Human erythroid 5-aminolevulinate synthase: promoter analysis and identification of an iron-responsive element in the mRNA.

Cox, Timothy C.; Bawden, Michael J.; Martin, Angela K.; May, Brian K.

doi:10.1002/j.1460-2075.1991.tb07715.x

Cited by 363 publications

(198 citation statements)

References 53 publications

(102 reference statements)

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“…For example erythroid aminoluvenyl synthase mRNA encodes a 5Ј-UTR cap site-specific IRE and is translated more efficiently during iron influx into reticulocytes, leading to enhanced heme biosynthesis during red blood cell production (43). Also, the iron transporter gene encoding IREG1/ferriportin is crucial for the movement of iron from the gut into the blood and is known to encode functional IREs in the 5Ј-UTR (44,45).…”

Section: Discussionmentioning

confidence: 99%

An Iron-responsive Element Type II in the 5′-Untranslated Region of the Alzheimer's Amyloid Precursor Protein Transcript

Rogers¹,

Randall²,

Cahill³

et al. 2002

Journal of Biological Chemistry

500

432

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Iron-responsive elements (IREs) are the RNA stem loops that control cellular iron homeostasis by regulating ferritin translation and transferrin receptor mRNA stability. We mapped a novel iron-responsive element (IRE-Type II) within the 5-untranslated region (5-UTR) of the Alzheimer's amyloid precursor protein (APP) transcript (؉51 to ؉94 from the 5-cap site). The APP mRNA IRE is located immediately upstream of an interleukin-1 responsive acute box domain (؉101 to ؉146). APP 5-UTR conferred translation was selectively downregulated in response to intracellular iron chelation using three separate reporter assays (chloramphenicol acetyltransferase, luciferase, and red fluorescent protein reflecting an inhibition of APP holoprotein translation in response to iron chelation. Iron influx reversed this inhibition. As an internal control to ensure specificity, a viral internal ribosome entry sequence was unresponsive to intracellular iron chelation with desferrioxamine. Using RNA mobility shift assays, the APP 5-UTRs, encompassing the IRE, bind specifically to recombinant iron-regulatory proteins (IRP) and to IRP from neuroblastoma cell lysates. IRP binding to the APP 5-UTR is reduced after treatment of cells with desferrioxamine and increased after interleukin-1 stimulation. IRP binding is abrogated when APP cRNA probe is mutated in the core IRE domain (⌬4 bases:⌬83AGAG86). Iron regulation of APP mRNA through the APP 5-UTR points to a role for iron in the metabolism of APP and confirms that this RNA structure can be a target for the selection of small molecule drugs, such as desferrioxamine (Fe chelator) and clioquinol (Fe, Cu, and Zn chelator), which reduce A␤ peptide burden during Alzheimer's disease. The amyloid precursor protein (APP)1 is cleaved into the 40 -42-amino acid A␤ peptides that constitute the main component of the neurotoxic amyloid plaques formed during the progression of Alzheimer's disease (AD) and Down's syndrome (1, 2). In healthy individuals, APP holoprotein is expressed ubiquitously as a protein resembling a type I transmembrane receptor and metal-binding protein (3-6). Secreted APP (APP(s)) is neurotrophic (7).There are now several reports supporting an important role for translational regulatory mechanisms to control APP synthesis and probably A␤ peptide secretion in biologically relevant circumstances (8). First, interleukin-1 (IL-1), the first cytokine released during the acute phase response, significantly increases APP protein synthesis in astrocytes without altering APP mRNA levels (9). IL-1 acts by regulating APP and ferritin genes at the level of message translation (9). Second, reversible ischemic assault significantly increases APP levels without any alteration in the steady-state levels of APP mRNA in rabbit spinal cord neurons (10). Third, APP mRNA 3Ј-UTR sequences located between alternative poly(A) selection sites maintain efficient translation of microinjected APP in Xenopus oocytes and in Chinese hamster ovary transfectants (11).Iron-responsive elements (IREs) are RNA stem loops...

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Section: Discussionmentioning

confidence: 99%

An Iron-responsive Element Type II in the 5′-Untranslated Region of the Alzheimer's Amyloid Precursor Protein Transcript

Rogers¹,

Randall²,

Cahill³

et al. 2002

Journal of Biological Chemistry

500

432

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“…In addition, comparison of the deduced amino acid sequences of different ALAS proteins revealed extensive similarity, particularly centered in the C-terminal 70% of the eukaryotic mature proteins. This region has been designated the catalytic domain of ALAS (Cox et al, 1991). The lysine 313 residue occurs in this domain.…”

Section: Discussionmentioning

confidence: 99%

Heme biosynthesis in mammalian systems: Evidence of a schiff base linkage between the pyridoxal 5′‐phosphate cofactor and a lysine residue in 5‐aminolevulinate synthase

1993

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5-Aminolevulinate synthase is the first enzyme of the heme biosynthetic pathway in nonplant higher eukaryotes. Murine erythroid 5-aminolevulinate synthase has been purified to homogeneity from an Escherichia coli overproducing strain, and the catalytic and spectroscopic properties of this recombinant enzyme were compared with those from nonrecombinant sources (Ferreira, G.C. & Dailey, H.A., 1993, J. Biol. Chem. 268, 584-590). 5-Aminolevulinate synthase is a pyridoxal 5"phosphate-dependent enzyme and is functional as a homodimer.The recombinant 5-aminolevulinate synthase holoenzyme was reduced with tritiated sodium borohydride and digested with trypsin. A single peptide contained the majority of the label. The tritiated peptide was isolated, and its amino acid sequence was determined; it corresponded to 15 amino acids around lysine 313, to which pyridoxal 5"phosphate is bound. Significantly, the pyridoxyllysine peptide is conserved in all known cDNA-derived 5-aminolevulinate synthase sequences and is present in the C-terminal (catalytic) domain.Mutagenesis of the 5-aminolevulinate synthase residue, which is involved in the Schiff base linkage with pyridoxal 5'-phosphate, from lysine to alanine or histidine abolished enzyme activity in the expressed protein.

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“…6,7 The former impose iron-dependent inhibition of ALA-S mRNA translation, which prevents synthesis of PpIX when there is no iron available to convert it into heme. The latter impose end-product inhibition of mitochondrial import by heme, which avoids production of heme in excess of that needed for incorporation into proteins such as haemoglobin, cytochrome c, catalase and peroxidase.…”

Section: Figure 6 Photosensitisation By Ala-s Virus (A) Flow Cytometmentioning

confidence: 99%

“…Translation of the erythroid form is coordinated with the availability of iron by iron response elements (IREs) in the 5Ј-untranslated region in the mRNA. 6 Both forms of the enzyme contain sequences called heme regulatory motifs (HRMs) which bind heme and prevent mitochondrial import of the ALA-S pro-enzyme. 7 Mutation of the HRMs permits import and processing of the pro-enzyme to the mature form irrespective of the cytoplasmic heme concentration.…”

Section: Introductionmentioning

confidence: 99%

A photosensitising adenovirus for photodynamic therapy

Gagnebin

Brunori²,

Otter³

et al. 1999

Gene Ther

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We have developed a new approach to photodynamic thervirus genome and used it to construct a virus expressing apy based on adenoviral transduction of the rate-limiting a mutant form of ALA-S lacking the iron response elements enzyme in heme synthesis. Conventional phototherapy which regulate ALA-S translation and the heme regulatory uses porphyrin-based chemical photosensitisers, including motifs which regulate import of ALA-S into mitochondria. ␦-aminolaevulinic acid (ALA) which is converted to protoThe virus induces a large increase in PpIX expression and porphyrin IX (PpIX) by the enzymes of the heme biosynconfers photosensitivity on cultured cells. Unlike conventhetic pathway. The lack of a specific mechanism for tartional photodynamic therapy, a viral approach makes it geting chemical photosensitisers and PpIX to tumour cells possible to restrict photosensitivity by biological rather than means that therapeutic irradiation can damage normal purely physical or chemical means. As with HSV thymidine tissue and exposure to sunlight following treatment can kinase, ALA-S expression is a general mechanism for cause severe burns. The rate limiting enzyme in PpIX sensitisation to a therapeutic agent which can easily be synthesis is ALA-synthase (ALA-S). We have developed a adapted to whatever means of gene delivery is most new yeast vector system for manipulation of the adenoeffective.

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Human erythroid 5-aminolevulinate synthase: promoter analysis and identification of an iron-responsive element in the mRNA.

Cited by 363 publications

References 53 publications

An Iron-responsive Element Type II in the 5′-Untranslated Region of the Alzheimer's Amyloid Precursor Protein Transcript

An Iron-responsive Element Type II in the 5′-Untranslated Region of the Alzheimer's Amyloid Precursor Protein Transcript

Heme biosynthesis in mammalian systems: Evidence of a schiff base linkage between the pyridoxal 5′‐phosphate cofactor and a lysine residue in 5‐aminolevulinate synthase

A photosensitising adenovirus for photodynamic therapy

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