Publications

• Human pantothenate kinase 4 is a pseudo-pantothenate kinase.

  Yao J., Subramanian C., Rock C.O., Jackowski S.

  Pantothenate kinase generates 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) biosynthesis. The human genome encodes three well-characterized and nearly identical pantothenate kinases (PANK1-3) plus a putative bifunctional protein (PANK4) with a predicted amino-te ... >> More

  Pantothenate kinase generates 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) biosynthesis. 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). However, all amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity. Biochemical analysis corroborates bioinformatic predictions-human PANK4 lacks pantothenate kinase activity. Introducing Glu138Val and Arg207Trp substitutions to the human PANK3 and plant PANK4 abolished their robust pantothenate kinase activity. Introducing both catalytic residues back into human PANK4 restored kinase activity, but only to a low level. This result suggests that epistatic changes to the rest of the protein already reduced the kinase activity prior to mutation of the catalytic residues in the course of evolution. The PANK4 from frog, an anamniote living relative encoding the catalytically active residues, had only a low level of kinase activity, supporting the view that HsPANK4 had reduced kinase activity prior to the catalytic residue substitutions in amniotes. Together, our data show that human PANK4 is a pseudo-pantothenate kinase-a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. The Glu138Val and Arg207Trp substitutions in amniotes (HsPANK3 numbering) completely deactivated the pantothenate kinase activity that had already been reduced by prior epistatic mutations. << Less

  Protein Sci. 28:1031-1047(2019) [PubMed] [EuropePMC]

• The metabolism of pantothenic acid.

  BROWN G.M.

  J Biol Chem 234:370-378(1959) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Prokaryotic type II and type III pantothenate kinases: the same monomer fold creates dimers with distinct catalytic properties.

  Hong B.S., Yun M.K., Zhang Y.-M., Chohnan S., Rock C.O., White S.W., Jackowski S., Park H.-W., Leonardi R.

  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-l ... >> More

  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. << Less

  Structure 14:1251-1261(2006) [PubMed] [EuropePMC]

• Plant coenzyme A biosynthesis: characterization of two pantothenate kinases from Arabidopsis.

  Tilton G.B., Wedemeyer W.J., Browse J., Ohlrogge J.

  In bacterial and animal coenzyme A (CoA) biosynthesis, pantothenate kinase (PANK) activity is critical in regulating intracellular CoA levels. Less is known about the role of PANK in plants, although a single plant isozyme from Arabidopsis, AtPANK1, was previously cloned and analyzed in vitro. We ... >> More

  In bacterial and animal coenzyme A (CoA) biosynthesis, pantothenate kinase (PANK) activity is critical in regulating intracellular CoA levels. Less is known about the role of PANK in plants, although a single plant isozyme from Arabidopsis, AtPANK1, was previously cloned and analyzed in vitro. We report here the characterization of a second pantothenate kinase of Arabidopsis, AtPANK2, as well as characterization of the physiological roles of both plant enzymes. The activity of the second pantothenate kinase, AtPANK2, was confirmed by its ability to complement the temperature-sensitive mutation of the bacterial pantothenate kinase in E. coli strain ts9. Knock-out mutation of either AtPANK1 or AtPANK2 did not inhibit plant growth, whereas pank1-1/pank2-1 double knockout mutations were embryo lethal. The phenotypes of the mutant plants demonstrated that only one of the AtPANK enzymes is necessary and sufficient for producing adequate CoA levels, and that no other enzyme can compensate for the loss of both isoforms. Real-time PCR measurements of AtPANK1 and AtPANK2 transcripts indicated that both enzymes are expressed with similar patterns in all tissues examined, further suggesting that AtPANK1 and AtPANK2 have complementary roles. The two enzymes have homologous pantothenate kinase domains, but AtPANK2 also carries a large C-terminal protein domain. Sequence comparisons indicate that this type of "bifunctional" pantothenate kinase is conserved in other higher eukaryotes as well. Although the function of the C-terminal domain is not known, homology structure modeling suggests it contains a highly conserved cluster of charged residues that likely constitute a metal-binding site. << Less

  Plant Mol. Biol. 61:629-642(2006) [PubMed] [EuropePMC]

• Purification and properties of D-pantothenate kinase from rat liver.

  Abiko Y., Ashida S.I., Shimizu M.

  Biochim Biophys Acta 268:364-372(1972) [PubMed] [EuropePMC]

• The phosphorylation of pantothenic acid by Lactobacillus arabinosus 17-5.

  PIERPOINT W.S., HUGHES D.E., BADDILEY J., MATHIAS A.P.

  Biochem J 61:368-374(1955) [PubMed] [EuropePMC]