Guanine Nucleotides; D011685:Purine Nucleotides; D011687:Purines; D006147:Guanine; D000225:Adenine; C030985:purine