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Literature summary for 2.7.1.33 extracted from

  • Subramanian, C.; Yun, M.K.; Yao, J.; Sharma, L.K.; Lee, R.E.; White, S.W.; Jackowski, S.; Rock, C.O.
    Allosteric regulation of mammalian pantothenate kinase (2016), J. Biol. Chem., 291, 22302-22314 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

Cloned (Comment) Organism
gene PANK1, PANK1alpha and PANK1beta are splice variants of the PANK1 gene Mus musculus
gene PANK1, PANK1alpha and PANK1beta are splice variants of the PANK1 gene Homo sapiens

Protein Variants

Protein Variants Comment Organism
G19V site-directed mutagenesis, PANK3(G19V) cannot bind ATP, and biochemical analyses of an engineered PANK3/PANK3(G19V) heterodimer confirmed that the two active sites are functionally coupled. Analysis of PANK3/PANK3(G19V) heterodimers, overview Homo sapiens
additional information generation of unction Pank1-/-Pank2-/-, Pank1-/-Pank3-/-, and Pank2-/- Pank-/-double knock-out mice Mus musculus
additional information generation of unction Pank1-/-Pank2-/-, Pank1-/-Pank3-/-, and Pank2-/-Pank-/-3 double knock-out mice Mus musculus

Inhibitors

Inhibitors Comment Organism Structure
acetyl-CoA feedback inhibition, competitive versus ATP, but acetyl-CoA binds far more tightly than ATP. The 1alpha and 1beta isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA; feedback inhibition, competitive versus ATP, but acetyl-CoA binds far more tightly than ATP. The 1alpha and 1beta isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA; feedback inhibition, competitive versus ATP, but acetyl-CoA binds far more tightly than ATP. The 1alpha and 1beta isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA Homo sapiens
acetyl-CoA feedback inhibition, competitive versus ATP, but acetyl-CoA binds far more tightly than ATP. The 1alpha and 1beta isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA; feedback inhibition, competitive versus ATP, but acetyl-CoA binds far more tightly than ATP. The 1alpha and 1beta isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA; feedback inhibition, competitive versus ATP, but acetyl-CoA binds far more tightly than ATP. The 1alpha and 1beta isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA. Comparison of the overall structures of the actyl-CoA-bound inactive and the active PANK3 conformations, overview Mus musculus

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
additional information allosteric regulation of mammalian pantothenate kinase Mus musculus
additional information
-
additional information allosteric regulation of mammalian pantothenate kinase Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytosol human isozyme 3 is cytosolic Homo sapiens 5829
-
cytosol isozyme 2 of mice is cytosolic Mus musculus 5829
-
cytosol isozyme 3 of mice is cytosolic Mus musculus 5829
-
endosome isozyme 1beta Mus musculus 5768
-
endosome isozyme 1beta Homo sapiens 5768
-
mitochondrion
-
Homo sapiens 5739
-
additional information isoform 1alpha is targeted to the nucleus, whereas isoform 1beta is associated with endosomes Mus musculus
-
-
additional information isoform 1alpha is targeted to the nucleus, whereas isoform 1beta is associated with endosomes Homo sapiens
-
-
additional information the PANK2 gene in humans encodes a protein with both nuclear localization and mitochondrial targeting sequences. Human PANK2 accumulates in the intra-membrane space in mitochondria Homo sapiens
-
-
nucleus
-
Homo sapiens 5634
-
nucleus isozyme 1alpha Mus musculus 5634
-
nucleus isozyme 1alpha Homo sapiens 5634
-

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Mus musculus
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + (R)-pantothenate Mus musculus
-
ADP + (R)-4'-phosphopantothenate
-
?
ATP + (R)-pantothenate Homo sapiens
-
ADP + (R)-4'-phosphopantothenate
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q8TE04
-
-
Homo sapiens Q9BZ23
-
-
Homo sapiens Q9H999
-
-
Mus musculus
-
-
-
Mus musculus Q8K4K6
-
-
Mus musculus Q8R2W9
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + (R)-pantothenate
-
Mus musculus ADP + (R)-4'-phosphopantothenate
-
?
ATP + (R)-pantothenate
-
Homo sapiens ADP + (R)-4'-phosphopantothenate
-
?

Subunits

Subunits Comment Organism
homodimer
-
Homo sapiens

Synonyms

Synonyms Comment Organism
hPanK1
-
Homo sapiens
hPANK2
-
Homo sapiens
hPanK3
-
Homo sapiens
mPank1
-
Mus musculus
mPanK2
-
Mus musculus
mPanK3
-
Mus musculus
PanK
-
Mus musculus
PanK
-
Homo sapiens
PanK1
-
Mus musculus
PanK1
-
Homo sapiens
PanK2
-
Mus musculus
PanK2
-
Homo sapiens
PanK3
-
Homo sapiens
PanK3
-
Mus musculus
pantothenate kinase 1
-
Mus musculus
pantothenate kinase 1
-
Homo sapiens
pantothenate kinase 2
-
Mus musculus
pantothenate kinase 2
-
Homo sapiens
pantothenate kinase 3
-
Homo sapiens
pantothenate kinase 3
-
Mus musculus

General Information

General Information Comment Organism
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 Mus musculus
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 Homo sapiens
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 Mus musculus
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 Mus musculus
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 Mus musculus
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 Homo sapiens
physiological function allosteric regulation of mammalian pantothenate kinase. Pantothenate kinase is the master regulator of CoA biosynthesis and is feedback-inhibited by acetyl-CoA Mus musculus
physiological function allosteric regulation of mammalian pantothenate kinase. Pantothenate kinase is the master regulator of CoA biosynthesis and is feedback-inhibited by acetyl-CoA Homo sapiens