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Ronald J.a. Wanders - One of the best experts on this subject based on the ideXlab platform.
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Peroxisomal Fatty Acid Alpha-and Beta-Oxidation in Health and Disease: New insights
Advances in Experimental Medicine and Biology, 2020Co-Authors: Ronald J.a. Wanders, Sacha Ferdinandusse, Gerbert A Jansen, Carlo W.t. Van Roermund, Wouter F. Visser, Daan M. Van Den Brink, J. Gloerich, Hans R. WaterhamAbstract:In humans, peroxisomes play a number of essential metabolic functions, of which most have to do with lipid metabolism including fatty acid Alpha-and beta-Oxidation. The importance of the peroxisomal Alpha-and Alpha-and systems in humans is stressed by the existence of a number of peroxisomal disorders, in which one or both of these pathways are disturbed. X-linked adrenoleukodystrophy is the most well known among the disorders of peroxisomal beta-Oxidation whereas Refsum disease is the prototype of the group of Alpha-Oxidation defects. In this paper we will describe the basic aspects of the peroxisomal Alpha-and beta-Oxidation systems with particular emphasis on recently acquired knowledge.
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Very-Long-Chain Fatty Acids and Phytanic Acid
Laboratory Guide to the Methods in Biochemical Genetics, 2020Co-Authors: Ronald J.a. Wanders, Marinus DuranAbstract:The peroxisomes are subcellular organelles with a variety of biochemical functions, amongst which a system for beta-Oxidation of very long-chain (C22-C26) fatty acids (VLCFA) and a system for Alpha-Oxidation of branched-chain fatty acids such as phytanic acid. The plasma concentrations of the VLCFA as well as those of phytanic acid and its immediate metabolite pristanic acid are important biomarkers for the assessment of peroxisomal dysfunction. A gas chromatography / mass spectrometry analysis of the tertiarybutyl-dimethylsilyl esters of the afore mentioned acids, using stable isotope labeled internal standards, is the method of choice for the diagnosis of peroxisome biogenesis defects (Zellweger spectrum patients) as well as isolated peroxisomal enzyme defects such as X-linked adrenoleucodystrophy, D-bifunctional protein deficiency and Refsum disease, amongst others. This approach is equally well suited for therapy monitoring of treatable disorders.
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Peroxisomes and Their Central Role in Metabolic Interaction Networks in Humans.
Sub-cellular biochemistry, 2018Co-Authors: Ronald J.a. Wanders, Hans R. Waterham, Sacha FerdinandusseAbstract:Peroxisomes catalyze a number of essential metabolic functions and impairments in any of these are usually associated with major clinical signs and symptoms. In contrast to mitochondria which are autonomous organelles that can catalyze the degradation of fatty acids, certain amino acids and other compounds all by themselves, peroxisomes are non-autonomous organelles which are highly dependent on the interaction with other organelles and compartments to fulfill their role in metabolism. This includes mitochondria, the endoplasmic reticulum, lysosomes, and the cytosol. In this paper we will discuss the central role of peroxisomes in different metabolic interaction networks in humans, including fatty acid Oxidation, ether phospholipid biosynthesis, bile acid synthesis, fatty acid Alpha-Oxidation and glyoxylate metabolism.
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CHAPTER 14:Phytanoyl-CoA Hydroxylase: A 2-Oxoglutarate-Dependent Dioxygenase Crucial for Fatty Acid Alpha-Oxidation in Humans
2-Oxoglutarate-Dependent Oxygenases, 2015Co-Authors: Ronald J.a. Wanders, Sacha Ferdinandusse, Merel S. Ebberink, Hans R. WaterhamAbstract:Phytanoyl-CoA hydroxylase belongs to the family of 2-oxoglutarate-dependent dioxygenases and plays a crucial role in the α-Oxidation of fatty acids. The complete α-Oxidation pathway involves five different enzymes localized in peroxisomes. Thus far, phytanoyl-CoA hydroxylase deficiency has remained the only genetically determined inborn error of metabolism affecting the α-Oxidation pathway. In this chapter we describe the current state of knowledge on fatty acid α-Oxidation with special emphasis on phytanoyl-CoA hydroxylase and its deficiency in Refsum disease.
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Peroxisomes in Humans: Metabolic Functions, Cross Talk with Other Organelles, and Pathophysiology of Peroxisomal Disorders
Molecular Machines Involved in Peroxisome Biogenesis and Maintenance, 2014Co-Authors: Ronald J.a. Wanders, Sacha Ferdinandusse, Hr WaterhamAbstract:Peroxisomes play a crucial role in cellular metabolism as exemplified by the devastating consequences caused by deficiencies of one or more peroxisomal enzymes in humans. The major metabolic functions of peroxisomes in humans include fatty acid beta-Oxidation, etherphospholipid biosynthesis, fatty acid Alpha-Oxidation; glyoxylate detoxification, bile acid synthesis, l-pipecolic acid Oxidation, and docosahexaenoic acid (DHA) formation. Except from the bile acids which are true metabolic end products of bile acid formation in the liver as generated in peroxisomes, all the other products of peroxisome metabolism are not true end products but require continued metabolism in other organelles to reach their final fate. This explains the crosstalk between peroxisomes and other subcellular organelles notably mitochondria and the endoplasmic reticulum. In this review we will discuss the metabolic functions of peroxisomes in humans and the crosstalk with other subcellular organelles. In addition we will discuss the pathophysiological consequences of genetic defects in peroxisome metabolism.
Paul P Van Veldhoven - One of the best experts on this subject based on the ideXlab platform.
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Alpha Oxidation of 3 methyl substituted fatty acids and its thiamine dependence
FEBS Journal, 2003Co-Authors: Minne Casteels, Veerle Foulon, Guy P Mannaerts, Paul P Van VeldhovenAbstract:3-Methyl-branched fatty acids, as phytanic acid, undergo peroxisomal α-Oxidation in which they are shortened by 1 carbon atom. This process includes four steps: activation, 2-hydroxylation, thiamine pyrophosphate dependent cleavage and aldehyde dehydrogenation. The thiamine pyrophosphate dependence of the third step is unique in peroxisomal mammalian enzymology. Human pathology due to a deficient Alpha-Oxidation is mostly linked to mutations in the gene coding for the second enzyme of the sequence, phytanoyl-CoA hydroxylase.
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Prenatal and postnatal development of peroxisomal lipid-metabolizing pathways in the mouse
Biochemical Journal, 2001Co-Authors: Steven Huyghe, Minne Casteels, Guy P Mannaerts, Paul P Van Veldhoven, Anneleen Janssen, Liesbeth Meulders, Peter Declercq, Myriam BaesAbstract:The ontogeny of the following peroxisomal metabolic pathways was evaluated in mouse liver and brain: Alpha-Oxidation, beta-Oxidation and ether phospholipid synthesis. In mouse embryos lacking functional peroxisomes (PEX5(-/-) knock-out), a deficiency of plasmalogens and an accumulation of the very-long-chain fatty acid C(26:0) was observed in comparison with control littermates, indicating that ether phospholipid synthesis and beta-Oxidation are already active at mid-gestation in the mouse. Northern analysis revealed that the enzymes required for the beta-Oxidation of straight-chain substrates are present in liver and brain during embryonic development but that those responsible for the degradation of branched-chain substrates are present only in liver from late gestation onwards. The expression pattern of transcripts encoding enzymes of the Alpha-Oxidation pathway suggested that Alpha-Oxidation is initiated in the liver around birth and is not active in brain throughout development. Remarkably, a strong induction of the mRNA levels of enzymes involved in Alpha-Oxidation and beta-Oxidation was observed around birth in the liver. In contrast, enzyme transcripts that were expressed in brain were present at rather constant levels throughout prenatal and postnatal development. These results suggest that the defective ether phospholipid synthesis and/or peroxisomal beta-Oxidation of straight-chain fatty acids might be involved in the pathogenesis of the prenatal organ defects in peroxisome-deficient mice and men.
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peroxisomal lipid degradation via beta and Alpha Oxidation in mammals
Cell Biochemistry and Biophysics, 2000Co-Authors: Guy P Mannaerts, Paul P Van Veldhoven, Minne CasteelsAbstract:Peroxisomal β-Oxidation is involved in the degradation of long chain and very long chain fatty acyl-(coenzyme A)CoAs, long chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs (e.g. pristanoyl-CoA), and the CoA esters of the bile acid intermediates di- and trihydroxycoprostanic acids (side chain of cholesterol).
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purification molecular cloning and expression of 2 hydroxyphytanoyl coa lyase a peroxisomal thiamine pyrophosphate dependent enzyme that catalyzes the carbon carbon bond cleavage during Alpha Oxidation of 3 methyl branched fatty acids
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Veerle Foulon, Guy P Mannaerts, Paul P Van Veldhoven, Kathleen Croes, Vasily D Antonenkov, Etienne Waelkens, Minne CasteelsAbstract:In the third step of the α-Oxidation of 3-methyl-branched fatty acids such as phytanic acid, a 2-hydroxy-3-methylacyl-CoA is cleaved into formyl-CoA and a 2-methyl-branched fatty aldehyde. The cleavage enzyme was purified from the matrix protein fraction of rat liver peroxisomes and identified as a protein made up of four identical subunits of 63 kDa. Its activity proved to depend on Mg2+ and thiamine pyrophosphate, a hitherto unrecognized cofactor of α-Oxidation. Formyl-CoA and 2-methylpentadecanal were identified as reaction products when the purified enzyme was incubated with 2-hydroxy-3-methylhexadecanoyl-CoA as the substrate. Hence the enzyme catalyzes a carbon–carbon cleavage, and we propose calling it 2-hydroxyphytanoyl-CoA lyase. Sequences derived from tryptic peptides of the purified rat protein were used as queries to recover human expressed sequence tags from the databases. The composite cDNA sequence of the human lyase contained an ORF of 1,734 bases that encodes a polypeptide with a calculated molecular mass of 63,732 Da. Recombinant human protein, expressed in mammalian cells, exhibited lyase activity. The lyase displayed homology to a putative Caenorhabditis elegans protein that resembles bacterial oxalyl-CoA decarboxylases. Similarly to the decarboxylases, a thiamine pyrophosphate-binding consensus domain was present in the C-terminal part of the lyase. Although no peroxisome targeting signal, neither 1 nor 2, was apparent, transfection experiments with constructs encoding green fluorescent protein fused to the full-length lyase or its C-terminal pentapeptide indicated that the C terminus of the lyase represents a peroxisome targeting signal 1 variant.
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stereochemistry of the Alpha Oxidation of 3 methyl branched fatty acids in rat liver
Journal of Lipid Research, 1999Co-Authors: Kathleen Croes, Minne Casteels, Guy P Mannaerts, Martine Dieuaidenoubhani, Paul P Van VeldhovenAbstract:The stereochemistry of the a -Oxidation of 3- methyl-branched fatty acids was studied in rat liver. R - and S - 3-methylhexadecanoic acid were equally well a -oxidized in intact hepatocytes and homogenates. Subcellular fraction- ation studies showed that a -Oxidation of both isomers is confined to peroxisomes. Dehydrogenation of 2-methylpen- tadecanal, the end-product of the peroxisomal a -Oxidation of 3-methylhexadecanoic acid, to 2-methylpentadecanoic acid, followed by derivatization with R -1-phenylethylamine and subsequent separation of the stereoisomers by gas chro- matography, revealed that the configuration of the methyl- branch is preserved throughout the whole a -Oxidation process. Metabolism and formation of the 2-hydroxy-3-methylhexa- decanoyl-CoA intermediate were also investigated. Separation of the methyl esters of the four isomers of 2-hydroxy-3-me- thylhexadecanoic acid was achieved by gas chromatography after derivatization of the hydroxy group with R -2-methoxy- 2-trifluoromethylphenylacetic acid chloride and the abso- lute configuration of the four isomers was determined. Al- though purified peroxisomes are capable of metabolizing all four isomers of 2-hydroxy-3-methylhexadecanoyl-CoA, they can only form the (2 S ,3 R ) and the (2 R ,3 S ) isomers. Our experiments exclude the racemization of the 3-methyl branch during the a -Oxidation process. The configuration of the 3-methyl branch does not influence the rate of a -oxida- tion, but determines the side of the 2-hydroxylation, hence the configuration of the 2-hydroxy-3-methylacyl-CoA inter- mediates formed during the process. —Croes, K., M. Casteels, M. Dieuaide-Noubhani, G. P. Mannaerts, and P. P. Van Veldhoven. Stereochemistry of the a -Oxidation of 3- methyl-branched fatty acids in rat liver. J. Lipid Res. 1999. 40: 601-609.
Minne Casteels - One of the best experts on this subject based on the ideXlab platform.
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Alpha-Oxidation of 3-methyl-branched fatty acids: unraveling of a pathway
Verhandelingen - Koninklijke Academie voor Geneeskunde van België, 2020Co-Authors: Minne CasteelsAbstract:: Peroxisomes have an important role in lipid metabolism e.g. beta-Oxidation of long and very long chain fatty acids, 2-methyl-branched fatty acids, dicarboxylic fatty acids, prostanoids and bile acid intermediates, and synthesis of ether lipids. Also the process of Alpha-Oxidation of 3-methyl-branched fatty acids, with phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) as the best known example, occurs in peroxisomes. Alpha-Oxidation is a process in which fatty acids are shortened by one carbon atom. The Alpha-Oxidation sequence of 3-methyl-branched fatty acids starts with an activation to the corresponding CoA-ester. Subsequently this acyl-CoA-ester undergoes a 2-hydroxylation by the peroxisomal phytanoyl-CoA hydroxylase (PAHX). In a third step the peroxisomal 2-hydroxyphytanoyl-CoA lyase (2-HPCL) splits the carbon carbon bond of the 2-hydroxy-intermediate into a 2-methyl(n-1)aldehyde and formyl-CoA, which is subsequently converted to formate and CO2. Finally the aldehyde is dehydrogenated by an aldehyde dehydrogenase to the corresponding acid, which, after its conversion to the acyl-CoA ester, can be a substrate for beta-Oxidation. 2-HPCL is the first thiamine pyrophosphate dependent peroxisomal enzyme in mammals. Apart from 2-hydroxy-3-methylacyl-CoAs also 2-hydroxyacyl-CoAs are substrates for this enzyme. This indicates that the 2-hydroxy function but not the 3-methyl function of acyl-CoA esters is needed for 2-HPCL-activity. Long and very long chain 2-hydroxy fatty acids are constituents of brain cerebrosides and sulfatides, which mainly occur in myelin.
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Thiamine Pyrophosphate: an essential Cofactor in the Mammalian Metabolism of 3-methyl-branched Fatty Acids
Advances in Experimental Medicine and Biology, 2020Co-Authors: Veerle Foulon, Minne Casteels, Guy P Mannaerts, Bruce D. Gelb, Paul P. VanveldhovenAbstract:A major breakthrough in the research on the Alpha-Oxidation of 3-methyl-branched fatty acids, such as the naturally occurring phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), was the identification of 2- hydroxyphytanoyl-CoA lyase (2-HPCL), a peroxisomal enzyme that catalyzes the carbon-carbon bond cleavage in the third step of the proposed pathway, and the observation that its activity depends on thiamine pyrophosphate (TPP), a hitherto unknown cofactor of Alpha-Oxidation (Foulons et al., 1999).
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Alpha Oxidation of 3 methyl substituted fatty acids and its thiamine dependence
FEBS Journal, 2003Co-Authors: Minne Casteels, Veerle Foulon, Guy P Mannaerts, Paul P Van VeldhovenAbstract:3-Methyl-branched fatty acids, as phytanic acid, undergo peroxisomal α-Oxidation in which they are shortened by 1 carbon atom. This process includes four steps: activation, 2-hydroxylation, thiamine pyrophosphate dependent cleavage and aldehyde dehydrogenation. The thiamine pyrophosphate dependence of the third step is unique in peroxisomal mammalian enzymology. Human pathology due to a deficient Alpha-Oxidation is mostly linked to mutations in the gene coding for the second enzyme of the sequence, phytanoyl-CoA hydroxylase.
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Prenatal and postnatal development of peroxisomal lipid-metabolizing pathways in the mouse
Biochemical Journal, 2001Co-Authors: Steven Huyghe, Minne Casteels, Guy P Mannaerts, Paul P Van Veldhoven, Anneleen Janssen, Liesbeth Meulders, Peter Declercq, Myriam BaesAbstract:The ontogeny of the following peroxisomal metabolic pathways was evaluated in mouse liver and brain: Alpha-Oxidation, beta-Oxidation and ether phospholipid synthesis. In mouse embryos lacking functional peroxisomes (PEX5(-/-) knock-out), a deficiency of plasmalogens and an accumulation of the very-long-chain fatty acid C(26:0) was observed in comparison with control littermates, indicating that ether phospholipid synthesis and beta-Oxidation are already active at mid-gestation in the mouse. Northern analysis revealed that the enzymes required for the beta-Oxidation of straight-chain substrates are present in liver and brain during embryonic development but that those responsible for the degradation of branched-chain substrates are present only in liver from late gestation onwards. The expression pattern of transcripts encoding enzymes of the Alpha-Oxidation pathway suggested that Alpha-Oxidation is initiated in the liver around birth and is not active in brain throughout development. Remarkably, a strong induction of the mRNA levels of enzymes involved in Alpha-Oxidation and beta-Oxidation was observed around birth in the liver. In contrast, enzyme transcripts that were expressed in brain were present at rather constant levels throughout prenatal and postnatal development. These results suggest that the defective ether phospholipid synthesis and/or peroxisomal beta-Oxidation of straight-chain fatty acids might be involved in the pathogenesis of the prenatal organ defects in peroxisome-deficient mice and men.
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peroxisomal lipid degradation via beta and Alpha Oxidation in mammals
Cell Biochemistry and Biophysics, 2000Co-Authors: Guy P Mannaerts, Paul P Van Veldhoven, Minne CasteelsAbstract:Peroxisomal β-Oxidation is involved in the degradation of long chain and very long chain fatty acyl-(coenzyme A)CoAs, long chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs (e.g. pristanoyl-CoA), and the CoA esters of the bile acid intermediates di- and trihydroxycoprostanic acids (side chain of cholesterol).
R. J. A. Wanders - One of the best experts on this subject based on the ideXlab platform.
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Peroxisomes, Refsum's disease and the Alpha- and omega-Oxidation of phytanic acid.
Biochemical Society transactions, 2020Co-Authors: R. J. A. Wanders, J C KomenAbstract:In the present paper, we describe the current state of knowledge regarding the enzymology of the phytanic acid Alpha-Oxidation pathway. The product of phytanic acid Alpha-Oxidation, i.e. pristanic acid, undergoes three cycles of beta-Oxidation in peroxisomes after which the products, including 4,8-dimethylnonanoyl-CoA, propionyl-CoA and acetyl-CoA, are exported from the peroxisome via one of two routes, including (i) the carnitine-dependent route, mediated by CRAT (carnitine acetyltransferase) and CROT (carnitine O-octanoyltransferase), and (ii) the free acid route, mediated by one or more of the peroxisomal ACOTs (acyl-CoA thioesterases). We also describe our recent data on the omega-Oxidation of phytanic acid, especially since pharmacological up-regulation of this pathway may form the basis of a new treatment strategy for ARD (adult Refsum's disease). In patients suffering from ARD, phytanic acid accumulates in tissues and body fluids due to a defect in the Alpha-Oxidation system.
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Peroxisomes, lipid metabolism, and peroxisomal disorders.
Molecular genetics and metabolism, 2020Co-Authors: R. J. A. WandersAbstract:Peroxisomes catalyse a large variety of different cellular functions of which most have to do with lipid metabolism. This paper deals with the role of peroxisomes in three key pathways of lipid metabolism, including: (1) etherphospholipid biosynthesis, (2) fatty acid beta-Oxidation, and (3) fatty acid Alpha-Oxidation. Apart from a brief description of the peroxisomal enzymes involved in each of these pathways, the interaction between peroxisomes and other subcellular organelles, notably microsomes and peroxisomes, will be discussed. Finally, the current state of knowledge with respect to the different disorders of peroxisomal lipid metabolism will be described.
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identification of pristanal dehydrogenase activity in peroxisomes conclusive evidence that the complete phytanic acid Alpha Oxidation pathway is localized in peroxisomes
Biochemical and Biophysical Research Communications, 2001Co-Authors: Gerrit Jansen, D M Van Den Brink, Rob Ofman, O Draghici, Georges Dacremont, R. J. A. WandersAbstract:Abstract Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which, due to the methyl-group at the 3-position, can not undergo β-Oxidation unless the terminal carboxyl-group is removed by α-Oxidation. The structure of the phytanic acid α-Oxidation machinery in terms of the reactions involved, has been resolved in recent years and includes a series of four reactions: (1) activation of phytanic acid to phytanoyl-CoA, (2) hydroxylation of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA, (3) cleavage of 2-hydroxyphytanoyl-CoA to pristanal and formyl-CoA, and (4) Oxidation of pristanal to pristanic acid. The subcellular localization of the enzymes involved has remained enigmatic, with the exception of phytanoyl-CoA hydroxylase and 2-hydroxyphytanoyl-CoA lyase which are both localized in peroxisomes. The Oxidation of pristanal to pristanic acid has been claimed to be catalysed by the microsomal aldehyde dehydrogenase FALDH encoded by the ALDH10 -gene. Making use of mutant fibroblasts deficient in FALDH activity, we show that phytanic acid α-Oxidation is completely normal in these cells. Furthermore, we show that pristanal dehydrogenase activity is not fully deficient in FALDH-deficient cells, implying the existence of one or more additional aldehyde dehydrogenases reacting with pristanal. Using subcellular localization studies, we now show that peroxisomes contain pristanal dehydrogenase activity which leads us to conclude that the complete phytanic acid α-Oxidation pathway is localized in peroxisomes.
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Phytanic acid Alpha-Oxidation: decarboxylation of 2-hydroxyphytanoyl-CoA to pristanic acid in human liver.
Journal of Lipid Research, 1997Co-Authors: N M Verhoeven, Gerbert A Jansen, R. J. A. Wanders, D. S. M. Schor, C.a.j.m. JakobsAbstract:: The degradation of the first intermediate in the Alpha-Oxidation of phytanic acid, 2-hydroxyphytanoyl-CoA, was investigated. Human liver homogenates were incubated with 2-hydroxyphytanoyl-CoA or 2-hydroxyphytanic acid, after which formation of 2-ketophytanic acid and pristanic acid were studied. 2-Hydroxyphytanic acid was converted into 2-ketophytanic acid and pristanic acid. When ATP, Mg2+, and coenzyme A were added to the incubation medium, higher amounts of pristanic acid were formed, whereas the formation of 2-ketophytanic acid strongly decreased. When 2-hydroxyphytanoyl-CoA was used as substrate, there was virtually no 2-ketophytanic acid formation. However, pristanic acid was formed in higher amounts than with 2-hydroxyphytanic acid as substrate. This reaction was stimulated by NAD+ and NADP+. Pristanic acid, and not pristanoyl-CoA was found to be the product of the reaction. These results suggest the existence of two pathways for decarboxylation of 2-hydroxyphytanic acid. The first one, starting from 2-hydroxyphytanic acid, involves the formation of 2-ketophytanic acid with only a small amount of pristanic acid being formed. The second pathway, which starts from 2-hydroxyphytanoyl-CoA, does not involve 2-ketophytanic acid and generates higher amounts of pristanic acid. The first pathway, which is peroxisomally localized, was found to be deficient in Zellweger syndrome, whereas the second pathway, localized in microsomes, was normally active. We conclude that the second pathway is predominant under in vivo conditions.
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resolution of the phytanic acid Alpha Oxidation pathway identification of pristanal as product of the decarboxylation of 2 hydroxyphytanoyl coa
Biochemical and Biophysical Research Communications, 1997Co-Authors: N M Verhoeven, R. J. A. Wanders, D. S. M. Schor, H Ten J Brink, C JakobsAbstract:Abstract The structure and enzymology of the phytanic acid α-Oxidation pathway have long remained an enigma. Recent studies have shown that phytanic acid first undergoes activation to its coenzyme A ester, followed by hydroxylation to 2-hydroxyphytanoyl-CoA. In this paper we have studied the mechanism of decarboxylation of 2-hydroxyphytanoyl-CoA in human liver. To this end, human liver homogenates were incubated with 2-hydroxyphytanoyl-CoA in the presence or absence of NAD+. Hereafter, the medium was analyzed for the presence of pristanal and pristanic acid by gas chromatography mass spectrometry. Our results show that pristanal is formed from 2-hydroxyphytanoyl-CoA. Pristanal is subsequently oxidized to pristanic acid in a NAD+dependent reaction. These results finally resolve the mechanism of the phytanic acid α-Oxidation process in human liver.
Guy P Mannaerts - One of the best experts on this subject based on the ideXlab platform.
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Thiamine Pyrophosphate: an essential Cofactor in the Mammalian Metabolism of 3-methyl-branched Fatty Acids
Advances in Experimental Medicine and Biology, 2020Co-Authors: Veerle Foulon, Minne Casteels, Guy P Mannaerts, Bruce D. Gelb, Paul P. VanveldhovenAbstract:A major breakthrough in the research on the Alpha-Oxidation of 3-methyl-branched fatty acids, such as the naturally occurring phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), was the identification of 2- hydroxyphytanoyl-CoA lyase (2-HPCL), a peroxisomal enzyme that catalyzes the carbon-carbon bond cleavage in the third step of the proposed pathway, and the observation that its activity depends on thiamine pyrophosphate (TPP), a hitherto unknown cofactor of Alpha-Oxidation (Foulons et al., 1999).
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Alpha Oxidation of 3 methyl substituted fatty acids and its thiamine dependence
FEBS Journal, 2003Co-Authors: Minne Casteels, Veerle Foulon, Guy P Mannaerts, Paul P Van VeldhovenAbstract:3-Methyl-branched fatty acids, as phytanic acid, undergo peroxisomal α-Oxidation in which they are shortened by 1 carbon atom. This process includes four steps: activation, 2-hydroxylation, thiamine pyrophosphate dependent cleavage and aldehyde dehydrogenation. The thiamine pyrophosphate dependence of the third step is unique in peroxisomal mammalian enzymology. Human pathology due to a deficient Alpha-Oxidation is mostly linked to mutations in the gene coding for the second enzyme of the sequence, phytanoyl-CoA hydroxylase.
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Prenatal and postnatal development of peroxisomal lipid-metabolizing pathways in the mouse
Biochemical Journal, 2001Co-Authors: Steven Huyghe, Minne Casteels, Guy P Mannaerts, Paul P Van Veldhoven, Anneleen Janssen, Liesbeth Meulders, Peter Declercq, Myriam BaesAbstract:The ontogeny of the following peroxisomal metabolic pathways was evaluated in mouse liver and brain: Alpha-Oxidation, beta-Oxidation and ether phospholipid synthesis. In mouse embryos lacking functional peroxisomes (PEX5(-/-) knock-out), a deficiency of plasmalogens and an accumulation of the very-long-chain fatty acid C(26:0) was observed in comparison with control littermates, indicating that ether phospholipid synthesis and beta-Oxidation are already active at mid-gestation in the mouse. Northern analysis revealed that the enzymes required for the beta-Oxidation of straight-chain substrates are present in liver and brain during embryonic development but that those responsible for the degradation of branched-chain substrates are present only in liver from late gestation onwards. The expression pattern of transcripts encoding enzymes of the Alpha-Oxidation pathway suggested that Alpha-Oxidation is initiated in the liver around birth and is not active in brain throughout development. Remarkably, a strong induction of the mRNA levels of enzymes involved in Alpha-Oxidation and beta-Oxidation was observed around birth in the liver. In contrast, enzyme transcripts that were expressed in brain were present at rather constant levels throughout prenatal and postnatal development. These results suggest that the defective ether phospholipid synthesis and/or peroxisomal beta-Oxidation of straight-chain fatty acids might be involved in the pathogenesis of the prenatal organ defects in peroxisome-deficient mice and men.
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peroxisomal lipid degradation via beta and Alpha Oxidation in mammals
Cell Biochemistry and Biophysics, 2000Co-Authors: Guy P Mannaerts, Paul P Van Veldhoven, Minne CasteelsAbstract:Peroxisomal β-Oxidation is involved in the degradation of long chain and very long chain fatty acyl-(coenzyme A)CoAs, long chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs (e.g. pristanoyl-CoA), and the CoA esters of the bile acid intermediates di- and trihydroxycoprostanic acids (side chain of cholesterol).
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purification molecular cloning and expression of 2 hydroxyphytanoyl coa lyase a peroxisomal thiamine pyrophosphate dependent enzyme that catalyzes the carbon carbon bond cleavage during Alpha Oxidation of 3 methyl branched fatty acids
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Veerle Foulon, Guy P Mannaerts, Paul P Van Veldhoven, Kathleen Croes, Vasily D Antonenkov, Etienne Waelkens, Minne CasteelsAbstract:In the third step of the α-Oxidation of 3-methyl-branched fatty acids such as phytanic acid, a 2-hydroxy-3-methylacyl-CoA is cleaved into formyl-CoA and a 2-methyl-branched fatty aldehyde. The cleavage enzyme was purified from the matrix protein fraction of rat liver peroxisomes and identified as a protein made up of four identical subunits of 63 kDa. Its activity proved to depend on Mg2+ and thiamine pyrophosphate, a hitherto unrecognized cofactor of α-Oxidation. Formyl-CoA and 2-methylpentadecanal were identified as reaction products when the purified enzyme was incubated with 2-hydroxy-3-methylhexadecanoyl-CoA as the substrate. Hence the enzyme catalyzes a carbon–carbon cleavage, and we propose calling it 2-hydroxyphytanoyl-CoA lyase. Sequences derived from tryptic peptides of the purified rat protein were used as queries to recover human expressed sequence tags from the databases. The composite cDNA sequence of the human lyase contained an ORF of 1,734 bases that encodes a polypeptide with a calculated molecular mass of 63,732 Da. Recombinant human protein, expressed in mammalian cells, exhibited lyase activity. The lyase displayed homology to a putative Caenorhabditis elegans protein that resembles bacterial oxalyl-CoA decarboxylases. Similarly to the decarboxylases, a thiamine pyrophosphate-binding consensus domain was present in the C-terminal part of the lyase. Although no peroxisome targeting signal, neither 1 nor 2, was apparent, transfection experiments with constructs encoding green fluorescent protein fused to the full-length lyase or its C-terminal pentapeptide indicated that the C terminus of the lyase represents a peroxisome targeting signal 1 variant.