Oxidation of 4‐hydroxy‐2‐nonenal by succinic semialdehyde dehydrogenase (ALDH5A)
Elevated levels of 4‐hydroxy‐trans‐2‐nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well‐characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non‐toxic metabolite in the rat cerebral c...
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| Veröffentlicht in: | Journal of neurochemistry 2003-07, Vol.86 (2), p.298-305 |
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| creator | Murphy, Tonya C. Amarnath, Venkataraman Gibson, K. Michael Picklo Sr, Matthew J. |
| description | Elevated levels of 4‐hydroxy‐trans‐2‐nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well‐characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non‐toxic metabolite in the rat cerebral cortex by mitochondrial aldehyde dehydrogenases (ALDHs). Two possible ALDH enzymes which might oxidize HNE in CNS mitochondria are ALDH2 and succinic semialdehyde dehydrogenase (SSADH/ALDH5A). It was previously established that hepatic ALDH2 can oxidize HNE. In this work, we tested the hypothesis that SSADH oxidizes HNE. SSADH is critical in the detoxification of the GABA metabolite, succinic semialdehyde (SSA). Recombinant rat SSADH oxidized HNE and other α,β‐unsaturated aldehydes. Inhibition and competition studies in rat brain mitochondria showed that SSADH was the predominant oxidizing enzyme for HNE but only contributed a portion of the total oxidizing activity in liver mitochondria. In vivo administration of diethyldithiocarbamate (DEDC) effectively inhibited (86%) ALDH2 activity but not HNE oxidation in liver mitochondria. The data suggest that a relationship between the detoxification of SSA and the neurotoxic aldehyde HNE exists in the CNS. Furthermore, these studies show that multiple hepatic aldehyde dehydrogenases are able to oxidize HNE. |
| doi_str_mv | 10.1046/j.1471-4159.2003.01839.x |
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Michael ; Picklo Sr, Matthew J.</creator><creatorcontrib>Murphy, Tonya C. ; Amarnath, Venkataraman ; Gibson, K. Michael ; Picklo Sr, Matthew J.</creatorcontrib><description>Elevated levels of 4‐hydroxy‐trans‐2‐nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well‐characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non‐toxic metabolite in the rat cerebral cortex by mitochondrial aldehyde dehydrogenases (ALDHs). Two possible ALDH enzymes which might oxidize HNE in CNS mitochondria are ALDH2 and succinic semialdehyde dehydrogenase (SSADH/ALDH5A). It was previously established that hepatic ALDH2 can oxidize HNE. In this work, we tested the hypothesis that SSADH oxidizes HNE. SSADH is critical in the detoxification of the GABA metabolite, succinic semialdehyde (SSA). Recombinant rat SSADH oxidized HNE and other α,β‐unsaturated aldehydes. Inhibition and competition studies in rat brain mitochondria showed that SSADH was the predominant oxidizing enzyme for HNE but only contributed a portion of the total oxidizing activity in liver mitochondria. In vivo administration of diethyldithiocarbamate (DEDC) effectively inhibited (86%) ALDH2 activity but not HNE oxidation in liver mitochondria. The data suggest that a relationship between the detoxification of SSA and the neurotoxic aldehyde HNE exists in the CNS. Furthermore, these studies show that multiple hepatic aldehyde dehydrogenases are able to oxidize HNE.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1046/j.1471-4159.2003.01839.x</identifier><identifier>PMID: 12871571</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>4-hydroxy-2-nonenal ; Aldehyde Dehydrogenase - antagonists & inhibitors ; Aldehyde Dehydrogenase - chemistry ; Aldehyde Dehydrogenase - metabolism ; Aldehyde Dehydrogenase, Mitochondrial ; aldehyde dehydrogenases ; Aldehyde Oxidoreductases - chemistry ; Aldehyde Oxidoreductases - isolation & purification ; Aldehyde Oxidoreductases - metabolism ; Aldehydes - chemistry ; Aldehydes - metabolism ; ALDH2 ; Alzheimer's disease ; Animals ; Benomyl - pharmacology ; Biological and medical sciences ; Brain Chemistry ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Ditiocarb - pharmacology ; Enzyme Inhibitors - pharmacology ; gamma-Aminobutyric Acid - analogs & derivatives ; gamma-Aminobutyric Acid - metabolism ; gamma-Aminobutyric Acid - pharmacology ; lipid peroxidation ; Male ; Medical sciences ; Mitochondria - chemistry ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria, Liver - chemistry ; Mitochondria, Liver - drug effects ; Mitochondria, Liver - metabolism ; Neurology ; Oxidation-Reduction - drug effects ; Rats ; Rats, Sprague-Dawley ; Succinate-Semialdehyde Dehydrogenase ; succinic semialdehyde dehydrogenase</subject><ispartof>Journal of neurochemistry, 2003-07, Vol.86 (2), p.298-305</ispartof><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4769-d86533a610d05821c7ed6d9382fdcc16ef8839c39e4ca2cc364a8331b9f72d13</citedby><cites>FETCH-LOGICAL-c4769-d86533a610d05821c7ed6d9382fdcc16ef8839c39e4ca2cc364a8331b9f72d13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1471-4159.2003.01839.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1471-4159.2003.01839.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,1433,27923,27924,45573,45574,46408,46832</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14940978$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12871571$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Murphy, Tonya C.</creatorcontrib><creatorcontrib>Amarnath, Venkataraman</creatorcontrib><creatorcontrib>Gibson, K. Michael</creatorcontrib><creatorcontrib>Picklo Sr, Matthew J.</creatorcontrib><title>Oxidation of 4‐hydroxy‐2‐nonenal by succinic semialdehyde dehydrogenase (ALDH5A)</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>Elevated levels of 4‐hydroxy‐trans‐2‐nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well‐characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non‐toxic metabolite in the rat cerebral cortex by mitochondrial aldehyde dehydrogenases (ALDHs). Two possible ALDH enzymes which might oxidize HNE in CNS mitochondria are ALDH2 and succinic semialdehyde dehydrogenase (SSADH/ALDH5A). It was previously established that hepatic ALDH2 can oxidize HNE. In this work, we tested the hypothesis that SSADH oxidizes HNE. SSADH is critical in the detoxification of the GABA metabolite, succinic semialdehyde (SSA). Recombinant rat SSADH oxidized HNE and other α,β‐unsaturated aldehydes. Inhibition and competition studies in rat brain mitochondria showed that SSADH was the predominant oxidizing enzyme for HNE but only contributed a portion of the total oxidizing activity in liver mitochondria. In vivo administration of diethyldithiocarbamate (DEDC) effectively inhibited (86%) ALDH2 activity but not HNE oxidation in liver mitochondria. The data suggest that a relationship between the detoxification of SSA and the neurotoxic aldehyde HNE exists in the CNS. Furthermore, these studies show that multiple hepatic aldehyde dehydrogenases are able to oxidize HNE.</description><subject>4-hydroxy-2-nonenal</subject><subject>Aldehyde Dehydrogenase - antagonists & inhibitors</subject><subject>Aldehyde Dehydrogenase - chemistry</subject><subject>Aldehyde Dehydrogenase - metabolism</subject><subject>Aldehyde Dehydrogenase, Mitochondrial</subject><subject>aldehyde dehydrogenases</subject><subject>Aldehyde Oxidoreductases - chemistry</subject><subject>Aldehyde Oxidoreductases - isolation & purification</subject><subject>Aldehyde Oxidoreductases - metabolism</subject><subject>Aldehydes - chemistry</subject><subject>Aldehydes - metabolism</subject><subject>ALDH2</subject><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Benomyl - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Brain Chemistry</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Ditiocarb - pharmacology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>gamma-Aminobutyric Acid - analogs & derivatives</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>gamma-Aminobutyric Acid - pharmacology</subject><subject>lipid peroxidation</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mitochondria - chemistry</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria, Liver - chemistry</subject><subject>Mitochondria, Liver - drug effects</subject><subject>Mitochondria, Liver - metabolism</subject><subject>Neurology</subject><subject>Oxidation-Reduction - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Succinate-Semialdehyde Dehydrogenase</subject><subject>succinic semialdehyde dehydrogenase</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkEtOwzAQhi0EgvK4AsoGBIsEj-049oJFVd6qYIPYWq7tgKs0gbgVzY4jcEZOgkMr2LKw_pH8jWf8IZQAzgAzfjbNgBWQMshlRjCmGQZBZbbcQIPfi000wJiQlGJGdtBuCFOMgTMO22gHiCggL2CAnh6W3uq5b-qkKRP29fH50tm2WXaxIvHUTe1qXSWTLgkLY3ztTRLczOvKuki65Cfa5jlSwSUnw_HFTT483Udbpa6CO1jnHnq8unwc3aTjh-vb0XCcGlZwmVrBc0o1B2xxLgiYwlluJRWktMYAd6WI_zJUOmY0MYZypgWlMJFlQSzQPXS8eva1bd4WLszVzAfjqkrXrlkEBULSgjMcQbECTduE0LpSvbZ-pttOAVa9UjVVvTnVm1O9UvWjVC1j6-F6xmIyc_avce0wAkdrQAejq7LVtfHhj2OSYVmIyJ2vuHdfue7fC6i7-1Ff0W-8R5O1</recordid><startdate>200307</startdate><enddate>200307</enddate><creator>Murphy, Tonya C.</creator><creator>Amarnath, Venkataraman</creator><creator>Gibson, K. Michael</creator><creator>Picklo Sr, Matthew J.</creator><general>Blackwell Science Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope></search><sort><creationdate>200307</creationdate><title>Oxidation of 4‐hydroxy‐2‐nonenal by succinic semialdehyde dehydrogenase (ALDH5A)</title><author>Murphy, Tonya C. ; Amarnath, Venkataraman ; Gibson, K. Michael ; Picklo Sr, Matthew J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4769-d86533a610d05821c7ed6d9382fdcc16ef8839c39e4ca2cc364a8331b9f72d13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>4-hydroxy-2-nonenal</topic><topic>Aldehyde Dehydrogenase - antagonists & inhibitors</topic><topic>Aldehyde Dehydrogenase - chemistry</topic><topic>Aldehyde Dehydrogenase - metabolism</topic><topic>Aldehyde Dehydrogenase, Mitochondrial</topic><topic>aldehyde dehydrogenases</topic><topic>Aldehyde Oxidoreductases - chemistry</topic><topic>Aldehyde Oxidoreductases - isolation & purification</topic><topic>Aldehyde Oxidoreductases - metabolism</topic><topic>Aldehydes - chemistry</topic><topic>Aldehydes - metabolism</topic><topic>ALDH2</topic><topic>Alzheimer's disease</topic><topic>Animals</topic><topic>Benomyl - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Brain Chemistry</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Ditiocarb - pharmacology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>gamma-Aminobutyric Acid - analogs & derivatives</topic><topic>gamma-Aminobutyric Acid - metabolism</topic><topic>gamma-Aminobutyric Acid - pharmacology</topic><topic>lipid peroxidation</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mitochondria - chemistry</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria, Liver - chemistry</topic><topic>Mitochondria, Liver - drug effects</topic><topic>Mitochondria, Liver - metabolism</topic><topic>Neurology</topic><topic>Oxidation-Reduction - drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Succinate-Semialdehyde Dehydrogenase</topic><topic>succinic semialdehyde dehydrogenase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Murphy, Tonya C.</creatorcontrib><creatorcontrib>Amarnath, Venkataraman</creatorcontrib><creatorcontrib>Gibson, K. Michael</creatorcontrib><creatorcontrib>Picklo Sr, Matthew J.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Murphy, Tonya C.</au><au>Amarnath, Venkataraman</au><au>Gibson, K. Michael</au><au>Picklo Sr, Matthew J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oxidation of 4‐hydroxy‐2‐nonenal by succinic semialdehyde dehydrogenase (ALDH5A)</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2003-07</date><risdate>2003</risdate><volume>86</volume><issue>2</issue><spage>298</spage><epage>305</epage><pages>298-305</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>Elevated levels of 4‐hydroxy‐trans‐2‐nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well‐characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non‐toxic metabolite in the rat cerebral cortex by mitochondrial aldehyde dehydrogenases (ALDHs). Two possible ALDH enzymes which might oxidize HNE in CNS mitochondria are ALDH2 and succinic semialdehyde dehydrogenase (SSADH/ALDH5A). It was previously established that hepatic ALDH2 can oxidize HNE. In this work, we tested the hypothesis that SSADH oxidizes HNE. SSADH is critical in the detoxification of the GABA metabolite, succinic semialdehyde (SSA). Recombinant rat SSADH oxidized HNE and other α,β‐unsaturated aldehydes. Inhibition and competition studies in rat brain mitochondria showed that SSADH was the predominant oxidizing enzyme for HNE but only contributed a portion of the total oxidizing activity in liver mitochondria. In vivo administration of diethyldithiocarbamate (DEDC) effectively inhibited (86%) ALDH2 activity but not HNE oxidation in liver mitochondria. The data suggest that a relationship between the detoxification of SSA and the neurotoxic aldehyde HNE exists in the CNS. Furthermore, these studies show that multiple hepatic aldehyde dehydrogenases are able to oxidize HNE.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>12871571</pmid><doi>10.1046/j.1471-4159.2003.01839.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 4-hydroxy-2-nonenal Aldehyde Dehydrogenase - antagonists & inhibitors Aldehyde Dehydrogenase - chemistry Aldehyde Dehydrogenase - metabolism Aldehyde Dehydrogenase, Mitochondrial aldehyde dehydrogenases Aldehyde Oxidoreductases - chemistry Aldehyde Oxidoreductases - isolation & purification Aldehyde Oxidoreductases - metabolism Aldehydes - chemistry Aldehydes - metabolism ALDH2 Alzheimer's disease Animals Benomyl - pharmacology Biological and medical sciences Brain Chemistry Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Ditiocarb - pharmacology Enzyme Inhibitors - pharmacology gamma-Aminobutyric Acid - analogs & derivatives gamma-Aminobutyric Acid - metabolism gamma-Aminobutyric Acid - pharmacology lipid peroxidation Male Medical sciences Mitochondria - chemistry Mitochondria - drug effects Mitochondria - metabolism Mitochondria, Liver - chemistry Mitochondria, Liver - drug effects Mitochondria, Liver - metabolism Neurology Oxidation-Reduction - drug effects Rats Rats, Sprague-Dawley Succinate-Semialdehyde Dehydrogenase succinic semialdehyde dehydrogenase |
| title | Oxidation of 4‐hydroxy‐2‐nonenal by succinic semialdehyde dehydrogenase (ALDH5A) |
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