Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutants of Saccharomyces cerevisiae, described as catalase and cytochromes deficient (Pachecka et al., 1974), have been analyzed for heme biosynthesis ability. Some enzymatic activities involved in protoheme synthesis were measured in acellular extracts, whereas whole cells were analyzed for cytochrome spectra and for possible accumulation of porphyrin synthesis intermediates. A good correlation was found between these in vitro and in vivo studies. Results show that two mutants were impaired in 5-aminolevulinate synthesis, two mutants were devoid of uroporphyrinogen I synthetase activity and one mutant presented defects in coproporphyrinogen III oxidase activity.
Mol Gen Genet 1977 Nov 14
PMID:Analysis of heme biosynthesis in catalase and cytochrome deficient yeast mutants. 34 Sep 1

1. The activities of the enzymes of haem biosynthesis were studied in 23 patients with acute intermittent porphyria. The mitochondrial enzymes delta-aminolaevulinate synthase, coproporphyrinogen oxidase and ferrochelatase were measured in leucocytes and the cytosolic enzymes delta-aminolaevulinate dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase in erythrocytes. 2. Leucocyte delta-aminolaevulinate synthase activity was elevated (P less than 0-001), with marked diminution of porphobilinogen deaminase activity (P less than 0-001) and reduction in the activities of delta-aminolaevulinate dehydratase (P less than 0-01) and uroporphyrinogen decarboxylase (P less than 0-005). 3. A therapeutic regimen based on intravenous laevulose infusion was studied. In four patients in acute attack and one in remission laevulose treatment was associated with a fall in delta-aminolaevulinate synthase activity, a rise in porphobilinogen deaminase and uroporphyrinogen decarboxylase activities, and a fall in urinary prophyrin precursor excretion (P less than 0-001). These studies provide a basis for the evaluation of the use of sugars in acute intermittent porphyria.
Clin Sci Mol Med 1977 10
PMID:The treatment of acute intermittent porphyria with laevulose. 91 61

The single-strand conformation polymorphism (SSCP) technique was used to detect carriers of the known point mutation in the first exon of the porphobilinogen deaminase gene in Finnish and Swedish families. The SSCP technique was a reliable and convenient way of distinguishing patients from healthy members in a family. This point mutation is thought to result from a splicing defect of the mRNA. The PCR-based analyses of a patient's cDNA did not reveal the presence of an abnormal mRNA population, suggesting that no abnormal mRNA is synthesized or that it is too unstable to be detected.
Mol Cell Probes 1992 Dec
PMID:Single-strand conformation polymorphism (SSCP) analysis applied to the diagnosis of acute intermittent porphyria. 136 48

Porphobilinogen deaminase is the third enzyme in the heme biosynthetic pathway. hem3 mutants in Saccharomyces cerevisiae are deficient in porphobilinogen deaminase activity. We have isolated the HEM3 gene by complementation of the heme auxotrophy of a hem3 mutant. Sequence analysis reveals an open reading frame of 981 nucleotides. The derived amino acid sequence of the protein encoded by HEM3 shows extensive homology to the reported sequences for porphobilinogen deaminase from a number of other sources, indicating that HEM3 is the structural gene for porphobilinogen deaminase. Earlier reports have suggested that expression of HEM3 is induced by porphobilinogen, the substrate of the encoded enzyme. We have investigated the transcription of HEM3 and have found that it is not affected by the ability of the cell to make porphobilinogen or heme. However, we have found that HAP2 and HAP3 gene products are involved in the expression of HEM3. An important element required for expression of HEM3 has been localized to a small region that contains a sequence homologous to the HAP2-3-4 binding sites of several genes including HEM1. These findings suggest that HEM3 expression is regulated in the same manner as that of HEM1 which encodes the first enzyme of the heme biosynthetic pathway.
Mol Gen Genet 1992 Aug
PMID:Structure and regulation of yeast HEM3, the gene for porphobilinogen deaminase. 150 49

All nucleated animal cells synthesize heme to provide the prosthetic group of respiratory cytochromes. Large amounts of heme are synthesized by erythroid cells for hemoglobin production and by liver cells for drug-induced cytochromes P450. This review focuses on the first enzyme of the heme biosynthetic pathway, 5-aminolevulinate synthase (ALAS), which catalyzes the rate-controlling step in liver and possibly other tissues. We report that there are two distinct human genes for ALAS: one, a housekeeping gene, is probably ubiquitously expressed while the other is active only in erythroid tissue. By contrast it has been reported that, for porphobilinogen deaminase, the third enzyme of the heme pathway, there is a single human gene with two promoters; one functional in all tissues, the other erythroid specific. In liver, transcription of the housekeeping ALAS gene is induced by drugs and repressed by heme. Heme also acts in a novel way to prevent transport of ALAS into mitochondria, its site of function. Porphyrias result from inherited defects in enzymes of the heme pathway subsequent to ALAS and the molecular abnormality is now known for the most common subtype of acute intermittent porphyria. In developing red cells, levels of ALAS are regulated by increased gene transcription and by a post-transcriptional mechanism, in which iron most probably controls translation of erythroid ALAS mRNA through an iron-responsive element identified in the 5' untranslated region of the mRNA. The human erythroid ALAS gene is located on the X-chromosome, suggesting that a defect in this gene may be responsible for X-linked sideroblastic anemias.
Mol Biol Med 1990 Oct
PMID:Molecular regulation of 5-aminolevulinate synthase. Diseases related to heme biosynthesis. 209 58

A 114-base-pair promoter fragment of the human porphobilinogen deaminase gene functioned in an erythroid-specific manner in transient transfection experiments. Site-directed mutagenesis of the binding site for the erythroid-specific transcription factor (NF-E1) or an adjacent CACCC motif abolished the promoter activity. Increasing the spacing between these sites progressively reduced promoter activity, but there was no evidence that a critical alignment of the two factors on the DNA helix was required.
Mol Cell Biol 1990 Jul
PMID:Synergy between the NF-E1 erythroid-specific transcription factor and the CACCC factor in the erythroid-specific promoter of the human porphobilinogen deaminase gene. 235 26

Molecular methods for directed mutagenesis in Candida albicans have relied on a combination of gene disruption by transformation to inactivate one allele and UV-induced mitotic recombination or point mutation to produce lesions in the second allele. An alternate method which uses two sequential gene disruptions was developed and used to construct a C. albicans mutant defective in a gene essential for synthesizing tetrapyrrole (uroporphyrinogen I synthase). The Candida gene was cloned from a random library by complementation of the hem3 mutation in Saccharomyces cerevisiae. The complementing region was limited to a approximately 2.0 kb fragment by subcloning and a Bg/II site was determined to be within an essential region. Linear fragments containing either the Candida URA3 or LEU2 gene inserted into the Bg/II site were used to disrupt both alleles of a leu2, ura3 mutant by sequential transformation. Ura+, Leu+ heme-requiring strains were recovered and identified as hem3 mutants by Southern hybridization, transformation to heme independence by the cloned gene, and enzyme assays.
Mol Gen Genet 1989 May
PMID:Isolation of hem3 mutants from Candida albicans by sequential gene disruption. 267 51

Porphyrins and activities of heme biosynthetic enzymes in Taenia solium cysticerci from porcine and human hosts, were examined in order to clarify the possible step where heme synthesis is interrupted. Porphyrins in the vesicular fluid of the parasite were predominantly coproporphyrin, followed by penta-carboxylated porphyrin, which together accounted for 90% of the accumulated porphyrins. Coproporphyrin and penta-carboxylated porphyrin were both type I and III isomers. Small amounts of protoporphyrin and uroporphyrin, and trace amounts of tri-, hexa- and hepta-carboxylated porphyrins were also detected. Fluorescence and phosphorescence spectra and lifetime studies revealed that at least 75% of the porphyrins were bound to metal, probably Zn, while the rest was free. Reverse phase high performance liquid chromatography monitored at an excitation wavelength of 417 nm and at an emission wavelength of 585 nm demonstrated that approximately 90% of these porphyrins were Zn-coproporphyrin. A fluorescence excitation peak at 283 nm with an emission peak at 585 nm and 625 nm indicated that some of the porphyrins were associated with proteins in the vesicular fluid of the parasite. Low levels of delta-aminolevulinic acid dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase activities, and heme concentrations were found in the extract of the parasite walls and scolex, but not in the vesicular fluid. The porphyrin accumulation pattern in this parasite can best be explained by postulating a deficiency of coproporphyrinogen oxidase activity, similar to that in human patients with hereditary coproporphyria. A parasite dissected from a human host was considerably less porphyric than those from pigs, but the pattern of accumulated porphyrins was quite similar in both. In view of their porphyrin contents, T. solium cysticerci could be light sensitive.
Mol Biochem Parasitol 1987 Jan 15
PMID:Analysis of porphyrins and enzymes in porphyrin synthesis in Taenia solium cysticercus from man and pig. 357 46

The inability to synthesize heme, a well known metabolic defect of trypanosomatid protozoa, accounts for their growth requirement for heme compounds in vitro. We now extend this finding to a pathogen Leishmania mexicana amazonensis, especially the intracellular replicative stage of amastigotes in the macrophage. We measured the level of heme and its biosynthetic enzymes, aminolevulinate dehydratase and porphobilinogen deaminase in the parasites and in infected and non-infected macrophages of J774G8 line. Succinylacetone was used to inhibit heme biosynthesis. Leishmanias transform and grow only in medium containing either heme (usually supplied as hemin) or protoporphyrin IX (the latter is leishmanicidal at high concentrations). We detected 1.2, 8.5 and 25 pmol mg-1 protein of heme in amastigotes, promastigotes and macrophages, respectively. The activities of porphobilinogen deaminase and aminolevulinate dehydratase in macrophages were 70 and 2400 pmol h-1 mg-1 protein, respectively. Leishmania-infected macrophages gave the same results and leishmanias had negligible activities of these enzymes. Succinylacetone at 10(-9)-10(-3) M had no effect on leishmanias, but dose-dependently inhibited the activity of aminolevulinate dehydratase to a negligible level and lowered that of porphobilinogen deaminase in macrophages, resulting in a maximum of 66% reduction in intracellular heme. Amastigotes grew equally well in succinylacetone-treated and control untreated macrophages. The results suggest that L. m. amazonensis, incapable of heme biosynthesis, acquires heme exogenously from the culture medium, i.e., fetal bovine serum, independent of the heme synthesized by the macrophages.
Mol Biochem Parasitol 1985 Sep
PMID:Heme requirement and acquisition by extracellular and intracellular stages of Leishmania mexicana amazonensis. 405 83

Heme-deficient mutants of Saccharomyces cerevisiae have been isolated from two isogenic strains with the use of an enrichment method based on photodynamic properties of Zn-protoporphyrin. They defined seven non-overlapping complementation groups. A mutant representative of each group was further analysed. Genetic analysis showed that each mutant carried a single nuclear recessive mutations. Biochemical studies showed that the observed accumulation and/or excretion of the different heme synthesis precursors by the mutant cells correlated well with the enzymatic deficiencies measured in acellular extracts. Six of the seven mutants were blocked in a different enzyme activity: 5-aminolevulinate synthase, porphobilinogen synthase, uroporphyrinogen I synthase, uroporphyrinogen decarboxylase, coproporphyrinogen III oxidase and ferrochelatase. The other mutant had the same phenotype as the mutant deficient in ferrochelatase activity. However, it possessed a normal ferrochelatase activity when measured in vitro, so this mutant was assumed to be deficient in protoporphyrinogen oxidase activity or in the transport and/or reduction of iron. The absence of PBG synthesis led to a total lack of uroporphyrinogen I synthase activity. The absence of heme, the end product, led to an important increase of coproporphyrinogen III oxidase activity, while the activity of 5-aminolevulinate synthase, the first enzyme of the pathway, was not changed. These results are discussed in terms of possible modes of regulation of heme synthesis pathway in yeast.
Mol Gen Genet 1981
PMID:Genetic and biochemical characterization of mutants of Saccharomyces cerevisiae blocked in six different steps of heme biosynthesis. 703 24


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