2.7.1.33: pantothenate kinase
This is an abbreviated version!
For detailed information about pantothenate kinase, go to the full flat file.
Word Map on EC 2.7.1.33
-
2.7.1.33
-
neurodegeneration
-
kinase-associated
-
panks
-
sign
-
dystonia
-
ganglia
-
hallervorden-spatz
-
extrapyramidal
-
parkinsonism
-
eye-of-the-tiger
-
pla2g6
-
phosphopantothenate
-
dysarthria
-
tiger
-
neuroaxonal
-
phosphopantetheine
-
hypointensity
-
medicine
-
4'-phosphopantothenate
-
pigmentary
-
pantothenamide
-
bradykinesia
-
synthesis
-
atp13a2
-
4'-phosphopantetheine
-
pantethine
-
drug development
-
neuroferritinopathy
-
choreoathetosis
-
phosphopantothenoylcysteine
- 2.7.1.33
- neurodegeneration
-
kinase-associated
-
panks
- sign
- dystonia
- ganglia
- hallervorden-spatz
-
extrapyramidal
- parkinsonism
-
eye-of-the-tiger
- pla2g6
- phosphopantothenate
- dysarthria
- tiger
-
neuroaxonal
- phosphopantetheine
-
hypointensity
- medicine
- 4'-phosphopantothenate
-
pigmentary
- pantothenamide
-
bradykinesia
- synthesis
-
atp13a2
- 4'-phosphopantetheine
- pantethine
- drug development
-
neuroferritinopathy
-
choreoathetosis
-
phosphopantothenoylcysteine
Reaction
Synonyms
4-phosphopantoate, BaPanK, Cab1, Cab1p, CoaA, coaW, CoaX, D-pantothenate kinase, EhPAnK, fumble, hPanK, hPanK1, hPANK2, hPanK3, hPanK4, HpPanK-III, HsPANK3, HsPANK4, kinase, pantothenate (phosphorylating), More, mPank, mPank1, mPanK2, mPanK3, MtCoaA, MtPanK, PAK, PanK, PanK-III, PanK1, PanK1alpha, PanK1b, PanK2, PanK3, PanK4, PanKBa, pantothenate kinase, pantothenate kinase 1, pantothenate kinase 2, pantothenate kinase 3, pantothenate kinase 4, pantothenate kinase-2, pantothenic acid kinase, PfPanK, Pfpank1, PoK, rPanK4, Rts protein
ECTree
Advanced search results
General Information
General Information on EC 2.7.1.33 - pantothenate kinase
Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
evolution
malfunction
metabolism
physiological function
additional information
comparison of MtPanK with the Escherichia coli enzyme EcPanK, overview. Despite the high sequence identity (52%) between EcPanK and MtPanK, the two enzymes differ in many respects, crystal structure comparison. While EcPanK is specific for ATP, MtPanK exhibits dual specificity and can make use of ATP as well as GTP for phosphorylating pantothenic acid. CoA binds nearly 40% more tightly to MtPanK than to EcPanK
evolution
isozyme PANK3 belongs to the ASKHA kinase superfamily, which typically uses either an Asp or Glu residue as the catalytic base to activate the substrate hydroxyl for attack on the gamma-phosphate of ATP
evolution
isozyme PANK3 belongs to the ASKHA kinase superfamily, which typically uses either an Asp or Glu residue as the catalytic base to activate the substrate hydroxyl for attack on the gamma-phosphate of ATP. Glu138 appears to be the logical candidate for the catalytic base
evolution
the human genome encodes three well-characterized and nearly identical pantothenate kinases (PANK1-3) plus a putative bifunctional protein (PANK4) with a predicted amino-terminal pantothenate kinase domain fused to a carboxy-terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). All amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity. Human PANK4 is a pseudo-pantothenate kinase, a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. Evolutionary history of PANK, phylogenetic analysis, overview
evolution
the human genome encodes three well-characterized and nearly identical pantothenate kinases (PANK1-3) plus a putative bifunctional protein (PANK4) with a predicted N-terminal pantothenate kinase domain fused to a C-terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). All amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity. Human PANK4 is a pseudo-pantothenate kinase, a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. Evolutionary history of PANK, overview
evolution
-
comparison of MtPanK with the Escherichia coli enzyme EcPanK, overview. Despite the high sequence identity (52%) between EcPanK and MtPanK, the two enzymes differ in many respects, crystal structure comparison. While EcPanK is specific for ATP, MtPanK exhibits dual specificity and can make use of ATP as well as GTP for phosphorylating pantothenic acid. CoA binds nearly 40% more tightly to MtPanK than to EcPanK
-
evolution
-
comparison of MtPanK with the Escherichia coli enzyme EcPanK, overview. Despite the high sequence identity (52%) between EcPanK and MtPanK, the two enzymes differ in many respects, crystal structure comparison. While EcPanK is specific for ATP, MtPanK exhibits dual specificity and can make use of ATP as well as GTP for phosphorylating pantothenic acid. CoA binds nearly 40% more tightly to MtPanK than to EcPanK
-
malfunction
-
pantothenate kinase-associated neurodegeneration, formerly known as Hallervorden-Spatz syndrome
malfunction
-
flies carrying a fumble loss-of-function allele have a 3fold increase in total zinc levels per dry weight when compared to control strains, but no change in total iron, copper or manganese levels
malfunction
-
the elimination of PanK1 reduces hepatic CoA levels. Pank1-deficient mice become hypoglycemic during a fast due to impaired gluconeogenesis
malfunction
altered pantothenate utilization dramatically alters the susceptibility of yeast cells to ergosterol biosynthesis inhibitors. Inhibition of pantothenic acid utilization synergizes with the activity of the ergosterol molecule-targeting antifungal amphotericin B and antagonizes that of the ergosterol pathway-targeting antifungal drug terbinafine. Inhibition of pantothenate utilization results in reduced susceptibility to terbinafine and enhanced susceptibility to amphotericin B. Inhibition of Cab1p activity results in reduced squalene and lanosterol levels
malfunction
epigenetic gene silencing of PanK resulting in a significant reduction of PanK activity, intracellular CoA concentrations, and growth retardation in vitro, reinforcing the importance of this gene in Entamoeba histolytica
malfunction
human PANK3 is inactivated by mutations Glu138Val and Arg207Trp
malfunction
human PANK4 is a pseudo-pantothenate kinase, a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. Pank4 encodes Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity
malfunction
mutant Pank1-/-Pank2-/- double knock-out mice are unable to metabolize fats and ketones resulting in early postnatal death, and Pank1-/-Pank3-/- and Pank2-/- Pank-/- double knock-out mice are both embryonic lethal. A chemical knockout of all pantothenate kinases in adult mice results in an 80% reduction in hepatic CoA levels and death within days
malfunction
mutant Pank1-/-Pank2-/- double knock-out mice are unable to metabolize fats and ketones resulting in early postnatal death, and Pank1-/-Pank3-/- and Pank2-/- Pank-/-x03 double knock-out mice are both embryonic lethal. A chemical knockout of all pantothenate kinases in adult mice results in an 80% reduction in hepatic CoA levels and death within days
malfunction
mutant Pank1-/-Pank2-/- double knock-out mice are unable to metabolize fats and ketones resulting in early postnatal death, and Pank1-/-Pank3-/- and Pank2-/-Pank3-/- double knock-out mice are both embryonic lethal. A chemical knockout of all pantothenate kinases in adult mice results in an 80% reduction in hepatic CoA levels and death within days
malfunction
mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues. Pfpank1 mutations mediate parasite resistance to PanOH and CJ-15,801. Parasites pressured with pantothenol or (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid (CJ-15,801) become resistant to these antiplasmodial pantothenate analogues. Whole-genome sequencing reveals 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. Different pantothenate analogue classes have different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes
malfunction
structure-activity analysis of (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid (CJ-15,801) analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation. The 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. The antiplasmodial potency of CJ-15,801 analogues, that retain the R-pantoyl and trans-substituted enamide moieties, correlates with inhibition of Plasmodium falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation
malfunction
A0A167Z3Z6
the potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) exhibit inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. The mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. Molecular interactions responsible for PanAm inhibitory activity, overview. The PanAms are phosphorylated by SaPanKII but remain bound at the active site, SaPanKII inhibition occurs via a delay in product release
malfunction
-
altered pantothenate utilization dramatically alters the susceptibility of yeast cells to ergosterol biosynthesis inhibitors. Inhibition of pantothenic acid utilization synergizes with the activity of the ergosterol molecule-targeting antifungal amphotericin B and antagonizes that of the ergosterol pathway-targeting antifungal drug terbinafine. Inhibition of pantothenate utilization results in reduced susceptibility to terbinafine and enhanced susceptibility to amphotericin B. Inhibition of Cab1p activity results in reduced squalene and lanosterol levels
-
malfunction
-
the potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) exhibit inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. The mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. Molecular interactions responsible for PanAm inhibitory activity, overview. The PanAms are phosphorylated by SaPanKII but remain bound at the active site, SaPanKII inhibition occurs via a delay in product release
-
pantothenate kinase catalyzes the rate-controlling step in coenzyme A biosynthesis
metabolism
A0A167Z3Z6
CoA biosynthesis and salvage pathways, overview. The Staphylococcus aureus atypical type II pantothenate kinase (SaPanKII) is active in bothe pathways
metabolism
detailed metabolic pathway from pantothenate to ergosterol involving enzyme Cab1, overview
metabolism
four key enzymes are involved in the CoA pathway: pantothenate kinase (PanK, EC 2.7.1.33), bifunctional phosphopantothenate-cysteine ligase/decarboxylase (PPCS-PPCDC), phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK)
metabolism
PanK is the rate-limiting enzyme for CoA synthesis in Saccharomyces cerevisiae, acetyl-CoA metabolism and associated naringenin synthesis pathway overview
metabolism
the biosynthesis of CoA consists of five enzymatically catalysed steps, the first of which involves the conversion of vitamin B5 (pantothenate) to 4'-phosphopantothenate by ATP-mediated phosphorylation carried out by pantothenate kinase
metabolism
-
PanK is the rate-limiting enzyme for CoA synthesis in Saccharomyces cerevisiae, acetyl-CoA metabolism and associated naringenin synthesis pathway overview
-
metabolism
-
PanK is the rate-limiting enzyme for CoA synthesis in Saccharomyces cerevisiae, acetyl-CoA metabolism and associated naringenin synthesis pathway overview
-
metabolism
-
detailed metabolic pathway from pantothenate to ergosterol involving enzyme Cab1, overview
-
metabolism
-
the biosynthesis of CoA consists of five enzymatically catalysed steps, the first of which involves the conversion of vitamin B5 (pantothenate) to 4'-phosphopantothenate by ATP-mediated phosphorylation carried out by pantothenate kinase
-
metabolism
-
the biosynthesis of CoA consists of five enzymatically catalysed steps, the first of which involves the conversion of vitamin B5 (pantothenate) to 4'-phosphopantothenate by ATP-mediated phosphorylation carried out by pantothenate kinase
-
metabolism
-
CoA biosynthesis and salvage pathways, overview. The Staphylococcus aureus atypical type II pantothenate kinase (SaPanKII) is active in bothe pathways
-
-
CoaA is essential for survival of Mycobacterium tuberculosis. The coax gene is unable to complement the loss of gene coaA. CoaX lacks pantothenate kinase activity in vitro and is not required for survival in macrophages and mice
physiological function
-
pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state
physiological function
allosteric regulation of mammalian pantothenate kinase. Pantothenate kinase is the master regulator of CoA biosynthesis and is feedback-inhibited by acetyl-CoA
physiological function
allosteric regulation of mammalian pantothenate kinase. Pantothenate kinase is the master regulator of CoA biosynthesis and is feedback-inhibited by acetyl-CoA
physiological function
pantothenate kinase generates 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) biosynthesis. Critical roles of Glu138 and Arg207 in HsPANK3
physiological function
pantothenate kinase generates 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) biosynthesis. Isozyme PanK4 is a putative bifunctional protein with a predicted amino-terminal pantothenate kinase domain fused to a carboxy-terminal phosphatase domain. HsPANK4 has reduced kinase activity prior to the catalytic residue substitutions in amniotes. Human PANK4 is a pseudo-pantothenate kinase, a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi
physiological function
pantothenate, the substrate for PanK and precursor for CoA, is directly related with acetyl-CoA biosynthesis in Saccharomyces cerevisiae. PanK is the rate-limiting step for CoA synthesis and pantothenate supplement helps to increase the CoA/acetyl-CoA level in mammalian and Escherichia coli cells, as well as in Saccharomyces cerevisiae cells
physiological function
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). Pfpank1 coding for a functional PanK that is essential for normal growth. Plasmodium falciparum parasites have previously been shown to survive equally well in a pantothenate-free complete RPMI 1640 medium supplemented with 0.1 mM CoA as compared to standard complete medium, consistent with them having the capacity to take up exogenous CoA, hence bypassing the need for any PfPanK activity
physiological function
the pantothenate kinase Cab1p catalyzes the first step in the metabolism of pantothenic acid for CoA biosynthesis in budding yeast (Saccharomyces cerevisiae), it significantly regulates the levels of sterol intermediates and the activities of ergosterol biosynthesis-targeting antifungals. This regulation is mediated by changes both in the expression of ergosterol biosynthesis genes and in the levels of sterol intermediates. The CoA metabolism controls ergosterol biosynthesis and susceptibility to antifungals
physiological function
-
pantothenate, the substrate for PanK and precursor for CoA, is directly related with acetyl-CoA biosynthesis in Saccharomyces cerevisiae. PanK is the rate-limiting step for CoA synthesis and pantothenate supplement helps to increase the CoA/acetyl-CoA level in mammalian and Escherichia coli cells, as well as in Saccharomyces cerevisiae cells
-
physiological function
-
CoaA is essential for survival of Mycobacterium tuberculosis. The coax gene is unable to complement the loss of gene coaA. CoaX lacks pantothenate kinase activity in vitro and is not required for survival in macrophages and mice
-
physiological function
-
pantothenate, the substrate for PanK and precursor for CoA, is directly related with acetyl-CoA biosynthesis in Saccharomyces cerevisiae. PanK is the rate-limiting step for CoA synthesis and pantothenate supplement helps to increase the CoA/acetyl-CoA level in mammalian and Escherichia coli cells, as well as in Saccharomyces cerevisiae cells
-
physiological function
-
the pantothenate kinase Cab1p catalyzes the first step in the metabolism of pantothenic acid for CoA biosynthesis in budding yeast (Saccharomyces cerevisiae), it significantly regulates the levels of sterol intermediates and the activities of ergosterol biosynthesis-targeting antifungals. This regulation is mediated by changes both in the expression of ergosterol biosynthesis genes and in the levels of sterol intermediates. The CoA metabolism controls ergosterol biosynthesis and susceptibility to antifungals
-
-
mitochondria-targeted human pantothenate kinase-2 is involved in pantothenate kinase-associated neurodegeneration
additional information
comparison of the human PANK3x02acetyl-CoA complex to the structures of PANK3 in four catalytically relevant complexes, 5'-adenylyl-beta,gamma-imidodiphosphate (AMPPNP)x02Mg2+, MPPNP-Mg2+-pantothenate, ADP-Mg2+-phosphopantothenate, and AMP phosphoramidate (AMPPN)-Mg2+, all reveal a large conformational change in the dimeric enzyme. The amino-terminal nucleotide binding domain rotates to close the active site, and this allows the P-loop to engage ATP and facilitates required substrate/product interactions at the active site. The transition between the inactive and active conformations, as assessed by the binding of either ATP-Mg2+ or acyl-CoA to PANK3, is highly cooperative indicating that both protomers move in concert. The communication between the two protomers is mediated by an alpha-helix that interacts with the ATP-binding site at its amino terminus and with the substrate/inhibitor-binding site of the opposite protomer at its carboxyl terminus. The two alpha-helices within the dimer together with the bound ligands create a ring that stabilizes the assembly in either the active closed conformation or the inactive open conformation. Thus, both active sites of the dimeric mammalian pantothenate kinases coordinately switch between the on and off states in response to intracellular concentrations of ATP and its key negative regulators, acetyl(acyl)-CoA. Analysis of PANK3 catalytic intermediates. Glu138 appears to be the logical candidate for the catalytic base, binding structure, and substrate/product interactions within the active site during the PANK3 catalytic cycle, detailed overview
additional information
comparison of the human PANK3x02acetyl-CoA complex to the structures of PANK3 in four catalytically relevant complexes, 5'-adenylyl-beta,gamma-imidodiphosphate (AMPPNP)x02Mg2+, MPPNP-Mg2+-pantothenate, ADP-Mg2+-phosphopantothenate, and AMP phosphoramidate (AMPPN)-Mg2+, all reveal a large conformational change in the dimeric enzyme. The amino-terminal nucleotide binding domain rotates to close the active site, and this allows the P-loop to engage ATP and facilitates required substrate/product interactions at the active site. The transition between the inactive and active conformations, as assessed by the binding of either ATP-Mg2+ or acyl-CoA to PANK3, is highly cooperative indicating that both protomers move in concert. The communication between the two protomers is mediated by an alpha-helix that interacts with the ATP-binding site at its amino terminus and with the substrate/inhibitor-binding site of the opposite protomer at its carboxyl terminus. The two alpha-helices within the dimer together with the bound ligands create a ring that stabilizes the assembly in either the active closed conformation or the inactive open conformation. Thus, both active sites of the dimeric mammalian pantothenate kinases coordinately switch between the on and off states in response to intracellular concentrations of ATP and its key negative regulators, acetyl(acyl)-CoA. Analysis of PANK3 catalytic intermediates. Glu138 appears to be the logical candidate for the catalytic base, binding structure, and substrate/product interactions within the active site during the PANK3 catalytic cycle, detailed overview
additional information
comparison of the human PANK3x02acetyl-CoA complex to the structures of PANK3 in four catalytically relevant complexes, 5'-adenylyl-beta,gamma-imidodiphosphate (AMPPNP)x02Mg2+, MPPNP-Mg2+-pantothenate, ADP-Mg2+-phosphopantothenate, and AMP phosphoramidate (AMPPN)-Mg2+, all reveal a large conformational change in the dimeric enzyme. The amino-terminal nucleotide binding domain rotates to close the active site, and this allows the P-loop to engage ATP and facilitates required substrate/product interactions at the active site. The transition between the inactive and active conformations, as assessed by the binding of either ATP-Mg2+ or acyl-CoA to PANK3, is highly cooperative indicating that both protomers move in concert. The communication between the two protomers is mediated by an alpha-helix that interacts with the ATP-binding site at its amino terminus and with the substrate/inhibitor-binding site of the opposite protomer at its carboxyl terminus. The two alpha-helices within the dimer together with the bound ligands create a ring that stabilizes the assembly in either the active closed conformation or the inactive open conformation. Thus, both active sites of the dimeric mammalian pantothenate kinases coordinately switch between the on and off states in response to intracellular concentrations of ATP and its key negative regulators, acetyl(acyl)-CoA. Analysis of PANK3 catalytic intermediates. Glu138 appears to be the logical candidate for the catalytic base, binding structure, and substrate/product interactions within the active site during the PANK3 catalytic cycle, detailed overview
additional information
-
comparison of the human PANK3x02acetyl-CoA complex to the structures of PANK3 in four catalytically relevant complexes, 5'-adenylyl-beta,gamma-imidodiphosphate (AMPPNP)x02Mg2+, MPPNP-Mg2+-pantothenate, ADP-Mg2+-phosphopantothenate, and AMP phosphoramidate (AMPPN)-Mg2+, all reveal a large conformational change in the dimeric enzyme. The amino-terminal nucleotide binding domain rotates to close the active site, and this allows the P-loop to engage ATP and facilitates required substrate/product interactions at the active site. The transition between the inactive and active conformations, as assessed by the binding of either ATP-Mg2+ or acyl-CoA to PANK3, is highly cooperative indicating that both protomers move in concert. The communication between the two protomers is mediated by an alpha-helix that interacts with the ATP-binding site at its amino terminus and with the substrate/inhibitor-binding site of the opposite protomer at its carboxyl terminus. The two alpha-helices within the dimer together with the bound ligands create a ring that stabilizes the assembly in either the active closed conformation or the inactive open conformation. Thus, both active sites of the dimeric mammalian pantothenate kinases coordinately switch between the on and off states in response to intracellular concentrations of ATP and its key negative regulators, acetyl(acyl)-CoA. Analysis of PANK3 catalytic intermediates. Glu138 appears to be the logical candidate for the catalytic base, binding structure, and substrate/product interactions within the active site during the PANK3 catalytic cycle, detailed overview
additional information
the structure of PfPanK1 minus its parasite-specific inserts is predicted by homology modeling using the AMPPNP and pantothenate-bound human PanK3 structure (PDB ID 5KPR) as a template. PfPanK1 shares 28% sequence identity with human PanK3 over the protein parts that are modeled
additional information
-
the structure of PfPanK1 minus its parasite-specific inserts is predicted by homology modeling using the AMPPNP and pantothenate-bound human PanK3 structure (PDB ID 5KPR) as a template. PfPanK1 shares 28% sequence identity with human PanK3 over the protein parts that are modeled