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Suzanne Jackowski - One of the best experts on this subject based on the ideXlab platform.
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A therapeutic approach to Pantothenate kinase associated neurodegeneration.
Nature communications, 2018Co-Authors: Lalit Kumar Sharma, Charles O. Rock, Matthew W. Frank, Chitra Subramanian, Mi-kyung Yun, Stephen W. White, Richard E. Lee, Suzanne JackowskiAbstract:Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to Pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the Pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.
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Correction of a genetic deficiency in Pantothenate kinase 1 using phosphoPantothenate replacement therapy.
Molecular genetics and metabolism, 2015Co-Authors: Stephen P. Zano, Charles O. Rock, Caroline Pate, Matthew W. Frank, Suzanne JackowskiAbstract:Coenzyme A (CoA) is a ubiquitous cofactor involved in numerous essential biochemical transformations, and along with its thioesters is a key regulator of intermediary metabolism. Pantothenate (vitamin B5) phosphorylation by Pantothenate kinase (PanK) is thought to control the rate of CoA production. Pantothenate kinase associated neurodegeneration is a hereditary disease that arises from mutations that inactivate the human PANK2 gene. Aryl phosphoramidate phosphoPantothenate derivatives were prepared to test the feasibility of using phosphoPantothenate replacement therapy to bypass the genetic deficiency in the Pank1(-/-) mouse model. The efficacies of candidate compounds were first compared by measuring the ability to increase CoA levels in Pank1(-/-) mouse embryo fibroblasts. Administration of selected candidate compounds to Pank1(-/-) mice corrected their deficiency in hepatic CoA. The PanK bypass was confirmed by the incorporation of intact phosphoPantothenate into CoA using triple-isotopically labeled compound. These results provide strong support for PanK as a master regulator of intracellular CoA and illustrate the feasibility of employing PanK bypass therapy to restore CoA levels in genetically deficient mice.
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biosynthesis of pantothenic acid and coenzyme a
EcoSal Plus, 2007Co-Authors: Roberta Leonardi, Suzanne JackowskiAbstract:Pantothenate is vitamin B5 and is the key precursor for the biosynthesis of coenzyme A (CoA), a universal and essential cofactor involved in a myriad of metabolic reactions, including the synthesis of phospholipids, the synthesis and degradation of fatty acids, and the operation of the tricarboxylic acid cycle. CoA is also the only source of the phosphopantetheine prosthetic group for enzymes that shuttle intermediates between the active sites of enzymes involved in fatty acid, nonribosomal peptide, and polyketide synthesis. Pantothenate can be synthesized de novo and/or transported into the cell through a Pantothenatepermease. Pantothenate uptake is essential for those organisms that lack the genes to synthesize this vitamin. The intracellular levels of CoA are controlled by the balance between synthesis and degradation. In particular, CoA is assembled in five enzymatic steps, starting from the phosphorylation of Pantothenate to phosphoPantothenatecatalyzed by Pantothenate kinase, the product of the coaA gene. In some bacteria, the production of phosphoPantothenate by Pantothenate kinase is the rate limiting and most regulated step in the biosynthetic pathway. CoA synthesis additionally networks with other vitamin-associated pathways, such as thiamine and folic acid.
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Prokaryotic Type II and Type III Pantothenate Kinases: The Same Monomer Fold Creates Dimers with Distinct Catalytic Properties.
Structure (London England : 1993), 2006Co-Authors: Bum Soo Hong, Suzanne Jackowski, Charles O. Rock, Yong-mei Zhang, Mi-kyung Yun, Stephen W. White, Heewon Park, Shigeru Chohnan, Roberta LeonardiAbstract:Three distinct isoforms of Pantothenate kinase (CoaA) in bacteria catalyze the first step in coenzyme A biosynthesis. The structures of the type II (Staphylococcus aureus, SaCoaA) and type III (Pseudomonas aeruginosa, PaCoaA) enzymes reveal that they assemble nearly identical subunits with actin-like folds into dimers that exhibit distinct biochemical properties. PaCoaA has a fully enclosed Pantothenate binding pocket and requires a monovalent cation to weakly bind ATP in an open cavity that does not interact with the adenine nucleotide. Pantothenate binds to an open pocket in SaCoaA that strongly binds ATP by using a classical P loop architecture coupled with specific interactions with the adenine moiety. The PaCoaA*Pan binary complex explains the resistance of bacteria possessing this isoform to the pantothenamide antibiotics, and the similarity between SaCoaA and human Pantothenate kinase 2 explains the molecular basis for the development of the neurodegenerative phenotype in three mutations in the human protein.
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Feedback regulation of murine Pantothenate kinase 3 by coenzyme A and coenzyme A thioesters.
The Journal of biological chemistry, 2005Co-Authors: Yong-mei Zhang, Charles O. Rock, Suzanne JackowskiAbstract:Pantothenate kinase catalyzes a key regulatory step in coenzyme A biosynthesis, and there are four mammalian genes that encode isoforms of this enzyme. Pantothenate kinase isoform PanK3 is highly related to the previously characterized PanK1beta isoform (79% identical, 91% similar), and these two almost identical proteins are expressed most highly in the same tissues. PanK1beta and PanK3 had very similar molecular sizes, oligomeric form, cytoplasmic cellular location, and kinetic constants for ATP and Pantothenate. However, these two PanK isoforms possessed distinct regulatory properties. PanK3 was significantly more sensitive to feedback regulation by acetyl-CoA (IC50 = 1 microm) than PanK1beta (IC50 = 10 microm), and PanK3 was stringently regulated by long-chain acyl-CoA (IC50 = 2 microm), whereas PanK1beta was not. Domain swapping experiments localized the difference in the two proteins to a 48-amino-acid domain, where they are the most divergent. Consistent with these more stringent regulatory properties, metabolic labeling experiments showed that coenzyme A (CoA) levels in cells overexpressing PanK3 were lower than in cells overexpressing an equivalent amount of PanK1beta. Thus, the distinct regulatory properties exhibited by the family of the Pantothenate kinases allowed the rate of CoA biosynthesis to be controlled by regulatory signals from CoA thioesters involved in different branches of intermediary metabolism.
Christina Spry - One of the best experts on this subject based on the ideXlab platform.
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Coenzyme A and Its Derivatives in Cellular Metabolism and Disease Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: the case for pantothenamides
2020Co-Authors: Kevin J Saliba, Christina SpryAbstract:Abstract Malaria kills more than half a million people each year. There is no vaccine, and recent reports suggest that resistance is developing to the antimalarial regimes currently recommended by the World Health Organization. New drugs are therefore needed to ensure malaria treatment options continue to be available. The intra-erythrocytic stage of the malaria parasite's life cycle is dependent on an extracellular supply of Pantothenate (vitamin B 5 ), the precursor of CoA (coenzyme A). It has been known for many years that proliferation of the parasite during this stage of its life cycle can be inhibited with Pantothenate analogues. We have shown recently that pantothenamides, a class of Pantothenate analogues with antibacterial activity, inhibit parasite proliferation at submicromolar concentrations and do so competitively with Pantothenate. These compounds, however, are degraded, and therefore rendered inactive, by the enzyme pantetheinase (vanin), which is present in serum. In the present mini-review, we discuss the two strategies that have been put forward to overcome pantetheinase-mediated degradation of pantothenamides. The strategies effectively provide an opportunity for pantothenamides to be tested in vivo. We also put forward our 'blueprint' for the further development of pantothenamides (and other Pantothenate analogues) as potential antimalarials
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mutations in the Pantothenate kinase of plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial Pantothenate analogues
PLOS Pathogens, 2018Co-Authors: Erick T Tjhin, Christina Spry, Leanne Barnard, Alan L Sewell, Annabelle Hoegl, Anna E Sexton, Ghizal Siddiqui, Vanessa M Howieson, Alexander G Maier, Darren J CreekAbstract:The malaria-causing blood stage of Plasmodium falciparum requires extracellular Pantothenate for proliferation. The parasite converts Pantothenate into coenzyme A (CoA) via five enzymes, the first being a Pantothenate kinase (PfPanK). Multiple antiplasmodial Pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial Pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different Pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes.
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structure activity analysis of cj 15 801 analogues that interact with plasmodium falciparum Pantothenate kinase and inhibit parasite proliferation
European Journal of Medicinal Chemistry, 2018Co-Authors: Christina Spry, Alan L Sewell, Yuliya Hering, Mathew V J Villa, Jonas Weber, Stephen J Hobson, Suzannah J Harnor, Sheraz Gul, Rodolfo MarquezAbstract:Abstract Survival of the human malaria parasite Plasmodium falciparum is dependent on Pantothenate (vitamin B5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of Pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting Pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing Pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum Pantothenate kinase (PfPanK)-catalyzed Pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity.
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mutations in the Pantothenate kinase of the malaria parasite p falciparum confer resistance or hypersensitivity to diverse Pantothenate analogues
bioRxiv, 2017Co-Authors: Erick T Tjhin, Christina Spry, Leanne Barnard, Alan L Sewell, Annabelle Hoegl, Anna E Sexton, Vanessa M Howieson, Alexander G Maier, Darren J Creek, Erick StraussAbstract:The malaria-causing blood stage of Plasmodium falciparum requires extracellular Pantothenate for proliferation. The parasite converts Pantothenate into coenzyme A (CoA) via five enzymes, the first being a Pantothenate kinase (PfPanK). Multiple antiplasmodial Pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial Pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different Pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes.
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antiplasmodial mode of action of pantothenamides Pantothenate kinase serves as a metabolic activator not as a target
ACS Infectious Diseases, 2017Co-Authors: Marianne De Villiers, Christina Spry, Cristiano Macuamule, Leanne Barnard, Gordon Wells, Kevin J Saliba, Erick StraussAbstract:N-Substituted pantothenamides (PanAms) are Pantothenate analogues with up to nanomolar potency against blood-stage Plasmodium falciparum (the most virulent species responsible for malaria). Although these compounds are known to target coenzyme A (CoA) biosynthesis and/or utilization, their exact mode of action (MoA) is still unknown. Importantly, PanAms that retain the natural β-alanine moiety are more potent than other variants, consistent with the involvement of processes that are selective for Pantothenate (the precursor of CoA) or its derivatives. The transport of Pantothenate and its phosphorylation by P. falciparum Pantothenate kinase (PfPanK, the first enzyme of CoA biosynthesis) are two such processes previously highlighted as potential targets for the PanAms’ antiplasmodial action. In this study, we investigated the effect of PanAms on these processes using their radiolabeled versions (synthesized here for the first time), which made possible the direct measurement of PanAm uptake by isolated blo...
Kevin J Saliba - One of the best experts on this subject based on the ideXlab platform.
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Coenzyme A and Its Derivatives in Cellular Metabolism and Disease Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: the case for pantothenamides
2020Co-Authors: Kevin J Saliba, Christina SpryAbstract:Abstract Malaria kills more than half a million people each year. There is no vaccine, and recent reports suggest that resistance is developing to the antimalarial regimes currently recommended by the World Health Organization. New drugs are therefore needed to ensure malaria treatment options continue to be available. The intra-erythrocytic stage of the malaria parasite's life cycle is dependent on an extracellular supply of Pantothenate (vitamin B 5 ), the precursor of CoA (coenzyme A). It has been known for many years that proliferation of the parasite during this stage of its life cycle can be inhibited with Pantothenate analogues. We have shown recently that pantothenamides, a class of Pantothenate analogues with antibacterial activity, inhibit parasite proliferation at submicromolar concentrations and do so competitively with Pantothenate. These compounds, however, are degraded, and therefore rendered inactive, by the enzyme pantetheinase (vanin), which is present in serum. In the present mini-review, we discuss the two strategies that have been put forward to overcome pantetheinase-mediated degradation of pantothenamides. The strategies effectively provide an opportunity for pantothenamides to be tested in vivo. We also put forward our 'blueprint' for the further development of pantothenamides (and other Pantothenate analogues) as potential antimalarials
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antiplasmodial mode of action of pantothenamides Pantothenate kinase serves as a metabolic activator not as a target
ACS Infectious Diseases, 2017Co-Authors: Marianne De Villiers, Christina Spry, Cristiano Macuamule, Leanne Barnard, Gordon Wells, Kevin J Saliba, Erick StraussAbstract:N-Substituted pantothenamides (PanAms) are Pantothenate analogues with up to nanomolar potency against blood-stage Plasmodium falciparum (the most virulent species responsible for malaria). Although these compounds are known to target coenzyme A (CoA) biosynthesis and/or utilization, their exact mode of action (MoA) is still unknown. Importantly, PanAms that retain the natural β-alanine moiety are more potent than other variants, consistent with the involvement of processes that are selective for Pantothenate (the precursor of CoA) or its derivatives. The transport of Pantothenate and its phosphorylation by P. falciparum Pantothenate kinase (PfPanK, the first enzyme of CoA biosynthesis) are two such processes previously highlighted as potential targets for the PanAms’ antiplasmodial action. In this study, we investigated the effect of PanAms on these processes using their radiolabeled versions (synthesized here for the first time), which made possible the direct measurement of PanAm uptake by isolated blo...
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Pantothenate utilization by plasmodium as a target for antimalarial chemotherapy
Infectious disorders drug targets, 2010Co-Authors: Christina Spry, Erick Strauss, D A Van Schalkwyk, Kevin J SalibaAbstract:In the absence of an effective vaccine against malaria suitable for widespread deployment, the control of this lethal infectious disease relies heavily on antimalarial chemotherapies. The most virulent of the parasites that cause malaria (Plasmodium falciparum) has, however, developed resistance to all antimalarial agents in clinical use, and there is a desperate need for new antimalarial agents that target previously unexploited parasite processes. P. falciparum requires an extracellular supply of Pantothenate to support its proliferation during the erythrocytic stage of its development in humans. This requirement highlights the mechanisms involved in the utilization (uptake and metabolism) of Pantothenate as potential targets for chemotherapeutic attack. Here we review the evidence demonstrating Pantothenate to be an essential nutrient for P. falciparum and data from studies investigating whether this parasite has the capacity to utilize exogenous supplies of the cofactor (coenzyme A; CoA) for which Pantothenate serves as a precursor. The results of recent studies aimed at characterizing the mechanisms by which Pantothenate is taken up by the P. falciparum-infected erythrocyte and intracellular parasite, and metabolized to CoA, are described. The unique properties that may be exploited to develop selective inhibitors of Pantothenate utilization by P. falciparum-infected erythrocytes are highlighted. The molecular identities of P. falciparum Pantothenate transporter(s) and CoA biosynthesis enzymes remain unconfirmed. We consider the possible identities, and emphasize the importance of generating these proteins in pure, functionally-active form. The tools currently available for identifying inhibitors of Pantothenate utilization that may be potent antiplasmodial agents are also discussed.
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h coupled Pantothenate transport in the intracellular malaria parasite
Journal of Biological Chemistry, 2001Co-Authors: Kevin J Saliba, Kiaran KirkAbstract:Abstract Pantothenate, the precursor of coenzyme A, is an essential nutrient for the intraerythrocytic stage of the malaria parasite Plasmodium falciparum. Pantothenate enters the malaria-infected erythrocyte via new permeation pathways induced by the parasite in the host cell membrane (Saliba, K. J., Horner, H. A., and Kirk, K. (1998) J. Biol. Chem. 273, 10190–10195). We show here that Pantothenate is taken up by the intracellular parasite via a novel H+-coupled transporter, quite different from the Na+-coupled transporters that mediate Pantothenate uptake into mammalian cells. The plasmodial H+:Pantothenate transporter has a low affinity for Pantothenate (K m ∼23 mm) and a stoichiometry of 1 H+:1 Pantothenate. It is inhibited by low concentrations of the bioflavonoid phloretin and the thiol-modifying agent p-chloromercuribenzene sulfonate. On entering the parasite, Pantothenate is phosphorylated (and thereby trapped) by an unusually high affinity Pantothenate kinase (K m ∼300 nm). The combination of H+-coupled transporter and kinase provides the parasite with an efficient, high affinity Pantothenate uptake system, which is distinct from that of the host and is therefore an attractive target for antimalarial chemotherapy.
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transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite plasmodium falciparum
Journal of Biological Chemistry, 1998Co-Authors: Kevin J Saliba, Heather A Horner, Kiaran KirkAbstract:The growth of the human malaria parasite,Plasmodium falciparum, within its host erythrocyte is reliant on the uptake of a number of essential nutrients from the extracellular medium. One of these is pantothenic acid, a water-soluble vitamin that is a precursor of coenzyme A. In this study we show that normal uninfected erythrocytes are impermeable to Pantothenate but that the vitamin is taken up rapidly into malaria-infected cells via a transport pathway that has the characteristics (furosemide sensitivity, nonsaturability) of previously characterized, broad specificity permeation pathways induced by the intracellular parasite in the host cell membrane. The transport of Pantothenate therefore constitutes a critical physiological role for these pathways. Inside the parasitized cell Pantothenate undergoes phosphorylation, the first step in its conversion to coenzyme A. Parasites within saponin-permeabilized erythrocytes were shown to take up and phosphorylate Pantothenate, consistent with the intracellular parasite having both a Pantothenate transporter and a Pantothenate kinase. Comparisons of the rate of phosphorylation of Pantothenate by lysates prepared from uninfected and infected erythrocytes revealed that the Pantothenate kinase activity of the P. falciparum trophozoite is some 10-fold higher than that of its host cell and that most, if not all, of the phosphorylation of Pantothenate within the malaria-infected cell occurs within the intracellular parasite. These results contrast with those of previous studies in which it was proposed that the avian malaria parasite Plasmodium lophurae lacks Pantothenate kinase (as well as the other enzymes for the synthesis of coenzyme A) and is reliant upon the uptake of preformed coenzyme A from the host cell cytosol.
Rodolfo Marquez - One of the best experts on this subject based on the ideXlab platform.
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structure activity analysis of cj 15 801 analogues that interact with plasmodium falciparum Pantothenate kinase and inhibit parasite proliferation
European Journal of Medicinal Chemistry, 2018Co-Authors: Christina Spry, Alan L Sewell, Yuliya Hering, Mathew V J Villa, Jonas Weber, Stephen J Hobson, Suzannah J Harnor, Sheraz Gul, Rodolfo MarquezAbstract:Abstract Survival of the human malaria parasite Plasmodium falciparum is dependent on Pantothenate (vitamin B5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of Pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting Pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing Pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum Pantothenate kinase (PfPanK)-catalyzed Pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity.
Kiaran Kirk - One of the best experts on this subject based on the ideXlab platform.
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h coupled Pantothenate transport in the intracellular malaria parasite
Journal of Biological Chemistry, 2001Co-Authors: Kevin J Saliba, Kiaran KirkAbstract:Abstract Pantothenate, the precursor of coenzyme A, is an essential nutrient for the intraerythrocytic stage of the malaria parasite Plasmodium falciparum. Pantothenate enters the malaria-infected erythrocyte via new permeation pathways induced by the parasite in the host cell membrane (Saliba, K. J., Horner, H. A., and Kirk, K. (1998) J. Biol. Chem. 273, 10190–10195). We show here that Pantothenate is taken up by the intracellular parasite via a novel H+-coupled transporter, quite different from the Na+-coupled transporters that mediate Pantothenate uptake into mammalian cells. The plasmodial H+:Pantothenate transporter has a low affinity for Pantothenate (K m ∼23 mm) and a stoichiometry of 1 H+:1 Pantothenate. It is inhibited by low concentrations of the bioflavonoid phloretin and the thiol-modifying agent p-chloromercuribenzene sulfonate. On entering the parasite, Pantothenate is phosphorylated (and thereby trapped) by an unusually high affinity Pantothenate kinase (K m ∼300 nm). The combination of H+-coupled transporter and kinase provides the parasite with an efficient, high affinity Pantothenate uptake system, which is distinct from that of the host and is therefore an attractive target for antimalarial chemotherapy.
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transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite plasmodium falciparum
Journal of Biological Chemistry, 1998Co-Authors: Kevin J Saliba, Heather A Horner, Kiaran KirkAbstract:The growth of the human malaria parasite,Plasmodium falciparum, within its host erythrocyte is reliant on the uptake of a number of essential nutrients from the extracellular medium. One of these is pantothenic acid, a water-soluble vitamin that is a precursor of coenzyme A. In this study we show that normal uninfected erythrocytes are impermeable to Pantothenate but that the vitamin is taken up rapidly into malaria-infected cells via a transport pathway that has the characteristics (furosemide sensitivity, nonsaturability) of previously characterized, broad specificity permeation pathways induced by the intracellular parasite in the host cell membrane. The transport of Pantothenate therefore constitutes a critical physiological role for these pathways. Inside the parasitized cell Pantothenate undergoes phosphorylation, the first step in its conversion to coenzyme A. Parasites within saponin-permeabilized erythrocytes were shown to take up and phosphorylate Pantothenate, consistent with the intracellular parasite having both a Pantothenate transporter and a Pantothenate kinase. Comparisons of the rate of phosphorylation of Pantothenate by lysates prepared from uninfected and infected erythrocytes revealed that the Pantothenate kinase activity of the P. falciparum trophozoite is some 10-fold higher than that of its host cell and that most, if not all, of the phosphorylation of Pantothenate within the malaria-infected cell occurs within the intracellular parasite. These results contrast with those of previous studies in which it was proposed that the avian malaria parasite Plasmodium lophurae lacks Pantothenate kinase (as well as the other enzymes for the synthesis of coenzyme A) and is reliant upon the uptake of preformed coenzyme A from the host cell cytosol.