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  1. Article: Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T schwannoma cells.

    Alderson, Nathan L / Hama, Hiroko

    Journal of lipid research

    2009  Volume 50, Issue 6, Page(s) 1203–1208

    Abstract: Sphingolipids are ubiquitous components of eukaryotic cells that regulate various cellular functions. In many cell types, a fraction of sphingolipids contain 2-hydroxy fatty acids, produced by fatty acid 2-hydroxylase (FA2H), as the N-acyl chain of ... ...

    Abstract Sphingolipids are ubiquitous components of eukaryotic cells that regulate various cellular functions. In many cell types, a fraction of sphingolipids contain 2-hydroxy fatty acids, produced by fatty acid 2-hydroxylase (FA2H), as the N-acyl chain of ceramide [hydroxyl fatty acid (hFA)-sphingolipids]. FA2H is highly expressed in myelin-forming cells of the nervous system and in epidermal keratinocytes. While hFA-sphingolipids are thought to enhance the physical stability of specialized membranes produced by these cells, physiological significance of hFA-sphingolipids in many other cell types is unknown. In this study, we report novel roles for FA2H and hFA-sphingolipids in the regulation of the cell cycle. Treatment of D6P2T Schwannoma cells with dibutyryl-cAMP (db-cAMP) induced exit from the cell cycle with concomitant upregulation of FA2H. Partial silencing of FA2H in D6P2T cells resulted in 60-70% reduction of hFA-dihydroceramide and hFA-ceramide, with no effect on nonhydroxy dihydroceramide and ceramide. Under these conditions, db-cAMP no longer induced cell cycle exit, and cells continued to grow and divide. Immunoblot analyses revealed that FA2H silencing prevented db-cAMP-induced upregulation of cyclin-dependent kinase inhibitors p21 and p27. These results provide evidence that FA2H is a negative regulator of the cell cycle and facilitates db-cAMP-induced cell cycle exit in D6P2T cells.
    MeSH term(s) Animals ; Bucladesine/pharmacology ; Cell Cycle/drug effects ; Cell Cycle/physiology ; Cell Line, Tumor ; Ceramides/metabolism ; Fatty Acids/metabolism ; Gene Silencing ; Mixed Function Oxygenases/antagonists & inhibitors ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Neurilemmoma/enzymology ; Neurilemmoma/pathology ; RNA, Small Interfering/genetics ; Rats ; Sphingolipids/metabolism ; Up-Regulation/drug effects
    Chemical Substances Ceramides ; Fatty Acids ; RNA, Small Interfering ; Sphingolipids ; Bucladesine (63X7MBT2LQ) ; Mixed Function Oxygenases (EC 1.-) ; fatty acid alpha-hydroxylase (EC 1.-)
    Language English
    Publishing date 2009-01-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    DOI 10.1194/jlr.M800666-JLR200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T Schwannoma cells

    Alderson, Nathan L / Hama, Hiroko

    Journal of lipid research JLR. 2009 June, v. 50, no. 6

    2009  

    Abstract: Sphingolipids are ubiquitous components of eukaryotic cells that regulate various cellular functions. In many cell types, a fraction of sphingolipids contain 2-hydroxy fatty acids, produced by fatty acid 2-hydroxylase (FA2H), as the N-acyl chain of ... ...

    Abstract Sphingolipids are ubiquitous components of eukaryotic cells that regulate various cellular functions. In many cell types, a fraction of sphingolipids contain 2-hydroxy fatty acids, produced by fatty acid 2-hydroxylase (FA2H), as the N-acyl chain of ceramide [hydroxyl fatty acid (hFA)-sphingolipids]. FA2H is highly expressed in myelin-forming cells of the nervous system and in epidermal keratinocytes. While hFA-sphingolipids are thought to enhance the physical stability of specialized membranes produced by these cells, physiological significance of hFA-sphingolipids in many other cell types is unknown. In this study, we report novel roles for FA2H and hFA-sphingolipids in the regulation of the cell cycle. Treatment of D6P2T Schwannoma cells with dibutyryl-cAMP (db-cAMP) induced exit from the cell cycle with concomitant upregulation of FA2H. Partial silencing of FA2H in D6P2T cells resulted in 60-70% reduction of hFA-dihydroceramide and hFA-ceramide, with no effect on nonhydroxy dihydroceramide and ceramide. Under these conditions, db-cAMP no longer induced cell cycle exit, and cells continued to grow and divide. Immunoblot analyses revealed that FA2H silencing prevented db-cAMP-induced upregulation of cyclin-dependent kinase inhibitors p21 and p27. These results provide evidence that FA2H is a negative regulator of the cell cycle and facilitates db-cAMP-induced cell cycle exit in D6P2T cells.
    Language English
    Dates of publication 2009-06
    Size p. 1203-1208.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: A novel method for the measurement of in vitro fatty acid 2-hydroxylase activity by gas chromatography-mass spectrometry

    Alderson, Nathan L / Walla, Michael D / Hama, Hiroko

    Journal of lipid research. 2005 Jul., v. 46, no. 7

    2005  

    Abstract: Fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is an enzyme responsible for the de novo synthesis of sphingolipids containing 2-hydroxy fatty acids. 2-Hydroxy sphingolipids are highly abundant in the brain, as major myelin galactolipids ( ... ...

    Abstract Fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is an enzyme responsible for the de novo synthesis of sphingolipids containing 2-hydroxy fatty acids. 2-Hydroxy sphingolipids are highly abundant in the brain, as major myelin galactolipids (galactosylceramide and sulfatide) contain a uniquely high proportion ([approximately]50%) of 2-hydroxy fatty acids. Other tissues, such as epidermis, epithelia of the digestive tract, and certain cancers, also contain 2-hydroxy sphingolipids. The physiological significance of the 2-hydroxylation on N-acyl chains of subsets of sphingolipids is poorly understood. To study the roles of FA2H and 2-hydroxy sphingolipids in various tissues, we developed a highly sensitive in vitro FA2H assay. FA2H-dependent fatty acid 2-hydroxylation requires an electron transfer system, which was reconstituted in vitro with an NADPH regeneration system and purified NADPH:cytochrome P-450 reductase. A substrate [3,3,5,5-D₄]tetracosanoic acid was solubilized in [alpha]-cyclodextrin solution, and the 2-hydroxylated product was quantified by gas chromatography-mass spectrometry after conversion to a trimethylsilyl ether derivative. When the microsomes of FA2H-transfected COS7 cells were incubated with the electron transfer system and deuterated tetracosanoic acid, deuterated 2-hydroxy tetracosanoic acid was formed in a time- and protein-dependent manner. With this method, FA2H activities were reproducibly measured in murine brains and tissue culture cell lines.
    Language English
    Dates of publication 2005-07
    Size p. 1569-1575.
    Document type Article
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    Database NAL-Catalogue (AGRICOLA)

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  4. Article: A novel method for the measurement of in vitro fatty acid 2-hydroxylase activity by gas chromatography-mass spectrometry.

    Alderson, Nathan L / Walla, Michael D / Hama, Hiroko

    Journal of lipid research

    2005  Volume 46, Issue 7, Page(s) 1569–1575

    Abstract: Fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is an enzyme responsible for the de novo synthesis of sphingolipids containing 2-hydroxy fatty acids. 2-Hydroxy sphingolipids are highly abundant in the brain, as major myelin galactolipids ( ... ...

    Abstract Fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is an enzyme responsible for the de novo synthesis of sphingolipids containing 2-hydroxy fatty acids. 2-Hydroxy sphingolipids are highly abundant in the brain, as major myelin galactolipids (galactosylceramide and sulfatide) contain a uniquely high proportion ( approximately 50%) of 2-hydroxy fatty acids. Other tissues, such as epidermis, epithelia of the digestive tract, and certain cancers, also contain 2-hydroxy sphingolipids. The physiological significance of the 2-hydroxylation on N-acyl chains of subsets of sphingolipids is poorly understood. To study the roles of FA2H and 2-hydroxy sphingolipids in various tissues, we developed a highly sensitive in vitro FA2H assay. FA2H-dependent fatty acid 2-hydroxylation requires an electron transfer system, which was reconstituted in vitro with an NADPH regeneration system and purified NADPH:cytochrome P-450 reductase. A substrate [3,3,5,5-D(4)]tetracosanoic acid was solubilized in alpha-cyclodextrin solution, and the 2-hydroxylated product was quantified by gas chromatography-mass spectrometry after conversion to a trimethylsilyl ether derivative. When the microsomes of FA2H-transfected COS7 cells were incubated with the electron transfer system and deuterated tetracosanoic acid, deuterated 2-hydroxy tetracosanoic acid was formed in a time- and protein-dependent manner. With this method, FA2H activities were reproducibly measured in murine brains and tissue culture cell lines.
    MeSH term(s) Animals ; Brain/enzymology ; COS Cells ; Chlorocebus aethiops ; Fatty Acids/metabolism ; Gas Chromatography-Mass Spectrometry/methods ; HeLa Cells ; Humans ; Mice ; Mixed Function Oxygenases/analysis
    Chemical Substances Fatty Acids ; Mixed Function Oxygenases (EC 1.-) ; fatty acid alpha-hydroxylase (EC 1.-) ; lignoceric acid (RK3VCW5Y1L)
    Language English
    Publishing date 2005-05-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    DOI 10.1194/jlr.D500013-JLR200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: FA2H is responsible for the formation of 2-hydroxy galactolipids in peripheral nervous system myelin

    Maldonado, Eduardo N / Alderson, Nathan L / Monje, Paula V / Wood, Patrick M / Hama, Hiroko

    Journal of lipid research JLR. 2008 Jan., v. 49, no. 1

    2008  

    Abstract: Myelin in the mammalian nervous system has a high concentration of galactolipids [galactosylceramide (GalCer) and sulfatide] with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is the major ... ...

    Abstract Myelin in the mammalian nervous system has a high concentration of galactolipids [galactosylceramide (GalCer) and sulfatide] with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is the major fatty acid 2-hydroxylase in the mouse brain. In this report, we show that FA2H also plays a major role in the formation of 2-hydroxy galactolipids in the peripheral nervous system. FA2H mRNA and FA2H activity in the neonatal rat sciatic nerve increased rapidly during developmental myelination. The contents of 2-hydroxy fatty acids were ~5% of total galactolipid fatty acids at 4 days of age and increased to 60% in GalCer and to 35% in sulfatides at 60 days of age. The chain length of galactolipid fatty acids also increased significantly during myelination. FA2H expression in cultured rat Schwann cells was highly increased in response to dibutyryl cyclic AMP, which stimulates Schwann cell differentiation and upregulates myelin genes, such as UDP-galactose:ceramide galactosyltransferase and protein zero. These observations indicate that FA2H is a myelination-associated gene. FA2H-directed RNA interference (RNAi) by short-hairpin RNA expression resulted in a reduction of cellular 2-hydroxy fatty acids and 2-hydroxy GalCer in D6P2T Schwannoma cells, providing direct evidence that FA2H-dependent fatty acid 2-hydroxylation is required for the formation of 2-hydroxy galactolipids in peripheral nerve myelin. Interestingly, FA2H-directed RNAi enhanced the migration of D6P2T cells, suggesting that, in addition to their structural role in myelin, 2-hydroxy lipids may greatly influence the migratory properties of Schwann cells.
    Language English
    Dates of publication 2008-01
    Size p. 153-161.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    Database NAL-Catalogue (AGRICOLA)

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  6. Article: FA2H-dependent fatty acid 2-hydroxylation in postnatal mouse brain

    Alderson, Nathan L / Maldonado, Eduardo N / Kern, Michael J / Bhat, Narayan R / Hama, Hiroko

    Journal of lipid research JLR. 2006 Dec., v. 47, no. 12

    2006  

    Abstract: 2-Hydroxy fatty acids are relatively minor species of membrane lipids found almost exclusively as N-acyl chains of sphingolipids. In mammals, 2-hydroxy sphingolipids are uniquely abundant in myelin galactosylceramide and sulfatide. Despite the well- ... ...

    Abstract 2-Hydroxy fatty acids are relatively minor species of membrane lipids found almost exclusively as N-acyl chains of sphingolipids. In mammals, 2-hydroxy sphingolipids are uniquely abundant in myelin galactosylceramide and sulfatide. Despite the well-documented abundance of 2-hydroxy galactolipids in the nervous system, the enzymatic process of the 2-hydroxylation is not fully understood. To fill this gap, we have identified a human fatty acid 2-hydroxylase gene (FA2H) that is highly expressed in brain. In this report, we test the hypothesis that FA2H is the major fatty acid 2-hydroxylase in mouse brain and that free 2-hydroxy fatty acids are formed as precursors of myelin 2-hydroxy galactolipids. The fatty acid compositions of galactolipids in neonatal mouse brain gradually changed during the course of myelination. The relative ratio of 2-hydroxy versus nonhydroxy galactolipids was very low at 2 days of age (~8% of total galactolipids) and increased 6- to 8-fold by 30 days of age. During this period, free 2-hydroxy fatty acid levels in mouse brain increased 5- to 9-fold, and their composition was reflected in the fatty acids in galactolipids, consistent with a precursor-product relationship. The changes in free 2-hydroxy fatty acid levels coincided with fatty acid 2-hydroxylase activity and with the upregulation of FA2H expression. Furthermore, mouse brain fatty acid 2-hydroxylase activity was inhibited by anti-FA2H antibodies. Together, these data provide evidence that FA2H is the major fatty acid 2-hydroxylase in brain and that 2-hydroxylation of free fatty acids is the first step in the synthesis of 2-hydroxy galactolipids.
    Language English
    Dates of publication 2006-12
    Size p. 2772-2780.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    Database NAL-Catalogue (AGRICOLA)

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  7. Article: FA2H is responsible for the formation of 2-hydroxy galactolipids in peripheral nervous system myelin.

    Maldonado, Eduardo N / Alderson, Nathan L / Monje, Paula V / Wood, Patrick M / Hama, Hiroko

    Journal of lipid research

    2007  Volume 49, Issue 1, Page(s) 153–161

    Abstract: Myelin in the mammalian nervous system has a high concentration of galactolipids [galactosylceramide (GalCer) and sulfatide] with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is the major ... ...

    Abstract Myelin in the mammalian nervous system has a high concentration of galactolipids [galactosylceramide (GalCer) and sulfatide] with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is the major fatty acid 2-hydroxylase in the mouse brain. In this report, we show that FA2H also plays a major role in the formation of 2-hydroxy galactolipids in the peripheral nervous system. FA2H mRNA and FA2H activity in the neonatal rat sciatic nerve increased rapidly during developmental myelination. The contents of 2-hydroxy fatty acids were approximately 5% of total galactolipid fatty acids at 4 days of age and increased to 60% in GalCer and to 35% in sulfatides at 60 days of age. The chain length of galactolipid fatty acids also increased significantly during myelination. FA2H expression in cultured rat Schwann cells was highly increased in response to dibutyryl cyclic AMP, which stimulates Schwann cell differentiation and upregulates myelin genes, such as UDP-galactose:ceramide galactosyltransferase and protein zero. These observations indicate that FA2H is a myelination-associated gene. FA2H-directed RNA interference (RNAi) by short-hairpin RNA expression resulted in a reduction of cellular 2-hydroxy fatty acids and 2-hydroxy GalCer in D6P2T Schwannoma cells, providing direct evidence that FA2H-dependent fatty acid 2-hydroxylation is required for the formation of 2-hydroxy galactolipids in peripheral nerve myelin. Interestingly, FA2H-directed RNAi enhanced the migration of D6P2T cells, suggesting that, in addition to their structural role in myelin, 2-hydroxy lipids may greatly influence the migratory properties of Schwann cells.
    MeSH term(s) Animals ; Cells, Cultured ; Galactolipids/metabolism ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Myelin Sheath/metabolism ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Schwann Cells/metabolism ; Sciatic Nerve/metabolism
    Chemical Substances Galactolipids ; Mixed Function Oxygenases (EC 1.-) ; fatty acid alpha-hydroxylase (EC 1.-)
    Language English
    Publishing date 2007-09-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    DOI 10.1194/jlr.M700400-JLR200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications.

    Metz, Thomas O / Alderson, Nathan L / Thorpe, Suzanne R / Baynes, John W

    Archives of biochemistry and biophysics

    2003  Volume 419, Issue 1, Page(s) 41–49

    Abstract: Pyridoxamine (PM), originally described as a post-Amadori inhibitor of formation of advanced glycation end-products (AGEs), also inhibits the formation of advanced lipoxidation end-products (ALEs) on protein during lipid peroxidation reactions. In ... ...

    Abstract Pyridoxamine (PM), originally described as a post-Amadori inhibitor of formation of advanced glycation end-products (AGEs), also inhibits the formation of advanced lipoxidation end-products (ALEs) on protein during lipid peroxidation reactions. In addition to inhibition of AGE/ALE formation, PM has a strong lipid-lowering effect in streptozotocin (STZ)-induced diabetic and Zucker obese rats, and protects against the development of nephropathy in both animal models. PM also inhibits the development of retinopathy and neuropathy in the STZ-diabetic rat. Several products of reaction of PM with intermediates in lipid autoxidation have been identified in model reactions in vitro and in the urine of diabetic and obese rats, confirming the action of PM as an AGE/ALE inhibitor. PM appears to act by a mechanism analogous to that of AGE-breakers, by reaction with dicarbonyl intermediates in AGE/ALE formation. This review summarizes current knowledge on the mechanism of formation of AGE/ALEs, proposes a mechanism of action of PM, and summarizes the results of animal model studies on the use of PM for inhibiting AGE/ALE formation and development of complications of diabetes and hyperlipidemia.
    MeSH term(s) Animals ; Diabetic Nephropathies/complications ; Diabetic Nephropathies/drug therapy ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/therapeutic use ; Glycation End Products, Advanced/antagonists & inhibitors ; Humans ; Lipid Peroxidation/drug effects ; Molecular Structure ; Pyridoxamine/chemistry ; Pyridoxamine/therapeutic use
    Chemical Substances Enzyme Inhibitors ; Glycation End Products, Advanced ; Pyridoxamine (6466NM3W93)
    Language English
    Publishing date 2003-10-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 523-x
    ISSN 1096-0384 ; 0003-9861
    ISSN (online) 1096-0384
    ISSN 0003-9861
    DOI 10.1016/j.abb.2003.08.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: FA2H-dependent fatty acid 2-hydroxylation in postnatal mouse brain.

    Alderson, Nathan L / Maldonado, Eduardo N / Kern, Michael J / Bhat, Narayan R / Hama, Hiroko

    Journal of lipid research

    2006  Volume 47, Issue 12, Page(s) 2772–2780

    Abstract: 2-Hydroxy fatty acids are relatively minor species of membrane lipids found almost exclusively as N-acyl chains of sphingolipids. In mammals, 2-hydroxy sphingolipids are uniquely abundant in myelin galactosylceramide and sulfatide. Despite the well- ... ...

    Abstract 2-Hydroxy fatty acids are relatively minor species of membrane lipids found almost exclusively as N-acyl chains of sphingolipids. In mammals, 2-hydroxy sphingolipids are uniquely abundant in myelin galactosylceramide and sulfatide. Despite the well-documented abundance of 2-hydroxy galactolipids in the nervous system, the enzymatic process of the 2-hydroxylation is not fully understood. To fill this gap, we have identified a human fatty acid 2-hydroxylase gene (FA2H) that is highly expressed in brain. In this report, we test the hypothesis that FA2H is the major fatty acid 2-hydroxylase in mouse brain and that free 2-hydroxy fatty acids are formed as precursors of myelin 2-hydroxy galactolipids. The fatty acid compositions of galactolipids in neonatal mouse brain gradually changed during the course of myelination. The relative ratio of 2-hydroxy versus nonhydroxy galactolipids was very low at 2 days of age ( approximately 8% of total galactolipids) and increased 6- to 8-fold by 30 days of age. During this period, free 2-hydroxy fatty acid levels in mouse brain increased 5- to 9-fold, and their composition was reflected in the fatty acids in galactolipids, consistent with a precursor-product relationship. The changes in free 2-hydroxy fatty acid levels coincided with fatty acid 2-hydroxylase activity and with the upregulation of FA2H expression. Furthermore, mouse brain fatty acid 2-hydroxylase activity was inhibited by anti-FA2H antibodies. Together, these data provide evidence that FA2H is the major fatty acid 2-hydroxylase in brain and that 2-hydroxylation of free fatty acids is the first step in the synthesis of 2-hydroxy galactolipids.
    MeSH term(s) Amino Acid Sequence ; Animals ; Animals, Newborn ; Base Sequence ; Brain/metabolism ; Cells, Cultured ; DNA Primers/genetics ; Fatty Acids/chemistry ; Fatty Acids/metabolism ; Galactolipids/biosynthesis ; Humans ; Hydroxylation ; Mice ; Mice, Inbred C57BL ; Mixed Function Oxygenases/antagonists & inhibitors ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Molecular Sequence Data ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
    Chemical Substances DNA Primers ; Fatty Acids ; Galactolipids ; RNA, Messenger ; Mixed Function Oxygenases (EC 1.-) ; fatty acid alpha-hydroxylase (EC 1.-)
    Language English
    Publishing date 2006-09-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    DOI 10.1194/jlr.M600362-JLR200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Chemical modification of proteins during peroxidation of phospholipids.

    Januszewski, Andrzej S / Alderson, Nathan L / Jenkins, Alicia J / Thorpe, Suzanne R / Baynes, John W

    Journal of lipid research

    2005  Volume 46, Issue 7, Page(s) 1440–1449

    Abstract: Chemical modification of proteins by advanced glycation and lipoxidation end products is implicated in the pathogenesis of macrovascular disease in aging and diabetes. To identify biomarkers of the lipoxidative modification of protein, we studied the ... ...

    Abstract Chemical modification of proteins by advanced glycation and lipoxidation end products is implicated in the pathogenesis of macrovascular disease in aging and diabetes. To identify biomarkers of the lipoxidative modification of protein, we studied the oxidation of phospholipids in the presence of the model protein RNase A and compared protein-bound products formed in these reactions with those formed during oxidation of plasma proteins. Metal-catalyzed oxidation of 1-palmitoyl-2-arachidonoyl-phosphatidylcholine or 1-palmitoyl-2-linoleoyl-phosphatidylcholine in the presence of RNase led to the loss of amino groups in RNase and the incorporation of phosphate, hexanoate, pentanedioate, nonanedioate, and palmitate into protein. Protein-bound palmitate and phosphate correlated strongly with one another, and protein-bound pentanedioate and nonanedioate, derived from arachidonate and linoleate, respectively, accounted for approximately 20% of the cross-linking of lipid phosphorus to protein. Similar results were obtained on oxidation of total plasma or isolated LDL. We conclude that alkanedioic acids are quantitatively important linkers of oxidized phospholipids to proteins and that measurement of protein-bound phosphate and long-chain fatty acids may be useful for assessing long-term lipid peroxidative damage to proteins in vivo. Analyses of plasma proteins from control and diabetic patients indicated significant increases in lipoxidative modification of protein in diabetic compared with control subjects.
    MeSH term(s) Adult ; Blood Proteins/chemistry ; Catalysis ; Copper Sulfate/chemistry ; Diabetes Mellitus, Type 1/blood ; Dicarboxylic Acids/chemistry ; Female ; Glutarates/chemistry ; Glycation End Products, Advanced/chemistry ; Humans ; Lipid Peroxidation/physiology ; Lipoproteins, LDL/chemistry ; Lysine/analogs & derivatives ; Lysine/chemistry ; Lysophosphatidylcholines/chemistry ; Male ; Oxidation-Reduction ; Phospholipids/metabolism ; Ribonuclease, Pancreatic/chemistry
    Chemical Substances 1-palmitoyl-2-lysophosphatidylcholine ; Blood Proteins ; Dicarboxylic Acids ; Glutarates ; Glycation End Products, Advanced ; Lipoproteins, LDL ; Lysophosphatidylcholines ; Phospholipids ; Ribonuclease, Pancreatic (EC 3.1.27.5) ; azelaic acid (F2VW3D43YT) ; glutaric acid (H849F7N00B) ; Lysine (K3Z4F929H6) ; Copper Sulfate (LRX7AJ16DT)
    Language English
    Publishing date 2005-04-01
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    DOI 10.1194/jlr.M400442-JLR200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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