The role of 2-hydroxyacyl-CoA lyase, a thiamin pyrophosphate-dependent enzyme, in the peroxisomal metabolism of 3-methyl-branched fatty acids and 2-hydroxy straight-chain fatty acids

Casteels, Minne; Sniekers, Mieke; Fraccascia, Patrizia; Mannaerts, Guy P.; Veldhoven, Paul P. Van

doi:10.1042/bst0350876

Cited by 65 publications

(47 citation statements)

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“…In addition to incorporation into lipid species, 2-OH FAs could be further catabolized by the ␣ oxidation pathway ( Scheme 1 ). In that pathway, 2-OH phytanoyl CoA lyase cleaves 2-OH acyl-CoA to an aldehyde with one less carbon and thiamin pyrophosphate is required for its enzymatic activity ( 31 ). It will be interesting to examine the metabolic consequence of the accumulative reactive lipid aldehydes.…”

Section: Discussionmentioning

confidence: 99%

Stereospecificity of fatty acid 2-hydroxylase and differential functions of 2-hydroxy fatty acid enantiomers

Guo

Zhang

Zhou

et al. 2012

Journal of Lipid Research

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(FA2H) is a recently identifi ed NAD(P)H-dependent enzyme that catalyzes the hydroxylation of FA at the C-2 position to produce 2-hydroxy FAs (2-OH FAs) ( Scheme 1 ) Scheme 1( 2, 3 ). In addition to undergoing ␣ oxidation to form oddchain-length FAs ( 4 ), the FA2H-generated 2-OH FAs are incorporated into a long-chain sphingosine base via an amide bond to generate 2-hydroxy sphingolipids (2-OH sphingolipids) ( Scheme 1 ) ( 5 ). The 2-OH sphingolipids are important components of plasma membrane lipid rafts, which host a variety of signaling and traffi cking events. Specifi c functions of 2-OH sphingolipids in membrane endocytosis were fi rst demonstrated in Saccharomyces cerevisiae yeast strains with defective SCS7/FA2H ( 6, 7 ). Recent genetic studies suggest a critical role of FA2H and possibly 2-OH sphingolipids in multiple neurodegenerative diseases. Loss of FA2H in mice causes signifi cant demyelination and profound axonal loss ( 8,9 ). Mutations in the FA2H gene in humans are associated with leukodystrophy ( 10 ), spastic paraplegia ( 11 ), and neurodegeneration with brain iron accumulation ( 12 ). FA2H may also play a signifi cant role in metabolism. We recently showed decreased levels of glucose transporter 4 (GLUT4) proteins and thus cellular glucose uptake in FA2H knockdown adipocytes ( 13 ). A recent study also suggested a role of FA2H in synthesis of specifi c sebaceous gland or sebum lipids and in regulating the hair follicle homeostasis ( 14 ).2-OH FAs are chiral due to the asymmetric carbon bearing the hydroxyl group, and a specifi c 2-hydroxylase usually generates enantiopure products. Biological samples and diets therefore have different enantio-enrichments of Abstract FA 2-hydroxylase (FA2H) is an NAD(P)H-dependent enzyme that initiates FA ␣ oxidation and is also responsible for the biosynthesis of 2-hydroxy FA (2-OH FA)-containing sphingolipids in mammalian cells. The 2-OH FA is chiral due to the asymmetric carbon bearing the hydroxyl group. Our current study performed stereochemistry investigation and showed that FA2H is stereospecifi c for the production of ( R )-enantiomers. FA2H knockdown in adipocytes increases diffusional mobility of raft-associated lipids, leading to reduced GLUT4 protein level, glucose uptake, and lipogenesis. The effects caused by Manuscript received 23 February 2012 and in revised form 29 March 2012. Published, JLR Papers in Press, April 19, 2012 DOI 10.1194 Stereospecifi city of fatty acid 2-hydroxylase and differential functions of 2-hydroxy fatty acid enantiomers Abbreviations: Cer, ceramide; CHO, Chinese hamster ovary; CTxB, cholera toxin subunit B; D, diffusion coeffi cient; FA2H, FA 2-hydroxylase; FAME, FA methyl ester; FRAP, fl uorescence recovery after photobleaching; GLUT4, glucose transporter 4; HexCer, hexosylceramide; Mf, mobile fraction; MTPA, ␣ -methoxy-␣ -trifl uoromethylphenylacetyl; NCI-MS, negative chemical ionization mass spectrometry; NL, neutral loss; 2-OH Cer, 2-hydroxy ceramide; 2-OH FA, 2-hydroxy FA; 2-OH PA, 2-OH palmitic acid; 2-OH sphingo...

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Section: Discussionmentioning

confidence: 99%

Stereospecificity of fatty acid 2-hydroxylase and differential functions of 2-hydroxy fatty acid enantiomers

Guo

Zhang

Zhou

et al. 2012

Journal of Lipid Research

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“…2 ). More recently, long-chain 2-hydroxylated FAs (2OH-FA) were proven to be ␣ -oxidized ( 19 ), and an ␣ -oxidative mechanism is supposedly responsible for the presence/formation of odd-numbered longchain FAs in brain ( 20 ).…”

Section: Enzymology Of Peroxisomal ␣ -Oxidationmentioning

confidence: 99%

Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism

Veldhoven

2010

Journal of Lipid Research

286

290

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“…5 c), CO may first be converted to formate and subsequently to formyl-CoA in a ligase reaction converting ATP to AMP plus pyrophosphate. The further path could follow a concept that was originally developed for the TDP-catalyzed α-oxidation of 2-hydroxy-3-methyl fatty acids in which the C1 atom is released as formyl-CoA [Casteels et al, 2007]. Translated to the present problem and run in reverse, formyl-CoA could be condensed with acetone to form 2-hydroxyisobutyryl-CoA.…”

Section: Acetone Activation In Sulfate Reducersmentioning

confidence: 99%

Activation of Acetone and Other Simple Ketones in Anaerobic Bacteria

et al. 2016

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Acetone and other ketones are activated for subsequent degradation through carboxylation by many nitrate-reducing, phototrophic, and obligately aerobic bacteria. Acetone carboxylation leads to acetoacetate, which is subsequently activated to a thioester and degraded via thiolysis. Two different types of acetone carboxylases have been described, which require either 2 or 4 ATP equivalents as an energy supply for the carboxylation reaction. Both enzymes appear to combine acetone enolphosphate with carbonic phosphate to form acetoacetate. A similar but more complex enzyme is known to carboxylate the aromatic ketone acetophenone, a metabolic intermediate in anaerobic ethylbenzene metabolism in denitrifying bacteria, with simultaneous hydrolysis of 2 ATP to 2 ADP. Obligately anaerobic sulfate-reducing bacteria activate acetone to a four-carbon compound as well, but via a different process than bicarbonate- or CO₂-dependent carboxylation. The present evidence indicates that either carbon monoxide or a formyl residue is used as a cosubstrate, and that the overall ATP expenditure of this pathway is substantially lower than in the known acetone carboxylase reactions.

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The role of 2-hydroxyacyl-CoA lyase, a thiamin pyrophosphate-dependent enzyme, in the peroxisomal metabolism of 3-methyl-branched fatty acids and 2-hydroxy straight-chain fatty acids

Cited by 65 publications

References 48 publications

Stereospecificity of fatty acid 2-hydroxylase and differential functions of 2-hydroxy fatty acid enantiomers

Stereospecificity of fatty acid 2-hydroxylase and differential functions of 2-hydroxy fatty acid enantiomers

Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism

Activation of Acetone and Other Simple Ketones in Anaerobic Bacteria

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