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Herbert L. Bonkovsky – One of the best experts on this subject based on the ideXlab platform.

  • phase 3 trial of rnai therapeutic givosiran for acute intermittent porphyria
    The New England Journal of Medicine, 2020
    Co-Authors: Manisha Balwani, Herbert L. Bonkovsky, Eliane Sardh, David C Rees, Montgomery D Bissell, Paolo Ventura, Paula Aguilera Peiro, Ulrich Stolzel, Jerzy Windyga, Karl E. Anderson

    Abstract:

    Abstract Background Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the path…

  • phase 1 trial of an rna interference therapy for acute intermittent porphyria
    The New England Journal of Medicine, 2019
    Co-Authors: Eliane Sardh, Robert J Desnick, John D Phillips, Pauline Harper, Manisha Balwani, Penelope E Stein, David C Rees, Montgomery D Bissell, Charles J Parker, Herbert L. Bonkovsky

    Abstract:

    Abstract Background Induction of delta aminolevulinic acid synthase 1 (ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations…

  • Differential regulation of human ALAS1 mRNA and protein levels by heme and cobalt protoporphyrin
    Molecular and Cellular Biochemistry, 2008
    Co-Authors: Jianyu Zheng, Ying Shan, Richard W. Lambrecht, Susan E. Donohue, Herbert L. Bonkovsky

    Abstract:

    5-Aminolevulinic acid synthase 1 (ALAS1) is the first and rate-controlling enzyme of heme biosynthesis. This study was to determine the effects of heme and selected nonheme metalloporphyrins on human ALAS1 gene expression in hepatocytes. We found that, upon heme and cobalt protoporphyrin (CoPP) treatments, ALAS1 mRNA levels were down-regulated significantly by ca. 50% or more. Measurement of mRNA in the presence of actinomycin D showed that these down-regulations were due to the decreases in mRNA half-lives. Furthermore, the levels of mitochondrial mature ALAS1 protein were down-regulated by 60–70%, but those of the cytosolic precursor protein were up-regulated by 2–5-fold. Measurement of protein in the presence of cycloheximide (CHX) suggests that elevation of the precursor form is due to the increase in protein half-lives. These results provide novel insights into the mechanisms of heme repressional effects on ALAS1 and provide a rationale for further investigation of CoPP as a therapeutic agent for acute porphyric syndromes.

F. Annane – One of the best experts on this subject based on the ideXlab platform.

  • first principle investigation of alas and alp compounds and ordered ALAS1 xpx alloys
    Computational Materials Science, 2010
    Co-Authors: F. Annane, H. Meradji, S. Ghemid, El Haj F Hassan

    Abstract:

    Abstract We have investigated the structural and electronic properties of AlAs and AlP compounds and of ordered ALAS1−xPx alloys using the full potential linearized augmented plane wave plus local orbitals (FP-LAPW + lo) method based on density functional theory. The total energies and structural quantities of those compounds have been calculated for different approximations of exchange–correlation energy. The electronic quantities have been found to be in good agreement with the corresponding measured ones when the compounds were defined by the lattice constants of Perdew–Wang-generalized gradient approximation (PW-GGA) scheme. The PW-GGA approach was also applied on ordered ALAS1−xPx alloys to study the effect of composition on lattice constant, band gap, and refractive index of ALAS1−xPx ternary alloys. The calculated lattice constants scale linearly with composition (Vegard’s law). The microscopic origins of the gap bowing were explained by using the approach of Zunger and co-workers. In addition to (FP-LAPW + lo) method, the composition dependence of the refractive index was studied by Reedy and Nazeer model. The thermodynamic stability of these alloys was investigated by calculating the excess enthalpy of mixing ΔHm as well as the phase diagram.

  • First principle investigation of AlAs and AlP compounds and ordered ALAS1−xPx alloys
    Computational Materials Science, 2010
    Co-Authors: F. Annane, H. Meradji, S. Ghemid, F. El Haj Hassan

    Abstract:

    Abstract We have investigated the structural and electronic properties of AlAs and AlP compounds and of ordered ALAS1−xPx alloys using the full potential linearized augmented plane wave plus local orbitals (FP-LAPW + lo) method based on density functional theory. The total energies and structural quantities of those compounds have been calculated for different approximations of exchange–correlation energy. The electronic quantities have been found to be in good agreement with the corresponding measured ones when the compounds were defined by the lattice constants of Perdew–Wang-generalized gradient approximation (PW-GGA) scheme. The PW-GGA approach was also applied on ordered ALAS1−xPx alloys to study the effect of composition on lattice constant, band gap, and refractive index of ALAS1−xPx ternary alloys. The calculated lattice constants scale linearly with composition (Vegard’s law). The microscopic origins of the gap bowing were explained by using the approach of Zunger and co-workers. In addition to (FP-LAPW + lo) method, the composition dependence of the refractive index was studied by Reedy and Nazeer model. The thermodynamic stability of these alloys was investigated by calculating the excess enthalpy of mixing ΔHm as well as the phase diagram.

Robert J Desnick – One of the best experts on this subject based on the ideXlab platform.

  • 5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin.
    Molecular genetics and metabolism, 2020
    Co-Authors: Arian Pourmehdi Lahiji, Robert J Desnick, Karl E. Anderson, Amy Chan, Amy Simon, V. M. Sadagopa Ramanujam

    Abstract:

    Abstract Background 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an ultrarare autosomal recessive disease, with only eight documented cases, all of whom were males. Although classified as an acute hepatic porphyria (AHP), induction of the rate limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) has not been demonstrated, and the marrow may also contribute excess 5-aminolevulinic acid (ALA). Two patients have died and reported follow up for the others is limited, so the natural history of this disease is poorly understood and treatment experience limited. Methods We report new molecular findings and update the clinical course and treatment of the sixth reported ADP patient, now 31 years old and the only known case in the Americas, and review published data regarding genotype-phenotype correlation and treatment. Results Circulating hepatic 5-aminolevulinic acid synthase-1 (ALAS1) mRNA was elevated in this case, as in other AHPs. Gain of function mutation of erythroid specific ALAS2 – an X-linked modifying gene in some other porphyrias – was not found. Seven reported ADP cases had compound heterozygous ALAD mutations resulting in very low residual ALAD activity and symptoms early in life or adolescence. One adult with a germline ALAD mutant allele developed ADP in association with a clonal myeloproliferative disorder, polycythemia vera. Conclusions Elevation in circulating hepatic ALAS1 and response to treatment with hemin indicate that the liver is an important source of excess ALA in ADP, although the marrow may also contribute. Intravenous hemin was effective in most reported cases for treatment and prevention of acute attacks of neurological symptoms.

  • phase 1 trial of an rna interference therapy for acute intermittent porphyria
    The New England Journal of Medicine, 2019
    Co-Authors: Eliane Sardh, Robert J Desnick, John D Phillips, Pauline Harper, Manisha Balwani, Penelope E Stein, David C Rees, Montgomery D Bissell, Charles J Parker, Herbert L. Bonkovsky

    Abstract:

    Abstract Background Induction of delta aminolevulinic acid synthase 1 (ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations…

  • Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants
    BMC, 2019
    Co-Authors: Vassili Tchaikovskii, Robert J Desnick, David F Bishop

    Abstract:

    Abstract Background X-linked protoporphyria (XLP) (MIM 300752) is an erythropoietic porphyria due to gain-of-function mutations in the last exon (Ducamp et al., Hum Mol Genet 22:1280-88, 2013) of the erythroid-specific aminolevulinate synthase gene (ALAS2). Five ALAS2 exon 11 variants identified by the NHBLI Exome sequencing project (p.R559H, p.E565D, p.R572C, p.S573F and p.Y586F) were expressed, purified and characterized in order to assess their possible contribution to XLP. To further characterize the XLP gain-of-function region, five novel ALAS2 truncation mutations (p.P561X, p.V562X, p.H563X, p.E569X and p.F575X) were also expressed and studied. Methods Site-directed mutagenesis was used to generate ALAS2 mutant clones and all were prokaryotically expressed, purified to near homogeneity and characterized by protein and enzyme kinetic assays. Standard deviations were calculated for 3 or more assay replicates. Results The five ALAS2 single nucleotide variants had from 1.3- to 1.9-fold increases in succinyl-CoA Vmax and 2- to 3-fold increases in thermostability suggesting that most could be gain-of-function modifiers of porphyria instead of causes. One SNP (p.R559H) had markedly low purification yield indicating enzyme instability as the likely cause for XLSA in an elderly patient with x-linked sideroblastic anemia. The five novel ALAS2 truncation mutations had increased Vmax values for both succinyl-CoA and glycine substrates (1.4 to 5.6-fold over wild-type), while the Kms for both substrates were only modestly changed. Of interest, the thermostabilities of the truncated ALAS2 mutants were significantly lower than wild-type, with an inverse relationship to Vmax fold-increase. Conclusions Patients with porphyrias should always be assessed for the presence of the ALAS2 gain-of-function modifier variants identified here. A key region of the ALAS2 carboxyterminal region is identified by the truncation mutations studied here and the correlation of increased thermolability with activity suggests that increased molecular flexibility/active site openness is the mechanism of enhanced function of mutations in this region providing further insights into the role of the carboxyl-terminal region of ALAS2 in the regulation of erythroid heme synthesis