Molecular cloning and nucleotide sequence of cDNA encoding rat kidney long‐chain <scp>l</scp>‐2‐hydroxy acid oxidase

Belmouden, Ahmed; Le, Kim; Lederer, Florence; Garchon, Henri‐Jean

doi:10.1111/j.1432-1033.1993.tb17891.x

Cited by 18 publications

(20 citation statements)

References 64 publications

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“…In our search for human 2-hydroxy acid oxidases, we expected to find one homolog of the rat long chain 2-hydroxy acid oxidase (25). Instead, we found two.…”

Section: Discussioncontrasting

confidence: 46%

Identification and Characterization of HAOX1, HAOX2, and HAOX3, Three Human Peroxisomal 2-Hydroxy Acid Oxidases

Jones

Morrell

Gould³

2000

Journal of Biological Chemistry

109

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Computer-based approaches identified three distinct human 2-hydroxy acid oxidase genes, HAOX1, HAOX2, and HAOX3, that encode proteins with significant sequence similarity to plant glycolate oxidase, a prototypical 2-hydroxy acid oxidase. The products of these genes are targeted to peroxisomes and have 2-hydroxy acid oxidase activities. Each gene displays a distinct tissuespecific pattern of expression, and each enzyme exhibits distinct substrate preferences. HAOX1 is expressed primarily in liver and pancreas and is most active on the two-carbon substrate, glycolate, but is also active on 2-hydroxy fatty acids. HAOX2 is expressed predominantly in liver and kidney and displays highest activity toward 2-hydroxypalmitate. HAOX3 expression was detected only in pancreas, and this enzyme displayed a preference for the medium chain substrate 2-hydroxyoctanoate. These results indicate that all three human 2-hydroxy acid oxidases are involved in the oxidation of 2-hydroxy fatty acids and may also contribute to the general pathway of fatty acid ␣-oxidation. Primary hyperoxaluria type 1 (PH1) is caused by defects in peroxisomal alanine-glyoxylate aminotransferase, the enzyme that normally eliminates intraperoxisomal glyoxylate. The presence of HAOX1 in liver and kidney peroxisomes and the ability of HAOX1 to oxidize glyoxylate to oxalate implicate HAOX1 as a mediator of PH1 pathophysiology.

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“…In our search for human 2-hydroxy acid oxidases, we expected to find one homolog of the rat long chain 2-hydroxy acid oxidase (25). Instead, we found two.…”

Section: Discussioncontrasting

confidence: 46%

Identification and Characterization of HAOX1, HAOX2, and HAOX3, Three Human Peroxisomal 2-Hydroxy Acid Oxidases

Jones

Morrell

Gould³

2000

Journal of Biological Chemistry

109

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“…Previous studies have identified mammalian LAAO activity in peroxisomes and mitochondria of rat kidney or liver (42,43). This LAAO activity was due to the B form of L-␣-hydroxy acid oxidase (EC 1.1.3.15) (30), which has no sequence similarity with IL4I1 or LAAO from snake venom or fish (44,45). Thus, we have characterized IL4I1 as a novel mammalian LAAO with unique properties.…”

Section: Discussionmentioning

confidence: 99%

IL-4-Induced Gene-1 Is a Leukocyte l-Amino Acid Oxidase with an Unusual Acidic pH Preference and Lysosomal Localization

Mason

Naidu

Barcia

et al. 2004

The Journal of Immunology

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IL-4-induced gene-1 (Il4i1 or Fig1) initially isolated as a gene of unknown function from mouse B lymphocytes, is limited in expression to primarily immune tissues and genetically maps to a region of susceptibility to autoimmune disease. The predicted Il4i1 protein (IL4I1) sequence is most similar to apoptosis-inducing protein and Apoxin I, both l-amino acid oxidases (LAAO; Enzyme Commission 1.4.3.2). We demonstrate that IL4I1 has unique LAAO properties. IL4I1 has preference for aromatic amino acid substrates, having highest specific activity with phenylalanine. In support of this selectivity, IL4I1 is inhibited by aromatic competitors (benzoic acid and para-aminobenzoic acid), but not by nonaromatic LAAO inhibitors. Il4i1 protein and enzyme activity is found in the insoluble fraction of transient transfections, implying an association with cell membrane and possibly intracellular organelles. Indeed, IL4I1 has the unique property of being most active at acidic pH (pH 4), suggesting it may reside preferentially in lysosomes. IL4I1 is N-linked glycosylated, a requirement for lysosomal localization. Confocal microscopy of cells expressing IL4I1 translationally fused to red fluorescent protein demonstrated that IL4I1 colocalized with GFP targeted to lysosomes and with acriflavine, a green fluorescent dye that is taken up into lysosomes. Thus, IL4I1 is a unique mammalian LAAO targeted to lysosomes, an important subcellular compartment involved in Ag processing.

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“…Consequently, 10% glycerol was included in all the solutions used throughout the purification procedure, whereas the enzyme storage buffer was supplemented with 100 mM NaCl. 3 Following this procedure, ϳ8 mg of GOX were routinely purified to high levels ( Fig. 2) out of 1 g of wet cell paste, with a specific activity of ϳ4.0 units/mg using 10 mM glycolate and atmospheric oxygen at pH 7.0 and 30°C.…”

Section: Expression and Purification Of Recombinant Humanmentioning

confidence: 99%

“…The enzyme has been identified in plants and mammals and contains tightly but not covalently linked FMN. GOX has been grouped in the superfamily of the ␣-hydroxy acid oxidases, which includes among others long-chain hydroxy acid oxidase, lactate oxidase, mandelate dehydrogenase, and the flavin-binding domain of yeast flavocytochrome b 2 (2)(3)(4)(5)(6). In plants, GOX is localized in the glyoxysome of photosynthetic tissues, where it participates in photorespiration (7,8).…”

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confidence: 99%

Involvement of Ionizable Groups in Catalysis of Human Liver Glycolate Oxidase

Pennati

Gadda

2009

Journal of Biological Chemistry

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Glycolate oxidase is a flavin-dependent, peroxisomal enzyme that oxidizes ␣-hydroxy acids to the corresponding ␣-keto acids, with reduction of oxygen to H 2 O 2 . In plants, the enzyme participates in photorespiration. In humans, it is a potential drug target for treatment of primary hyperoxaluria, a genetic disorder where overproduction of oxalate results in the formation of kidney stones. In this study, steady-state and presteady-state kinetic approaches have been used to determine how pH affects the kinetic steps of the catalytic mechanism of human glycolate oxidase. The enzyme showed a Ping-Pong Bi-Bi kinetic mechanism between pH 6.0 and 10.0. Both the overall turnover of the enzyme (k cat ) and the rate constant for anaerobic substrate reduction of the flavin were pH-independent at pH values above 7.0 and decreased slightly at lower pH, suggesting the involvement of an unprotonated group acting as a base in the chemical step of glycolate oxidation. The second-order rate constant for capture of glycolate (k cat /K glycolate ) and the K d(app) for the formation of the enzyme-substrate complex suggested the presence of a protonated group with apparent pK a of 8.5 participating in substrate binding. The k cat /K oxygen values were an order of magnitude faster when a group with pK a of 6.8 was unprotonated. These results are discussed in the context of the available three-dimensional structure of GOX.Glycolate oxidase (EC 1.1.3.15; glycolate:oxygen oxidoreductase; GOX) 2 catalyzes the FMN-mediated oxidation of glycolate to glyoxylate with reduction of oxygen to hydrogen peroxide (Scheme 1) (1). The enzyme has been identified in plants and mammals and contains tightly but not covalently linked FMN. GOX has been grouped in the superfamily of the ␣-hydroxy acid oxidases, which includes among others long-chain hydroxy acid oxidase, lactate oxidase, mandelate dehydrogenase, and the flavin-binding domain of yeast flavocytochrome b 2 (2-6). In plants, GOX is localized in the glyoxysome of photosynthetic tissues, where it participates in photorespiration (7,8). In humans and other vertebrates, such as pigs, the enzyme is found in the peroxisomes of liver and kidney and is involved in the production of oxalate (9 -11). The latter finding recently prompted considerable interest in the study of the mechanistic and structural properties of human GOX for the potential development of therapeutic agents targeting the treatment of primary hyperoxaluria (12), a genetic disorder in which overproduction of oxalate results in large deposits of calcium oxalate.To date, the GOX that is best characterized in its structural, kinetic, and biochemical properties is the one from spinach leaves (13-19). Recently, the structure of the enzyme from human liver has been solved in complex with a number of ligands to resolutions of Յ1.95 Å (20). In the active site of the human enzyme (Fig. 1) has been proposed to initiate catalysis by acting as the proton acceptor for the deprotonation of the hydroxyl group or the ␣-carbon of the substrate (19,2...

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Molecular cloning and nucleotide sequence of cDNA encoding rat kidney long‐chain l‐2‐hydroxy acid oxidase

Cited by 18 publications

References 64 publications

Identification and Characterization of HAOX1, HAOX2, and HAOX3, Three Human Peroxisomal 2-Hydroxy Acid Oxidases

Identification and Characterization of HAOX1, HAOX2, and HAOX3, Three Human Peroxisomal 2-Hydroxy Acid Oxidases

IL-4-Induced Gene-1 Is a Leukocyte l-Amino Acid Oxidase with an Unusual Acidic pH Preference and Lysosomal Localization

Involvement of Ionizable Groups in Catalysis of Human Liver Glycolate Oxidase

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