Disease relevance of PTS

• 6-Pyruvoyl-tetrahydropterin synthase (PTS), a key enzyme in the synthesis of tetrahydrobiopterin in man, is defective in the most frequent variant of tetrahydrobiopterin-deficient hyperphenylalaninaemia (atypical phenylketonuria) [1].
• The human liver cDNA for PTPS was previously isolated, and the recombinant protein was found to be active when expressed in Escherichia coli [2].
• In contrast to its inactivity in these cells, the K129E mutant was 2-3 fold more active than wild-type PTPS when transfected into COS-1 or the human hepatoma cell line Hep G2 [3].
• Structure and function of proteins involved in sugar transport by the PTS of gram-positive bacteria [4].
• A number of PTS components, including HPr, Enzyme I and some Enzymes II, have been studied at the biochemical and/or genetical level in Streptococcus salivarius, Streptococcus mutans and Streptococcus sobrinus [5].

Psychiatry related information on PTS

• BH4 deficiency results in hyperphenylalaninemia and monoamine neurotransmitter depletion associated with progressive mental retardation and is most commonly due to autosomal recessive mutations in 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme for cofactor biosynthesis [6].
• L. plantarum is a species that is encountered in many different environmental niches, and this flexible and adaptive behavior is reflected by the relatively large number of regulatory and transport functions, including 25 complete PTS sugar transport systems [7].
• The subjects were assessed by psychotherapeutic interview, Offer Self-Image Questionnaire (OSIQ), questionnaires of depressive symptoms, war stressors, posttraumatic reactions (PTS-reactions) and general data [8].

High impact information on PTS

• The disparate subcellular locations of PTS receptor homologs have led to proposals of receptor shuttling between the cytosol and the peroxisomal membrane, and to the suggestion that some of these molecules may even reside normally in the peroxisomal matrix [9].
• To carry out its catalytic function in sugar transport and phosphorylation, the PTS uses PEP as an energy source and phosphoryl donor [10].
• The organization of the PTS as a four-step phosphoryl transfer system, in which all P derivatives exhibit similar energy (phosphorylation occurs at histidyl or cysteyl residues), is surprising, as a single protein (or domain) coupling energy transfer and sugar phosphorylation would be sufficient for PTS function [10].
• As we shall see, the PTS regulation network not only controls carbohydrate uptake and metabolism but also interferes with the utilization of nitrogen and phosphorus and the virulence of certain pathogens [10].
• We report analyses of 202 fully sequenced genomes for homologues of known protein constituents of the bacterial phosphoenolpyruvate-dependent phosphotransferase system (PTS) [11].

Chemical compound and disease context of PTS

• All three mutations, R25Q, R16C, and K120-->Stop, affect evolutionarily conserved residues in PTPS, result in reduced enzymatic activity when reconstituted in E. coli, and are thus believed to be the molecular cause for the BH4 deficiency [2].
• The new combined loading test was performed in nine patients with primary HPA, three with classical phenylketonuria (PKU), three with DHPR deficiency, and three with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency [12].
• The genes encoding the proteins of the fructose-specific phosphotransferase system (PTS) of Rhodobacter capsulatus were sequenced, and the deduced amino acyl sequences of the energy-coupling protein, Enzyme I, and the transport protein, Enzyme IIfru, were compared with published sequences [13].
• While most strains of Streptococcus thermophilus do not or poorly metabolize glucose, compelling evidence suggests that S. thermophilus possesses the genes that encode the glucose/mannose general and specific PTS proteins [14].
• Most strains of Escherichia coli K-12 are unable to use the enzyme IIA/IIB (enzyme IIMan) complex of the phosphoenolpyruvate:sugar phosphotransferase system (PTS) in anaerobic growth and therefore cannot utilize glucosamine anaerobically [15].

Biological context of PTS

• The PTS gene was mapped to the chromosomal region 11q22.3-q23.3, and the PCD/DCOH gene was mapped to the 10q22 band of the genome [16].
• The PTS gene spans about 8 kb and consists of 6 exons, as revealed by DNA-sequence analysis [17].
• We used the previously isolated PTPS cDNA as a probe and identified the human gene, PTS, located on chromosome 11q22.3-q23.3, and a retropseudogene, PTS-P1, assigned to 9p12-p13 (symbols approved by the human genome nomenclature committee) [17].
• The metabolic phenotype in heterozygotes (urine biopterin excretion) did not correlate with erythrocyte PTS activity [18].
• Erythrocyte activity of PTS in homozygotes (or compound heterozygotes) is less than 10% of normal [18].

Anatomical context of PTS

• We examined 8 patients with DRD, 3 with autosomal recessive GTPCH deficiency, 7 with PTPS deficiency, 3 with DHPR deficiency, and 49 controls (35 fibroblast and 14 amniocyte samples) [19].
• Herein we investigated the molecular mechanism and relevance of cytokine-dependent regulation of 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme in BH4 synthesis, in human coronary artery endothelial cells (HCAECs) [20].
• We speculate that our patient has residual 6-PTS activity in the central nervous system, such as in the liver, and we suggest that residual, but insufficient production of tetrahydrobiopterin may play an important role in causing diurnal fluctuation of symptoms [21].
• The PTS activity was higher in younger erythrocytes, including reticulocytes, than in older ones [1].
• Regulation of 6-pyruvoyltetrahydropterin synthase activity and messenger RNA abundance in human vascular endothelial cells [22].

Associations of PTS with chemical compounds

• PTPS- and DHPR-deficient cells showed no enzyme activities; in PTPS deficiency the pattern of pterin production was typical (neopterin, 334-734 pmol/mg; controls, 18-98 pmol/mg; biopterin, 0 pmol/mg; controls, 154-303 pmol/mg) [19].
• Autosomal recessive mutations in the 6-pyruvoyltetrahydropterin synthase (PTPS) gene are the most common reason for hyperphenylalaninemia due to tetrahydrobiopterin deficiency [17].
• The deficient enzyme in these subjects is 6-pyruvoyl tetrahydropterin synthase (PTS) [18].
• The G-to-A transition at the consensus sequence of splicing donor site of exon 3 (IVS3+1G>A) resulted in exon 3 skipping of the PTS transcript and caused a frameshift stop after lysine of codon 54 (K54X) [23].
• This is the first report describing mutations in PTPS that lead to BH4 deficiency [2].

Enzymatic interactions of PTS

• HPr kinase/phosphorylases (HprKs) regulate catabolite repression and sugar transport in Gram-positive bacteria by phosphorylating the small phosphotransferase system (PTS) protein HPr on a serine residue [24].

Other interactions of PTS

• PTS-P1 has 74% similarity to the 3' portion of PTPS cDNA [17].
• Importantly, IL-1beta induced PTPS rather than GTPCH [20].
• In order to investigate their putative function and biosynthetic regulation, we performed quantitative analysis of not only the intracellular pteridines by HPLC but also the biosynthetic enzymes (GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase, SR, and aldose reductase-like enzyme) by Northern blot analysis and activity assay [25].
• This study indicates that genetic abnormality in the 6-PTS gene may be a hereditary dystonia disorder [21].
• Using a more purified human liver sepiapterin reductase fraction which gave a lower yield than a crude preparation, adult controls (n = 8) showed a mean erythrocyte PTS activity of 17.6 (range 11.0-29.5) microU/g Hb [1].

Analytical, diagnostic and therapeutic context of PTS

• On immunostimulation, PTPS became rate-limiting [20].
• In this study, five additional mutations in the PTS gene, namely 200C>T (T67M), 226C>T (L76F), IVS3+1G>A (K54X), 116-119delTGTT (K38X) and 169-171delGTG (V57del), were identified by PCR and DNA sequencing in Chinese PTS-deficient patients [23].
• Two single base alterations of PTPS cDNA, a C-to-T transition at nucleotide 259 and a novel A-to-G transition at nucleotide 155 (according to cDNA sequence), were identified in two Chinese PTPS-deficient siblings by the reverse transcription-polymerase chain reaction (RT-PCR) [26].
• However, although thrombolytic therapy is advantageous over anticoagulation as measured by early vein patency, a benefit in terms of a reduction in PTS risk, is unproven [27].
• The intra and interlaboratory reproducibilities of Recombiplastin, calculated on the basis of either PTS expressed in seconds, or of the International Normalized Ratio (INR), were good, with coefficients of variation (CV) similar to those observed with the 5 other reagents used by the different laboratories (2% < CV < 8%) [28].

References