Differential regulation of human ALAS1 mRNA and protein levels by heme and cobalt protoporphyrin.

Molecular and Cellular Biochemistry
Jianyu ZhengH 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.

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Citations

Dec 6, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Christopher Trent BrewerTaosheng Chen
Sep 13, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Laurent GouyaKarl E Anderson
Dec 19, 2014·Reviews in Endocrine & Metabolic Disorders·Xinhui WangFudi Wang
Apr 30, 2011·Future Medicinal Chemistry·Laura A SoltThomas P Burris
Jan 8, 2020·Naunyn-Schmiedeberg's Archives of Pharmacology·Zuoyan WangJianjun Peng
Dec 19, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jennifer L EstallBruce M Spiegelman
Nov 6, 2014·Metabolites·Siddesh BesurHerbert L Bonkovsky
May 2, 2014·Frontiers in Pharmacology·Deborah ChiabrandoEmanuela Tolosano
Nov 22, 2015·The Journal of Pharmacology and Experimental Therapeutics·Madhav SacharXiaochao Ma
Mar 29, 2014·Archaea : an International Microbiological Journal·Melanie KühnerGunhild Layer
Mar 26, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Sheila MaestroAntonio Fontanellas
Nov 29, 2011·Biochimica Et Biophysica Acta·Sundararajan VenkateshCarolyn K Suzuki

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