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6 Pyruvoyltetrahydropterin Synthase

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Nenad Blau – One of the best experts on this subject based on the ideXlab platform.

Young Shik Park – One of the best experts on this subject based on the ideXlab platform.

  • Structural basis of a novel activity of bacterial 6Pyruvoyltetrahydropterin Synthase homologues distinct from mammalian 6Pyruvoyltetrahydropterin Synthase activity.
    Acta Crystallographica Section D Biological Crystallography, 2014
    Co-Authors: Kyung Hye Seo, Young Shik Park, Ningning Zhuang, Ki Hun Park, Kon Ho Lee
    Abstract:

    Escherichia coli 6-carboxytetrahydropterin Synthase (eCTPS), a homologue of 6Pyruvoyltetrahydropterin Synthase (PTPS), possesses a much stronger catalytic activity to cleave the side chain of sepiapterin in vitro compared with genuine PTPS activity and catalyzes the conversion of dihydroneopterin triphosphate to 6-carboxy-5,6,7,8-tetrahydropterin in vivo. Crystal structures of wild-type apo eCTPS and of a Cys27Ala mutant eCTPS complexed with sepiapterin have been determined to 2.3 and 2.5 A resolution, respectively. The structures are highly conserved at the active site and the Zn2+ binding site. However, comparison of the eCTPS structures with those of mammalian PTPS homologues revealed that two specific residues, Trp51 and Phe55, that are not found in mammalian PTPS keep the substrate bound by stacking it with their side chains. Replacement of these two residues by site-directed mutamutagenesis to the residues Met and Leu, which are only found in mammalian PTPS, converted eCTPS to the mammalian PTPS activity. These studies confirm that these two aromatic residues in eCTPS play an essential role in stabilizing the substrate and in the specific enzyme activity that differs from the original PTPS activity. These aromatic residues Trp51 and Phe55 are a key signature of bacterial PTPS enzymes that distinguish them from mammalian PTPS homologues.

  • Purification, crystallization and preliminary crystallographic analysis of a 6Pyruvoyltetrahydropterin Synthase homologue from Esherichia coli.
    Acta Crystallographica Section F Structural Biology and Crystallization Communications, 2008
    Co-Authors: Kyung Hye Seo, Young Shik Park, Che Ok Jeon, Supangat, Hye Lim Kim, Kon Ho Lee
    Abstract:

    6Pyruvoyltetrahydropterin Synthase from E. coli (ePTPS) has been crystallized using the hanging-drop vapour-diffusion method. Hexagonal- and rectangular-shaped crystals were obtained. Diffraction data were collected from the hexagonal and rectangular crystals to 3.0 and 2.3 A resolution, respectively. The hexagonal plate-shaped crystals belonged to space group P321, with unit-cell parameters a = b = 112.59, c = 68.82 A , and contained two molecules in the asymmetric unit. The rectangular crystals belonged to space group I222, with unit-cell parameters a = 112.76, b = 117.66, c = 153.57 A , and contained six molecules in the asymmetric unit. The structure of ePTPS in both crystal forms has been determined by molecular replacement.

  • 6Pyruvoyltetrahydropterin Synthase orthologs of either a single or dual domain structure are responsible for tetrahydrobiopterin synthesis in bacteria
    FEBS letters, 2006
    Co-Authors: Jin Sun Kong, Kon Ho Lee, Hye Lim Kim, Ji-youn Kang, O-seob Kwon, Young Shik Park
    Abstract:

    6Pyruvoyltetrahydropterin Synthase (PTPS) catalyzes the second step of tetrahydrobiopterin (BH4) synthesis. We previously identified PTPS orthologs (bPTPS-Is) in bacteria which do not produce BH4. In this study we disrupted the gene encoding bPTPS-I in Synechococcus sp. PCC 7942, which produces BH4-glucoside. The mutant was normal in BH4-glucoside production, demonstrating that bPTPS-I does not participate in BH4 synthesis in vivo and bringing us a new PTPS ortholog (bPTPS-II) of a bimodular polypeptide. The recombinant Synechococcus bPTPS-II was assayed in vitro to show PTPS activity higher than human enzyme. Further computational analysis revealed the presence of mono and bimodular bPTPS-II orthologs mostly in green sulfur bacteria and cyanobacteria, respectively, which are well known for BH4-glycoside production. In summary we found new bacterial PTPS orthologs, having either a single or dual domain structure and being responsible for BH4 synthesis in vivo, thereby disclosing all the bacterial PTPS homologs.

Beat Thöny – One of the best experts on this subject based on the ideXlab platform.

Takahide Nomura – One of the best experts on this subject based on the ideXlab platform.

  • Partial Biopterin Deficiency Disturbs Postnatal Development of the Dopaminergic System in the Brain
    The Journal of biological chemistry, 2010
    Co-Authors: Daigo Homma, Chiho Sumi-ichinose, Takahide Nomura, Kazunao Kondo, Kazuhisa Ikemoto, Hirofumi Tokuoka, Setsuko Katoh, Hiroshi Ichinose
    Abstract:

    Postnatal development of dopaminergic system is closely related to the development of psychomotor function. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of dopamine and requires tetrahydrobiopterin (BH4) as a cofactor. To clarify the effect of partial BH4 deficiency on postnatal development of the dopaminergic system, we examined two lines of mutant mice lacking a BH4-biosynthesizing enzyme, including sepiapterin reductase knock-out (Spr−/−) mice and genetically rescued 6Pyruvoyltetrahydropterin Synthase knock-out (DPS-Pts−/−) mice. We found that biopterin contents in the brains of these knock-out mice were moderately decreased from postnatal day 0 (P0) and remained constant up to P21. In contrast, the effects of BH4 deficiency on dopamine and TH protein levels were more manifested during the postnatal development. Both of dopamine and TH protein levels were greatly increased from P0 to P21 in wild-type mice but not in those mutant mice. Serotonin levels in those mutant mice were also severely suppressed after P7. Moreover, striatal TH immunoreactivity in Spr−/− mice showed a drop in the late developmental stage, when those mice exhibited hind-limb clasping behavior, a type of motor dysfunction. Our results demonstrate a critical role of biopterin in the augmentation of TH protein in the postnatal period. The developmental manifestation of psychomotor symptoms in BH4 deficiency might be attributable at least partially to high dependence of dopaminergic development on BH4 availability.

  • Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: regulation of dopaminergic neural transmission by tyrosine hydroxylase protein at nerve terminals.
    Journal of pharmacological sciences, 2010
    Co-Authors: Chiho Sumi-ichinose, Takahide Nomura, Hiroshi Ichinose, Kazuhisa Ikemoto, Kazunao Kondo
    Abstract:

    5R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) is an essential cofactor for tyrosine hydroxylase (TH). Recently, a type of dopa-responsive dystonia (DRD) (DYT5, Segawa’s disease) was revealed to be caused by dominant mutations of the gene encoding GTP cyclohydrolase I (GCHI), which is the rate-limiting enzyme of BH(4) biosynthesis. In order to probe the role of BH(4) in vivo, we established BH(4)-depleted mice by disrupting the 6Pyruvoyltetrahydropterin Synthase (PTS) gene (Pts(-/-)) and rescued them by introducing human PTS cDNA under the control of the human dopamine β-hydroxylase (DBH) promoter (Pts(-/-)-DPS). The Pts(-/-)-DPS mice developed hyperphenylalaninemia. Interestingly, tyrosine hydroxylase protein was dramatically reduced in the dopaminergic nerve terminals of these mice, and they developed abnormal posture and motor disturbance. We propose that the biochemical and pathologic changes of Pts(-/-)-DPS mice are caused by mechanisms common to human DRD, and understanding these mechanisms could give us insight into other movement disorders.

  • Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities.
    Journal of neurochemistry, 2005
    Co-Authors: Chiho Sumi-ichinose, Fumi Urano, Hiroaki Shiraishi, Hiroshi Ichinose, Kazuhisa Ikemoto, Atsushi Shimomura, Takashi Sato, Takao Senda, Takahide Nomura
    Abstract:

    One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa’s disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. Based on our findings on 6Pyruvoyltetrahydropterin Synthase (PTS) gene-disrupted (Pts–/–) mice, we suggested that the amount of tyrosine hydroxylase (TH) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4. In this present work, we rescued Pts–/– mice by transgenic introduction of human PTS cDNA under the control of the dopamine β-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4-insufficiency. The DPS-rescued (Pts–/–, DPS) mice showed severe hyperphenylalaninemia. Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. Biopterin and dopamine contents, and TH activity in the striatum were poorly restored compared with those in the midbrain. TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens. We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4-insufficiency. Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD.

H Wachter – One of the best experts on this subject based on the ideXlab platform.