Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.61 (porphobilinogen deaminase)
 637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the level of transcripts encoding enzymes of the heme biosynthetic pathway as well as those encoding ubiquitous proteins were examined in murine Friend virus-transformed erythroleukemia cells during erythroid cell differentiation induced by chemicals including dimethyl sulfoxide (DMSO). Early changes following DMSO treatment were marked decreases in mRNAs for three ubiquitous proteins, i.e., a 70 kDa heat shock protein (less than 6 h), heme oxygenase and nonspecific delta-aminolevulinate synthase (ALAS) (less than 12 h). These changes were followed by sequential increases in mRNAs for enzymes in the heme biosynthetic pathway. Namely, mRNAs for the erythroid-specific ALAS, delta-aminolevulinate dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase started to increase at 12, 18, 18-24 and 24 h, respectively. Nuclear runoff studies revealed that these changes are largely transcriptional. Treatments with other inducers of erythroid differentiation, e.g., hexamethylene bisacetamide, n-butyric acid and N'-methylnicotinamide, also showed similar effects on mRNAs as those following DMSO. These findings suggest that both suppression of ubiquitous genes and activation of heme pathway enzyme genes are associated with erythroid differentiation, and the former occurs preceding changes in the latter.
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PMID:Sequential activation of genes for heme pathway enzymes during erythroid differentiation of mouse Friend virus-transformed erythroleukemia cells. 195 53

Heme synthesis and degradation play pivotal roles in the regulation of growth and differentiation of erythroid and non-erythroid cells. Heme synthesis in mammalian cells involves eight enzymes which are localized in mitochondrial and cytoplasmic compartments. These enzymes have been well-characterized and cDNAs for six of the enzymes has been cloned. Two enzymes in the enzymes of the heme biosynthetic pathway, delta-aminolevulinic acid synthase (ALAS) and porphobilinogen deaminase (PBG-D) have special features and may have regulatory functions in heme synthesis by hematopoietic cells. ALAS exists as two isozymes which are encoded by non-erythroid and erythroid-specific genes, respectively. By contrast, PBG-D, which also exists as two isozymes, arises from a single gene comprised of two overlapping transcriptional units, each with its own promoter. Transcription from one or the other of these promoters gives rise through differential splicing to two distinct mRNA species which encode the distinct nonerythroid and erythroid isoforms. On the other hand, heme catabolism is determined by the levels of the heme oxygenase system. The enzyme has been purified and the cDNA for heme oxygenase has been cloned. Repression of heme oxygenase in erythroid progenitor cells may initiate differentiation. In addition, recent evidence has suggested that heme may have a broader role in hematopoiesis and in the network of cytokine production by adherent stromal cells.
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PMID:Molecular regulation--biological role of heme in hematopoiesis. 203 26

In this study, we demonstrated that benzene and its metabolites, phenol and hydroquinone, were toxic to human burst-forming unit-erythroid (BFU-E) growth, hydroquinone being the most toxic. Phenol (10(-4) M) was also found to have a marked toxicity on stromal cell colony formation. BFU-E binding with human-tumor necrosis factor (rHu-TNF) was linear with the number of BFU-E colonies. Recombinant rHu-TNF suppressed BFU-E growth in a dose-dependent manner and this was reversed with anti-TNF antibody. Binding studies of rHu-TNF for human K562 cells indicated that K562 cells have a binding constant of approximately 1075 per cell. The heme pathway enzymes, uroporphyrinogen deaminase, and heme oxygenase activities were measured in BFU-E cultures exposed to iron, interleukins (1 and 2), and various lymphocyte and macrophage-conditioned media with or without hemin. In most instances, hemin was found to stimulate the heme synthetic pathway in the presence of these agents. Iron and adherent (macrophage) cell conditioned media (CM) were found to stimulate heme oxygenase activity. Macrophage CM was found to suppress erythropoiesis in contrast to phytohemagglutinin-stimulated leukocyte (PHAL)-CM, which enhanced erythroid growth. In addition, porphobilinogen deaminase levels were greater in 14-day cultures containing hemin plus PHAL-CM as compared with hemin alone. These results are discussed with respect to the generation of hematopoietic inhibitory-stimulatory factors by the marrow microenvironment and their effects on heme synthesis and degradation.
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PMID:Microenvironmental cytokines and expression of erythroid heme metabolic enzymes. 331 Dec 13

The treatment of rats with cis-platinum for 7 days caused a profound, and seemingly selective, decrease (70-80%) in the microsomal cytochrome P-450 levels in the testis. This decrease was accompanied by marked reductions (70-80%) in steroid 17 alpha-hydroxylase activity and in plasma testosterone concentration. The treatment of rats with human chorionic gonadotropin partially restored the cytochrome P-450 concentration and 17 alpha-hydroxylase activity and permitted the plasma testosterone level to approach control values. The effect of cis-platinum on the testicular cytochrome P-450 appeared unrelated to deficiencies in heme metabolic processes, in so far that neither was the activity of delta-aminolevulinate synthetase decreased, nor was that of heme oxygenase increased. These enzymes are rate-limiting in heme biosynthesis and degradation pathways, respectively. Also, the activities of uroporphyrinogen I synthetase, delta-aminolevulinate dehydratase, and ferrochelatase and the concentration of total porphyrins in the testis remained unchanged. The sodium dodecyl sulfate-gel electrophoresis of the microsomal preparation did not reveal a diminished level of apocytochrome; however, in this preparation, heme could not be detected in molecular weight regions corresponding to cytochrome P-450. The microsomal cytochrome b5 and the mitochondrial heme concentrations were not decreased in cis-platinum-treated rats. It is suggested that the mechanism of depletive action of cis-platinum on microsomal cytochrome P-450 involves an impairment of the effective assembly of heme and apoprotein moieties. It is further suggested that the anterior pituitary hormones control the factor(s) involved in this assembly, a process which is interrupted by cis-platinum.
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PMID:Inhibition of testicular cytochrome P-450-dependent steroid biosynthesis by cis-platinum. Reversal by human chorionic gonadotropin. 403 24

Alterations in heme biosynthetic and degradative capabilities and in the activities of several heme-containing enzymes were examined in hepatic tissues of streptozotocin (STZ)-diabetic female Sprague-Dawley rats. Activities were measured 10, 30 and 90 days following the administration of STZ (65 mg/kg, i.v.). The activities of the key enzymes involved in heme synthesis, delta-aminolevulinic acid (ALA) synthase, ALA dehydratase, and uroporphyrinogen synthase, were decreased markedly in STZ-diabetic rats as compared to sham-operated animals. Furthermore, the catabolism of heme which occurs via microsomal heme oxygenase (MHO) remained unaltered in these animals. Microsomal content of heme and cytochrome P-450, and the activities of tryptophan pyrrolase and the drug-metabolizing enzymes benzo[a]pyrene (BP) hydroxylase and aniline hydroxylase, were increased in the livers of diabetic rats. By contrast, the activity of the heme-containing enzyme catalase was decreased in these animals. Cobalt chloride produced a marked increase in MHO with a concomitant decrease in microsomal content of cytochrome P-450 and its associated BP hydroxylase activity in normal as well as chronically diabetic rats. It was of interest, however, that the increase in ALA synthase that is normally produced by this metal was not seen in chronic diabetic animals. Thus, chronic diabetes produced subtle and important disruptions in cellular metabolism, which may have been the result of long-term alterations in key enzymes involved in heme synthesis.
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PMID:Heme and hemoproteins in streptozotocin-diabetic female rats. 668 50

Arsenic can modify the urinary excretion of porphyrins in animals and humans. Arsenic also interferes with the activities of several enzymes of the heme biosynthesis pathway, such as aminolevulinate synthase (ALA-S), porphobilinogen deaminase (PBGD), uroporphyrinogen III synthase (Uro III S), uroporphyrinogen decarboxylase (URO-D), coproporphyrinogen oxidase (COPRO-O), ferrochelatase and heme oxygenase (H-O). This review deals with HPLC-based techniques for the analysis of porphyrins in human and rodent urine and several heme enzymes with discussion on their usefulness as early biomarkers of arsenic toxicity.
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PMID:Urinary porphyrins and heme biosynthetic enzyme activities measured by HPLC in arsenic toxicity. 894 8

The mode of expression of delta-aminolevulinate synthase (ALAS), as well as that of mRNAs for other heme pathway enzymes, was examined in the rat Harderian gland. Northern blot and in situ hybridization analyses demonstrated that the non-specific ALAS (ALAS-N) mRNA is highly expressed in this tissue, whereas the erythroid-specific ALAS (ALAS-E) mRNA is not. Immunoblot analysis of ALAS also confirmed this finding at the protein level. ALAS-N mRNA was maximally induced in the Harderian gland and was not increased further by treatment of animals with 2-allyl-2-isopropylacetamide (AIA). 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. The level of ferrochelatase (FeC) mRNA in the gland was, however, lower than that in the liver. The gland contained an extremely high level of protoporphyrin, while heme was undetectable. Microsomal heme oxygenase-1 (HO-1) mRNA levels were significantly higher in the Harderian gland than in the liver. When isolated glands were incubated with hemin in vitro in organ cultures, the level of HO-1 mRNA was increased, whereas the ALAS-N mRNA level was not. These findings indicate that markedly elevated levels of protoporphyrin and extremely low levels of heme in the Harderian gland are the results of both decreased expression of FeC and markedly increased expression of ALAS-N and HO-1. The constitutive expression of the ALAS-N gene in the Harderian gland suggests a novel transcriptional control mechanism of this gene.
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PMID:Novel regulation of delta-aminolevulinate synthase in the rat harderian gland. 911 83

Zinc mesoporphyrin (ZnMP) is a potent inhibitor of heme oxygenase (HO) and represses 5-aminolevulinic acid synthase (ALAS). These properties make it a potential candidate for treatment of inducible acute hepatic porphyrias, diseases characterized by neurovisceral symptoms, and massive ALAS induction. Effects of intraperitoneal ZnMP (2.5-10 micromol/kg/d) and heme arginate (3-6 mg/kg/d) on plasma levels of 5-aminolevulinic acid (ALA), on messenger RNA (mRNA), and activity of hepatic ALAS and HO were studied in porphobilinogen deaminase-deficient mice treated with phenobarbital (100 mg/kg/d) to induce ALAS. ZnMP (5 micromol/kg/d) led to a significant reduction of plasma ALA levels to 31% of controls (P < .01) by lowering the activity of hepatic mitochondrial and cytosolic ALAS to 29% and 25% of controls, respectively (P < .03). ZnMP decreased the mRNA levels of hepatic ALAS to 53% (P < .03) of controls and this repression was more pronounced than that achieved with heme arginate. In contrast to heme arginate, ZnMP led to a significant reduction of HO activity. We conclude that the combined effect of ZnMP on highly induced ALAS and on HO may be of potential benefit for human acute hepatic porphyrias and therefore merits further in vivo investigations addressing questions raised by this study.
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PMID:Zinc mesoporphyrin represses induced hepatic 5-aminolevulinic acid synthase and reduces heme oxygenase activity in a mouse model of acute hepatic porphyria. 1134 51

Heme is an essential cell metabolite, intracellular regulatory molecule, and protein prosthetic group. Given the known alterations in heme metabolism and redox metal distribution and the up-regulation of heme oxygenase enzyme in Alzheimer's disease (AD), we hypothesized that heme dyshomeostasis plays a key role in the pathogenesis. To begin testing this hypothesis, we used qRT-PCR to quantify the expression of aminolevulinate synthase (ALAS1) and porphobilinogen deaminase (PBGD), rate-limiting enzymes in the heme biosynthesis pathway. The relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, was significantly (p<0.05) reduced by nearly 90% in AD compared to control. Coordinately, the relative expression of PBGD mRNA, which encodes porphobilinogen deaminase, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, was also significantly (p<0.02) reduced by nearly 60% in AD brain compared to control and significantly related to apolipoprotein E genotype (p<0.005). In contrast, the relative expression of ALAD mRNA, which encodes aminolevulinate dehydratase, the second and a non-rate-limiting enzyme for heme biosynthesis, was unchanged between the two groups. Taken together, our results suggest regulation of cerebral heme biosynthesis is profoundly altered in AD and may contribute toward disease pathogenesis by affecting cell metabolism as well as iron homeostasis.
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PMID:Down-regulation of aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in Alzheimer's disease. 1947 21