Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.61 (porphobilinogen deaminase)
 637 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

Mutants of Escherichia coli K12 which accumulated the haem precursor porphobilinogen are described. The mutants grew very slowly on carbon and energy sources which K12 uses only oxidatively, and they had low catalase activities, suggesting that they were deficient in haem. Extracts had one-tenth of the parental activity of the enzyme porphobilinogen deaminase. In transduction, the mutation mapped close to genes ilvD and metE at minute 84. The gene was tentatively identified as hemC, coding for porphobilinogen deaminase. The gene symbol hemC replaces the earlier and temporary symbol popE.
J Gen Microbiol 1979 Mar
PMID:Mutants of Escherichia coli K12 accumulating porphobilinogen: a new locus, hemC. 37 77

Four independent porphobilinogen-accumulating mutants of Salmonella typhimurium LT2 were isolated by selecting for dwarf colony formation on neomycin agar media. Cell-free extracts of the parent strain, but not of the mutants, were able to convert 5-aminolaevulinic acid or porphobilinogen to porphyrins. The results indicated that the mutants were deficient in uroporphyrinogen I synthase (EC. 4.3.I. 8) activity: these are the first mutants of this type reported in S. typhimurium LT2. Mapping of the hemC locus (for uroporphyrinogen I synthase) by F-mediated conjugation and by P22-mediated transduction showed the gene sequence ilvEDAC-hemC-cya-metE.
J Gen Microbiol 1976 Jun
PMID:Porphobilinogen-accumulating mutants of Salmonella typhimurium LT2. 78 Nov 81

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

The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score, less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.
Arch Gen Psychiatry 1991 Jul
PMID:No linkage between D2 dopamine receptor gene region and schizophrenia. 206 95

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

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

The long arm of chromosome 11 is of interest in schizophrenia research because of three independent reports of balanced 11q translocations cosegregating with schizophrenia and other major psychiatric illness in pedigrees. In addition, a number of candidate genes for psychosis are located in the translocated regions. These include the dopamine D2 receptor, porphobilinogen deaminase, which has shown an allelic association with schizophrenia, and neural cell adhesion molecule, a cell surface glycoprotein involved in neuronal cell-cell recognition during brain development. To search for a schizophrenia locus on chromosome 11q, we conducted linkage analyses in 12 multiplex pedigrees. Sixteen DNA markers, including the above three candidate genes, were used to screen the entire long arm of chromosome 11. None of these markers were supportive of linkage to schizophrenia regardless of whether the affected phenotype was defined narrowly or broadly, whether high or low penetrance was assumed. Both dominant and recessive models tested more than 130 centimorgans of chromosome 11q, and therefore, the reported translocation regions. The results provide no evidence for a susceptibility locus for schizophrenia on chromosome 11q in these pedigrees.
Arch Gen Psychiatry 1993 Mar
PMID:A linkage study of chromosome 11q in schizophrenia. 843 42

Human porphobilinogen deaminase (PBGD), the third enzyme in the heme pathway, catalyzes four times a single reaction to convert porphobilinogen into hydroxymethylbilane. Remarkably, PBGD employs a single active site during the process, with a distinct yet chemically equivalent bond formed each time. The four intermediate complexes of the enzyme have been biochemically validated and they can be isolated but they have never been structurally characterized other than the apo- and holo-enzyme bound to the cofactor. We present crystal structures for two human PBGD intermediates: PBGD loaded with the cofactor and with the reaction intermediate containing two additional substrate pyrrole rings. These results, combined with SAXS and NMR experiments, allow us to propose a mechanism for the reaction progression that requires less structural rearrangements than previously suggested: the enzyme slides a flexible loop over the growing-product active site cavity. The structures and the mechanism proposed for this essential reaction explain how a set of missense mutations result in acute intermittent porphyria.
Biochim Biophys Acta Gen Subj 2018 09
PMID:Structural basis of pyrrole polymerization in human porphobilinogen deaminase. 2990 16