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Alpha Oxidation

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Ronald J.a. Wanders – 1st expert on this subject based on the ideXlab platform

  • Peroxisomal Fatty Acid Alpha-and Beta-Oxidation in Health and Disease: New insights
    Advances in Experimental Medicine and Biology, 2020
    Co-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. Waterham

    Abstract:

    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 AlphaOxidation 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.

  • Very-Long-Chain Fatty Acids and Phytanic Acid
    Laboratory Guide to the Methods in Biochemical Genetics, 2020
    Co-Authors: Ronald J.a. Wanders, Marinus Duran

    Abstract:

    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 AlphaOxidation 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.

  • Peroxisomes and Their Central Role in Metabolic Interaction Networks in Humans.
    Sub-cellular biochemistry, 2018
    Co-Authors: Ronald J.a. Wanders, Hans R. Waterham, Sacha Ferdinandusse

    Abstract:

    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 AlphaOxidation and glyoxylate metabolism.

Paul P Van Veldhoven – 2nd expert on this subject based on the ideXlab platform

  • Alpha Oxidation of 3 methyl substituted fatty acids and its thiamine dependence
    FEBS Journal, 2003
    Co-Authors: Minne Casteels, Veerle Foulon, Guy P Mannaerts, Paul P Van Veldhoven

    Abstract:

    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 AlphaOxidation is mostly linked to mutations in the gene coding for the second enzyme of the sequence, phytanoyl-CoA hydroxylase.

  • Prenatal and postnatal development of peroxisomal lipid-metabolizing pathways in the mouse
    Biochemical Journal, 2001
    Co-Authors: Steven Huyghe, Minne Casteels, Paul P Van Veldhoven, Guy P Mannaerts, Anneleen Janssen, Liesbeth Meulders, Peter Declercq, Myriam Baes

    Abstract:

    The ontogeny of the following peroxisomal metabolic pathways was evaluated in mouse liver and brain: AlphaOxidation, 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 AlphaOxidation pathway suggested that AlphaOxidation 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 AlphaOxidation 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.

  • peroxisomal lipid degradation via beta and Alpha Oxidation in mammals
    Cell Biochemistry and Biophysics, 2000
    Co-Authors: Guy P Mannaerts, Paul P Van Veldhoven, Minne Casteels

    Abstract:

    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).

Minne Casteels – 3rd expert on this subject based on the ideXlab platform

  • AlphaOxidation of 3-methyl-branched fatty acids: unraveling of a pathway
    Verhandelingen – Koninklijke Academie voor Geneeskunde van België, 2020
    Co-Authors: Minne Casteels

    Abstract:

    : 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 AlphaOxidation of 3-methyl-branched fatty acids, with phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) as the best known example, occurs in peroxisomes. AlphaOxidation is a process in which fatty acids are shortened by one carbon atom. The AlphaOxidation 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.

  • Thiamine Pyrophosphate: an essential Cofactor in the Mammalian Metabolism of 3-methyl-branched Fatty Acids
    Advances in Experimental Medicine and Biology, 2020
    Co-Authors: Veerle Foulon, Minne Casteels, Guy P Mannaerts, Bruce D. Gelb, Paul P. Vanveldhoven

    Abstract:

    A major breakthrough in the research on the AlphaOxidation 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 AlphaOxidation (Foulons et al., 1999).

  • Alpha Oxidation of 3 methyl substituted fatty acids and its thiamine dependence
    FEBS Journal, 2003
    Co-Authors: Minne Casteels, Veerle Foulon, Guy P Mannaerts, Paul P Van Veldhoven

    Abstract:

    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 AlphaOxidation is mostly linked to mutations in the gene coding for the second enzyme of the sequence, phytanoyl-CoA hydroxylase.