Pantothenic Acid Biosynthesis in the Parasite Toxoplasma gondii: a Target for Chemotherapy

Mageed, Sarmad N.; Cunningham, Fraser; Hung, Alvin W.; Silvestre, H.L.; Wen, Shulin; Blundell, Tom L.; Abell, Chris; McConkey, Glenn A.

doi:10.1128/aac.02640-14

Cited by 14 publications

(15 citation statements)

References 50 publications

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“…In plants, fungi, and bacteria, pantothenate is synthesized de novo from pyruvate via a conserved three-enzyme pathway; 133 however, animals must acquire pantothenate through their diet or from gastrointestinal bacteria. By searching the T. gondii genome for orthologs of the pantothenate synthesis pathway, Mageed et al 134 identified three conserved genes coding for de novo pantothenate biosynthesis in T. gondii . Among these genes is the terminal enzyme in the pathway, pantothenate synthetase that converts pantoate to pantothenate.…”

Section: Pantothenate Synthetase Inhibitorsmentioning

confidence: 99%

Drugs in development for toxoplasmosis: advances, challenges, and current status

Alday

Doggett

2017

DDDT

265

243

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Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

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Section: Pantothenate Synthetase Inhibitorsmentioning

confidence: 99%

Drugs in development for toxoplasmosis: advances, challenges, and current status

Alday

Doggett

2017

DDDT

265

243

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“…In contrast to these co-factors, tachyzoites appear unable to scavenge pantothenate, a precursor for coenzyme A, in significant amounts. Instead, they possess the entire synthesis machinery for pantothenate 44 and parasite growth is sensitive to its pharmacological inhibition.…”

Section: Ingredients To Make a Tachyzoitementioning

confidence: 99%

Metabolic interactions between Toxoplasma gondii and its host

Blume

Seeber

2018

F1000Res

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Toxoplasma gondii is an obligate intracellular parasite belonging to the phylum Apicomplexa that infects all warm-blooded animals, including humans. T. gondii can replicate in every nucleated host cell by orchestrating metabolic interactions to derive crucial nutrients. In this review, we summarize the current status of known metabolic interactions of T. gondii with its host cell and discuss open questions and promising experimental approaches that will allow further dissection of the host–parasite interface and discovery of ways to efficiently target both tachyzoite and bradyzoite forms of T. gondii, which are associated with acute and chronic infection, respectively.

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“…Interestingly, T. gondii encodes the pathway in two sequences conserved within the coccidians, which include Hammondia, Neospora, Besnoitia, Cyclospora, and Eimeria genera. The PAN synthesis pathway has been partially characterized in T. gondii, and its essentiality has been proposed based on the use of chemical inhibitors (51). However, the tested drugs had been developed for Mycobacterium tuberculosis homologue (panC), and off-target effects cannot be excluded.…”

Section: Vitamin Bmentioning

confidence: 99%

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Krishnan¹,

Kloehn²,

Lunghi³

et al. 2019

J. Biol. Chem.

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The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection.

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Pantothenic Acid Biosynthesis in the Parasite Toxoplasma gondii: a Target for Chemotherapy

Cited by 14 publications

References 50 publications

Drugs in development for toxoplasmosis: advances, challenges, and current status

Drugs in development for toxoplasmosis: advances, challenges, and current status

Metabolic interactions between Toxoplasma gondii and its host

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

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