title: Pantothenic acid biosynthesis in the parasite Toxoplasma gondii: a target for chemotherapy.
abstract: Toxoplasma gondii is a major food pathogen and neglected parasitic infection that causes eye disease, birth defects, and fetal abortion and plays a role as an opportunistic infection in AIDS. In this study, we investigated pantothenic acid (vitamin B5) biosynthesis in T. gondii. Genes encoding the full repertoire of enzymes for pantothenate synthesis and subsequent metabolism to coenzyme A were identified and are expressed in T. gondii. A panel of inhibitors developed to target Mycobacterium tuberculosis pantothenate synthetase were tested and found to exhibit a range of values for inhibition of T. gondii growth. Two inhibitors exhibited lower effective concentrations than the currently used toxoplasmosis drug pyrimethamine. The inhibition was specific for the pantothenate pathway, as the effect of the pantothenate synthetase inhibitors was abrogated by supplementation with pantothenate. Hence, T. gondii encodes and expresses the enzymes for pantothenate synthesis, and this pathway is essential for parasite growth. These promising findings increase our understanding of growth and metabolism in this important parasite and highlight pantothenate synthetase as a new drug target.
authors: Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
authors: Sarmad N
authors: SN
authors: Mageed
authors: Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
authors: Fraser
authors: F
authors: Cunningham
authors: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Alvin Wei
authors: AW
authors: Hung
authors: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Hernani Leonardo
authors: HL
authors: Silvestre
authors: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Shijun
authors: S
authors: Wen
authors: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Tom L
authors: TL
authors: Blundell
authors: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Chris
authors: C
authors: Abell
authors: Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom g.a.mcconkey@leeds.ac.uk.
authors: Glenn A
authors: GA
authors: McConkey
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D003065:Coenzyme A / Q000096:biosynthesis; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D009894:Opportunistic Infections / Q000188:drug therapy; D010205:Pantothenic Acid / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D016415:Sequence Alignment; D014122:Toxoplasma / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D010205:Pantothenic Acid; D010453:Peptide Synthases; C022318:pantothenate synthetase; D003065:Coenzyme A