Disease relevance of HPD

• Congenital HPD deficiency is a rare, relatively benign condition known as hereditary type III tyrosinemia [1].
• Finally, vaccinia virus-based expression provided evidence that HPD is subject to phosphorylation, and furthermore, allowed mapping of the HPD protein in the human keratinocyte 2D database [1].
• To obtain a genomic probe useful for fluorescence in situ hybridization (FISH) analysis we screened a human leukocyte genomic library and isolated a 13.4-kb phage clone, which by restriction fragment and sequence analyses was shown to contain exons 1-10 of HPD and approximately 2-kb upstream sequences [2].
• Peripheral neuropathy as the presenting feature of tyrosinaemia type I and effectively treated with an inhibitor of 4-hydroxyphenylpyruvate dioxygenase [3].
• The enzyme has 53% conserved amino acids and 27% identical amino acids in common with 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. P.J. 874 and 52% conserved and 28% identical residues, with a protein from Shewanella colwelliana [4].

Psychiatry related information on HPD

• The features of sleep parameters in the Rett syndrome were compared with those in early infantile autism (EIA) and hereditary progressive dystonia with marked diurnal fluctuation (HPD) [5].
• Including mixed cases, ie, PPD and multiple infarct dementia in estimates of the familial risk for AD can reduce the extent of underestimation of PPD [6].
• METHODS: Using a telephone survey and the Edinburgh Postnatal Depression Scale questionnaire we identified PPD in a sample of women who gave birth in HaEmek Medical Center. We also assessed the extent to which the women consulted with family physicians, gynecologists and/or pediatricians [7].
• CONCLUSIONS: Although many men in the postnatal period experience a variety of mental health problems, those who have a partner with PPD are themselves at increased risk for experiencing psychological symptoms and disturbances [8].
• We studied factors contributing to an increased risk of PPD positive status among 147 inpatients dually diagnosed for mental illness and substance abuse in a large urban hospital [9].

High impact information on HPD

• Functional studies revealed that, while both TCR-gamma/delta+ cell subsets showed CD3-mediated activation, only BB3+ (or Ti gamma A+) cells, but not delta TCS1+ cells, appeared to proliferate in response to PPD in PPD-reactive individuals [10].
• It also rises rapidly after inoculation with tetanus toxoid and PPD in sensitized individuals [11].
• Purified CD8+ but not CD4+ T cells activated in the AMLR in conditioned medium inhibited proliferation of autologous T cells by anti-CD3 or PPD [12].
• A comparative study of strongly positive PPD skin tests in patients with tuberculosis showed significant basophil accumulations in five of nine subjects [13].
• Inhibition of 4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver cirrhosis and abolish or diminish the risk of liver cancer [14].

Chemical compound and disease context of HPD

• Tyrosinemia type III (OMIM 276710) is an autosomal recessive disorder caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPD), the second enzyme in the tyrosine catabolic pathway [15].
• A mutation in the p53 gene was detected at codon 197, resulting in an amino acid change from leucine to phenylalanine, in both HPD and the three cell lines but in none of the 18 primary adenocarcinomas [16].
• Rhabdomyosarcoma tumors in rats made hyperglycemic by multiple injections of glucose exhibited a transient decrease in pH and an increased ability to accumulate derivatives of hematoporphyrin (HPD) [17].
• 4. In juvenile parkinsonism and Parkinson's disease, which have dopamine deficiency in the basal ganglia as HPD/DRD, the GCH gene may be normal, and the molecular mechanism of the dopamine deficiency in the basal ganglia is different from that in HPD/DRD [18].
• Mutations in the human HPD gene (encoding 4-hydroxyphenylpyruvic acid dioxygenase) cause hereditary tyrosinemia type 3 (HT3) [19].

Biological context of HPD

• In the present study high-resolution chromosome mapping localized the HPD gene to 12q24.31 [1].
• The human HPD gene is over 30 kb long and is split into 14 exons [20].
• Using human HPD cDNA as a probe, a chromosomal gene related to HPD was isolated from human gene libraries [20].
• A heterozygous missense mutation predicting an Ala to Thr change at codon 33 (A33T) was found in the same HPD gene in the two patients with hawkinsinuria [21].
• Overlapping DNA fragments spanning approximately 21 kb of genomic DNA and encompassing the human 4-hydroxyphenylpyruvate dioxygenase gene (HPD) have been cloned by screening a human leukocyte genomic library and by PCR amplification of human fibroblastic DNA [22].

Anatomical context of HPD

• The GCH1 activity that was expressed in mononuclear blood cells was almost half the normal value (usually 2-20% of the normal value (39.0+/-9.2pmol/ml) in patients with HPD/DRD) [23].
• Using a panel of human-rodent somatic cell hybrids, we have previously mapped the gene (HPD, previously called PPD) encoding 4-hydroxyphenylpyruvate dioxygenase to the distal half of the long arm of human chromosome 12, region q14-->qter [2].
• Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway [24].
• In both compound heterozygotes, tetrahydrobiopterin (BH4) levels in cerebrospinal fluid were lower than those in HPD/DRD [25].
• In the three HPD cell lines, which were confirmed to contain only cancer cells, a normal p53 gene allele was retained [16].

Associations of HPD with chemical compounds

• 4-hydroxyphenylpyruvate dioxygenase (HPD) (EC 1.13.11.27) is a key enzyme involved in tyrosine catabolism [1].
• The enzyme 4-hydroxyphenylpyruvic acid dioxygenase (HPD) catalyzes the reaction of 4-hydroxyphenylpyruvic acid to homogentisic acid in the tyrosine catabolism pathway [21].
• It has been postulated that hawkinsinuria, an autosomal dominant disorder characterized by the excretion of 'hawkinsin,' may also be a result of HPD deficiency [21].
• NTBC is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase and has been shown to efficiently prevent tyrosine degradation, and production of succinylacetone, in patients with tyrosinaemia [26].
• Hereditary progressive dystonia with marked diurnal fluctuation (HPD) is a childhood-onset, postural dystonia that is characterized by marked diurnal fluctuation and a dramatic response to levodopa [27].

Other interactions of HPD

• We report a case of a 46-year-old Japanese woman with hereditary progressive dystonia with marked diurnal fluctuations and dopa-responsive dystonia (HPD/DRD) [23].
• Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in both of primary and HPD tumors, the MT1-MMP mRNA level and proMMP-2 activation being significantly correlated (r = 0.893, P < 0.001) [28].
• Point mutations within the highly conserved HPD motif of the J-domain abolished activation of Hsc70 [29].
• Early decrease of TH due to deficiency of BH4 in HPD/DRD also affects the DA-D4 receptor of the tuberoinfundibular DA neuron and cause stagnation of increase of body length in childhood [30].
• The resulting HPX (hanging porphyrin xanthene) and HPD (hanging porphyrin dibenzofuran) systems permit both the orientation and acid-base properties of the hanging H-bonding group to be controlled [31].

Analytical, diagnostic and therapeutic context of HPD

• The highest level of expression of 4-hydroxyphenylpyruvate dioxygenase was found in human liver tissue as demonstrated by Northern blot analysis [22].
• Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D [32].
• Next, we examined the GTP cyclohydrolase I protein amount by western blot analysis in phytohemagglutinin-stimulated mononuclear blood cells from HPD/DRD patients [33].
• Hematoporphyrin and HPD: photophysics, photochemistry and phototherapy [34].
• Quantitative RT-PCR showed that the expression of normal GTP cyclohydrolase I mRNA decreased in their lymphocytes, while the HPD patient had more expression of mutant GTP cyclohydrolase I mRNA than his asymptomatic mother [35].

References