Identification of the Pathway of Alpha-oxidation of Cerebronic Acid in Peroxisomes

Overview

Journal Lipids

Specialty Biochemistry

Date 2000 Dec 5

PMID 11104019

Citations 4

Authors

R Sandhir

M Khan

I Singh

Affiliations

Soon will be listed here.

Abstract

Cerebronic acid (2-hydroxytetracosanoic acid), an alpha-hydroxy very long-chain fatty acid (VLCFA) and a component of cerebrosides and sulfatides, is unique to nervous tissues. Studies were carried out to identify the pathway and the subcellular site involved in the oxidation of cerebronic acid. The results from these studies revealed that cerebronic acid was catabolized by alpha-oxidation to CO2 and tricosanoic acid (23:0). Studies with subcellular fractions indicated that cerebronic acid was alpha-oxidized in fractions having particulate bound catalase and enzyme systems for the beta-oxidation of VLCFA (e.g., lignoceric acid), suggesting peroxisomes as the subcellular organelle responsible for alpha-oxidation of cerebronic acid. Etomoxir, an inhibitor of mitochondrial fatty acid oxidation, had no effect on cerebronic acid alpha-oxidation. Further, cerebronic acid oxidation was found to be dependent on the presence of NAD+ but not FAD, NADPH, ATP, Mg2+, or CoASH. Intraorganellar localization studies indicated that the enzyme system for the alpha-oxidation of cerebronic acid was associated with the peroxisomal limiting membranes. Studies on cultured fibroblasts from normal subjects and patients with peroxisomal disorders indicated an impairment of alpha-oxidation of cerebronic acid in cell lines that lack peroxisomes [e.g., Zellweger syndrome (ZS)]. On the other hand, alpha-oxidation of cerebronic acid was found to be normal in cell lines from X-linked adrenoleukodystrophy, adult Refsum disease, and rhizomelic chondrodysplasia punctata. Our results clearly demonstrate that alpha-oxidation of alpha-hydroxy VLCFA (cerebronic acid) is a peroxisomal function and that this oxidation is impaired in ZS. Furthermore, this alpha-oxidation enzyme system is distinct from the one for the alpha-oxidation of beta-carbon branched-chain fatty acids (e.g., phytanic acid).

Citing Articles

Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation.

Khalil Y, Carrino S, Lin F, Ferlin A, Lad H, Mazzacuva F Int J Mol Sci. 2022; 23(2).

PMID: 35055171 PMC: 8781152. DOI: 10.3390/ijms23020987.

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy.

Kleinecke S, Richert S, de Hoz L, Brugger B, Kungl T, Asadollahi E Elife. 2017; 6.

PMID: 28470148 PMC: 5417850. DOI: 10.7554/eLife.23332.

Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG- and gleason score-specific metabolomic alterations in prostate cancer.

Meller S, Meyer H, Bethan B, Dietrich D, Gonzalez Maldonado S, Lein M Oncotarget. 2015; 7(2):1421-38.

PMID: 26623558 PMC: 4811470. DOI: 10.18632/oncotarget.6370.

Stereoselective analysis of 2-hydroxysebacic acid in urine of patients with Zellweger syndrome and of premature infants fed with medium-chain triglycerides.

Muth A, Mosandl A, Wanders R, Nowaczyk M, Baric I, Bohles H J Inherit Metab Dis. 2003; 26(6):583-92.

PMID: 14605504 DOI: 10.1023/a:1025908216639.

References

Wanders R, van Grunsven E, Jansen G . Lipid metabolism in peroxisomes: enzymology, functions and dysfunctions of the fatty acid alpha- and beta-oxidation systems in humans. Biochem Soc Trans. 2000; 28(2):141-9. DOI: 10.1042/bst0280141. View

Mihalik S, Morrell J, Kim D, Sacksteder K, Watkins P, Gould S . Identification of PAHX, a Refsum disease gene. Nat Genet. 1997; 17(2):185-9. DOI: 10.1038/ng1097-185. View

Kunau W, Dommes V, Schulz H . beta-oxidation of fatty acids in mitochondria, peroxisomes, and bacteria: a century of continued progress. Prog Lipid Res. 1995; 34(4):267-342. DOI: 10.1016/0163-7827(95)00011-9. View

Singh I, Moser A, Goldfischer S, Moser H . Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A. 1984; 81(13):4203-7. PMC: 345397. DOI: 10.1073/pnas.81.13.4203. View

COOPERSTEIN S, LAZAROW A . A microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem. 1951; 189(2):665-70. View

Wanders R, van Roermund C, Schor D, Ten Brink H, Jakobs C . 2-Hydroxyphytanic acid oxidase activity in rat and human liver and its deficiency in the Zellweger syndrome. Biochim Biophys Acta. 1994; 1227(3):177-82. DOI: 10.1016/0925-4439(94)90092-2. View

Kishimoto Y, RADIN N . OCCURRENCE OF 2-HYDROXY FATTY ACIDS IN ANIMAL TISSUES. J Lipid Res. 1963; 4:139-43. View

Mihalik S, Rainville A, Watkins P . Phytanic acid alpha-oxidation in rat liver peroxisomes. Production of alpha-hydroxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors. Eur J Biochem. 1995; 232(2):545-51. DOI: 10.1111/j.1432-1033.1995.545zz.x. View

Lazo O, Contreras M, Singh I . Effect of ciprofibrate on the activation and oxidation of very long chain fatty acids. Mol Cell Biochem. 1991; 100(2):159-67. DOI: 10.1007/BF00234165. View

10.

Lippel K, Mead J . Alpha-oxidation of 2-hydroxystearic acid in vitro. Biochim Biophys Acta. 1968; 152(4):669-80. DOI: 10.1016/0005-2760(68)90113-6. View

11.

Singh I, Kishimoto Y . Effect of cyclodextrins on the solubilization of lignoceric acid, ceramide, and cerebroside, and on the enzymatic reactions involving these compounds. J Lipid Res. 1983; 24(5):662-5. View

12.

Sandhir R, Khan M, Chahal A, Singh I . Localization of nervonic acid beta-oxidation in human and rodent peroxisomes: impaired oxidation in Zellweger syndrome and X-linked adrenoleukodystrophy. J Lipid Res. 1998; 39(11):2161-71. View

13.

Braverman N, Steel G, Obie C, Moser A, Moser H, Gould S . Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet. 1997; 15(4):369-76. DOI: 10.1038/ng0497-369. View

14.

Akanuma H, Kishimoto Y . Synthesis of ceramides and cerebrosides containing both alpha-hydroxy and nonhydroxy fatty acids from lignoceroyl-CoA by rat brain microsomes. J Biol Chem. 1979; 254(4):1050-60. View

15.

McCarthy K, de Vellis J . Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 1980; 85(3):890-902. PMC: 2111442. DOI: 10.1083/jcb.85.3.890. View

16.

Chahal A, Khan M, Pai S, Barbosa E, Singh I . Restoration of phytanic acid oxidation in Refsum disease fibroblasts from patients with mutations in the phytanoyl-CoA hydroxylase gene. FEBS Lett. 1998; 429(1):119-22. DOI: 10.1016/s0014-5793(98)00575-4. View

17.

Ten Brink H, Schor D, Kok R, Poll-The B, Wanders R, Jakobs C . Phytanic acid alpha-oxidation: accumulation of 2-hydroxyphytanic acid and absence of 2-oxophytanic acid in plasma from patients with peroxisomal disorders. J Lipid Res. 1992; 33(10):1449-57. View

18.

Singh I, Kishimoto Y . Brain-specific ceramide synthesis activity: change during brain maturation and in jimpy mouse brain. Brain Res. 1982; 232(2):500-5. DOI: 10.1016/0006-8993(82)90296-7. View

19.

FULCO A, Mead J . The biosynthesis of lignoceric, cerebronic, and nervonic acids. J Biol Chem. 1961; 236:2416-20. View

20.

Singh I . Biochemistry of peroxisomes in health and disease. Mol Cell Biochem. 1997; 167(1-2):1-29. DOI: 10.1023/a:1006883229684. View