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Article: Control of 5-aminolevulinate synthase in animals.

TitleControl of 5-aminolevulinate synthase in animals.
Authors
Issue Date1986
Citation
Current Topics In Cellular Regulation, 1986, v. 28, p. 233-262 How to Cite?
AbstractThe proposed mechanism by which hepatic ALV-synthase mitochondrial levels are regulated is outlined in Fig. 2. ALV-synthase catalyzes the first and rate-limiting step in the heme pathway and is normally present in low amounts. A cytosolic, regulatory free heme pool tightly controls the amount of ALV-synthase in two ways. In the primary mechanism of regulation, heme is proposed to inhibit the synthesis of ALV-synthase mRNA. Most likely this would be mediated through the action of specific heme-binding protein(s) which recognize regulatory control regions of the ALV-synthase gene. Gene activity therefore is significantly repressed most of the time. When there is an increased demand for heme by newly synthesized cellular hemoproteins, the free heme pool is reduced, leading to a derepression of ALV-synthase mRNA synthesis. Once the need for increased heme synthesis is satisfied, inhibitory heme levels build up again. When drugs such as phenobarbital are administered to animals, there is a rapid induction in the liver of both cytochrome P-450 and ALV-synthase. It is proposed that the heme pool governing ALV-synthase levels is lowered by the increased heme demand due to cytochrome P-450 apoprotein formation. The primary event in the drug induction of ALV-synthase is therefore the increased synthesis of cytochrome P-450 apoprotein. However, the mechanism by which this occurs is unknown, although drugs do increase the synthesis of mRNA for cytochrome P-450 (Fig. 2). (There is evidence that for the aromatic hydrocarbons a specific cytosolic receptor exists.) In the acute hepatic porphyria diseases, uncontrolled synthesis of hepatic ALV-synthase occurs. The various forms are characterized by reduced levels of one of the heme pathway enzymes other than ALV-synthase. Attacks of the disease are commonly precipitated by drugs which induce cytochrome P-450, and the uncontrolled accumulation of ALV-synthase which accompanies these attacks results from the combined action of the block in the heme pathway and the increased cytochrome P-450 levels. A major challenge which now exists is to understand at the molecular level how the genes for ALV-synthase and cytochrome P-450 are regulated in the liver and other tissues.(ABSTRACT TRUNCATED AT 400 WORDS)
Persistent Identifierhttp://hdl.handle.net/10722/147781
ISSN
2001 Impact Factor: 4.364
2004 SCImago Journal Rankings: 2.922
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMay, BKen_US
dc.contributor.authorBorthwick, IAen_US
dc.contributor.authorSrivastava, Gen_US
dc.contributor.authorPirola, BAen_US
dc.contributor.authorElliott, WHen_US
dc.date.accessioned2012-05-29T06:09:11Z-
dc.date.available2012-05-29T06:09:11Z-
dc.date.issued1986en_US
dc.identifier.citationCurrent Topics In Cellular Regulation, 1986, v. 28, p. 233-262en_US
dc.identifier.issn0070-2137en_US
dc.identifier.urihttp://hdl.handle.net/10722/147781-
dc.description.abstractThe proposed mechanism by which hepatic ALV-synthase mitochondrial levels are regulated is outlined in Fig. 2. ALV-synthase catalyzes the first and rate-limiting step in the heme pathway and is normally present in low amounts. A cytosolic, regulatory free heme pool tightly controls the amount of ALV-synthase in two ways. In the primary mechanism of regulation, heme is proposed to inhibit the synthesis of ALV-synthase mRNA. Most likely this would be mediated through the action of specific heme-binding protein(s) which recognize regulatory control regions of the ALV-synthase gene. Gene activity therefore is significantly repressed most of the time. When there is an increased demand for heme by newly synthesized cellular hemoproteins, the free heme pool is reduced, leading to a derepression of ALV-synthase mRNA synthesis. Once the need for increased heme synthesis is satisfied, inhibitory heme levels build up again. When drugs such as phenobarbital are administered to animals, there is a rapid induction in the liver of both cytochrome P-450 and ALV-synthase. It is proposed that the heme pool governing ALV-synthase levels is lowered by the increased heme demand due to cytochrome P-450 apoprotein formation. The primary event in the drug induction of ALV-synthase is therefore the increased synthesis of cytochrome P-450 apoprotein. However, the mechanism by which this occurs is unknown, although drugs do increase the synthesis of mRNA for cytochrome P-450 (Fig. 2). (There is evidence that for the aromatic hydrocarbons a specific cytosolic receptor exists.) In the acute hepatic porphyria diseases, uncontrolled synthesis of hepatic ALV-synthase occurs. The various forms are characterized by reduced levels of one of the heme pathway enzymes other than ALV-synthase. Attacks of the disease are commonly precipitated by drugs which induce cytochrome P-450, and the uncontrolled accumulation of ALV-synthase which accompanies these attacks results from the combined action of the block in the heme pathway and the increased cytochrome P-450 levels. A major challenge which now exists is to understand at the molecular level how the genes for ALV-synthase and cytochrome P-450 are regulated in the liver and other tissues.(ABSTRACT TRUNCATED AT 400 WORDS)en_US
dc.languageengen_US
dc.relation.ispartofCurrent topics in cellular regulationen_US
dc.subject.mesh5-Aminolevulinate Synthetase - Metabolismen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCytosol - Enzymologyen_US
dc.subject.meshHeme - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshLiver - Enzymologyen_US
dc.subject.meshMitochondria - Enzymologyen_US
dc.subject.meshMitochondria, Liver - Enzymologyen_US
dc.subject.meshPorphyrias - Enzymologyen_US
dc.subject.meshReticulocytes - Enzymologyen_US
dc.titleControl of 5-aminolevulinate synthase in animals.en_US
dc.typeArticleen_US
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid3539534-
dc.identifier.scopuseid_2-s2.0-0023011663en_US
dc.identifier.volume28en_US
dc.identifier.spage233en_US
dc.identifier.epage262en_US
dc.identifier.isiWOS:A1986H888600006-
dc.publisher.placeUnited Statesen_US

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