Disease relevance of Hmbs

• Acute intermittent porphyria (AIP) is a genetic disorder caused by a deficiency of porphobilinogen deaminase (PBGD), the 3rd enzyme in heme synthesis [1].
• PBGD was observed in both nuclear and cytoplasmic fractions of C6 glioma cells by immunostaining [2].
• Photosensitization of cultured R3230AC rat mammary adenocarcinoma cells with delta-aminolaevulinic acid-induced protoporphyrin IX resulted in the inhibition of porphobilinogen deaminase, an enzyme in the haem biosynthetic pathway, and a concomitant decrease in protoporphyrin IX levels [3].
• As an initial approach to optimize delta-aminolaevulinic acid (delta-ALA)-induced photosensitization of tumours, we examined the response of three enzymes of the haem biosynthetic pathway: delta-ALA dehydratase, porphobilinogen deaminase (PBGD) and ferrochelatase [4].
• N-Benzyl-D-glucamine dithiocarbamate (BGD), N-p-isopropylbenzyl-D-glucamine dithiocarbamate (PBGD), and diethyl-dithiocarbamate (DED) were compared for their protective effects against the testicular toxicity in rats induced by acute exposure to cadmium [5].

High impact information on Hmbs

• Using this approach, we demonstrated dose-dependent manifold upregulation of the ratio of TNF-alpha mRNA copies per one copy of PBGD mRNA in alveolar macrophages of the challenged lungs [6].
• Experiments using actinomycin D and cycloheximide suggest that transcription is required for the erythropoietin-induced porphobilinogen deaminase activity, indicating that induction is probably at the level of de novo synthesis of enzyme [7].
• Rat porphobilinogen deaminase cDNA: nucleotide sequence of the erythropoietic form [8].
• Quantifying porphobilinogen deaminase mRNA in microdissected nephron segments by a modified RT-PCR [9].
• Phenylhydrazine treatment induced hydroxymethylbilane synthase activity (EC 4.3.1.8) in rat spleen, erythrocytes and liver by 40-fold, 7.5-fold and 6-fold respectively [10].

Chemical compound and disease context of Hmbs

• We hypothesized that estrogenic alterations, ovariectomy or tamoxifen administration, might also alter the response of porphobilinogen deaminase activity and/or protoporphyrin IX production to delta-aminolevulinic acid administration in the hormonally responsive R3230AC rat mammary adenocarcinoma [11].

Biological context of Hmbs

• Housekeeping PBG-D contains coiled-coil segments known to be involved in dynamic rearrangements in the active site [12].
• In this study, we provide the first full sequence of a 1086bp cDNA covering the coding region for the rat ubiquitous PBG-D and its primary amino acid sequence [12].
• Rat kidney porphobilinogen deaminase kinetics. Detection of enzyme-substrate complexes [13].
• Stimulation of C6 glioma cell differentiation by butyrate induced a marked decrease in porphobilinogen deaminase both in the nucleus and in the cytoplasm as determined by Western blotting and fluorescence immuno-localisation [14].
• Over-expression of the human housekeeping porphobilinogen deaminase in the glioma cells, using the housekeeping-porphobilinogen deaminase plasmid, induced a G1 cell cycle attenuation accompanied by increases in enzyme activity and c6 differentiation toward astrocytes [14].

Anatomical context of Hmbs

• So, accumulated porphyrin may act as an regulator of PBG-D activity in rat harderian gland [15].
• Cells cultured under the same incubation conditions but exposed to 30 mJ cm(-2) irradiation after a 3-h incubation with delta-aminolaevulinic acid showed a significant reduction in protoporphyrin IX, 2.28 x 10(-16) mol per cell, and an 80% reduction in porphobilinogen deaminase activity to 0.0088 fmol uroporphyrin per 30 min per cell [3].
• Porphobilinogen deaminase activity was higher and iron concentration was lower in the mucosa than in the muscularis (P < 0.001) [16].
• The aim of the present study was to examine the activity and the immunohistochemical localization of PBGD in the following tissues of wistar female rats: brain, heart, submandibular gland, liver, kidney, pancreas, ovary, stomach, duodenum, jejunum, ileum, colon and musculature [17].
• After treatment with BGD, MBGD, and PBGD, cadmium was excreted mainly in the feces and the effect of MBGD and PBGD on the fecal excretion of cadmium was much larger than that of BGD [18].

Associations of Hmbs with chemical compounds

• 1. Incubation of PBG-D with 5.0 mM N-ethylmaleimide and 5.0 mM 5,5'-dithiobis(2-nitrobenzoic acid) at pH 8.0 led to inhibitions of 70 and 50%, respectively [15].
• This study points to the liver as the main producer of PBG and ALA in the phenobarbital-induced PBGD-deficient mice and demonstrates efficient removal of accumulated PBG in plasma and urine by enzyme-replacement therapy [1].
• Biochemical characterization of porphobilinogen deaminase-deficient mice during phenobarbital induction of heme synthesis and the effect of enzyme replacement [1].
• Administration of the anti-estrogen tamoxifen to tumor-bearing rats resulted in a significant increase in porphobilinogen deaminase in both tumor and Harderian gland [11].
• PBGD and DED significantly decreased the cadmium concentration in the testes, but DED increased the cadmium concentration in the kidney and brain [5].

Other interactions of Hmbs

• The mRNA levels of PGRP/tag7 were measured by RT-PCR and compared to the housekeeping gene porphobilinogen deaminase (PBD) [19].
• The levels of mRNAs for other heme pathway enzymes, i.e., delta-aminolevulinate dehydratase, porphobilinogen deaminase, uroporphyrinogen decarboxylase, and coproporphyrinogen oxidase, also were increased markedly in the Harderian gland and not influenced by AIA treatment [20].
• Our data thus show that, following focal cerebral ischemia in hyperglycemic conditions, beta-actin is an unsuitable housekeeping gene whereas PBG-D is more appropriate [21].
• Exposure to 3.9 microM As(III) inhibited UROIII-S activity (down to 34%), and PBG-D and URO-D activities to a lower extent; these effects were magnified by ALA supplementation [22].
• Influence of protein calorie malnutrition and fasting on the activities of delta-aminolevulinic acid dehydratase and porphobilinogen deaminase in rats [23].

Analytical, diagnostic and therapeutic context of Hmbs

• RESULTS: Purified rat kidney PBG-D is a monomeric enzyme showing only a single protein band after SDS-PAGE, Western blot and isoelectric focusing (pI 4.9) [13].

References