Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite increasing insight into peroxisomal beta-oxidation, it is still not clear which enzymes catalyze very-long-chain fatty acid degradation. Using the northern blot and RT-PCR techniques, a brain-specific expression is demonstrated for acyl-CoA oxidase 3II mRNA, thiolase-A and trans2,3enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase multifunctional enzyme type 2.
Brain Res Mol Brain Res 1999 Dec 10
PMID:Gene expression of peroxisomal beta-oxidation enzymes in rat brain. 1064 Jun 93

Peroxisomes and peroxisomal enzyme expression were investigated biochemically and morphometrically in guinea pig intestinal epithelial cells at different stages of their migration along the crypt-villus axis. Epithelial cells were sequentially isolated along the axis and the specific activities of the peroxisomal enzymes catalase and acyl-CoA oxidase were found to be significantly higher in differentiated and mature cells situated at the villus tip and stem than in the crypt. Conversely, 1-alk-1'enyl, 2-acyl phospholipid (plasmalogen) concentration in the crypt and middle villus was significantly higher than in villus tip cells. Assay of alkyl DHAP synthase and fatty acyl CoA reductase (enzymes responsible for the production of plasmalogen precursors) showed no correlating activity gradient with plasmalogen concentration. Morphometric analysis revealed that peroxisomes were present even in the most immature stem cells, however, their number and volume and surface densities increased as the epithelial cell developed as did the proportion of elongated and vermiform peroxisomes to spherical structures. Senescent cells at the tip of the villus, however, showed a dramatic decrease in number of peroxisomes per cell possibly due to cellular degradation. We conclude that the peroxisomal compartment of the guinea pig small intestinal epithelial cell develops as a function of cell development possibly reflecting adaptation to maximise its metabolic capacity.
Mol Cell Biochem 2000 Jan
PMID:Peroxisome distribution along the crypt-villus axis of the guinea pig small intestine. 1072 40

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is responsible for the hypolipidemic, peroxisome proliferation and carcinogenic effects of fibrates. Rats and mice are responsive, but guinea pigs and primates are resistant to the proliferative and carcinogenic effects of these drugs, but the hypolipidemic effect is still manifest. It is not yet clear whether humans should be considered unresponsive, and there is concern about the long-term safety of fibrates. We present molecular evidence for the reported resistance of human cells to peroxisome proliferation by describing a deficient interaction of nuclear extracts from human cells with an acyl-CoA oxidase (ACO)-peroxisome proliferator response element probe upon fibrate addition. Electrophoretic mobility shift assay analysis showed that ciprofibrate elicited a concentration-dependent increase in the binding of nuclear extracts from cells of rat (Morris) and human (HepG2) origin to an ACO-peroxisome proliferator response element probe, although in HepG2 cells the increase was of marginal statistical significance. In Morris cells, the increase was more marked than in HepG2 cells (4-fold versus 1.5-fold at 0.2 mM ciprofibrate), and maximal binding was achieved earlier in Morris (30 min) than in HepG2 cells (3 h). Morris cells responded to the addition of ciprofibrate by increasing the levels of ACO mRNA, whereas HepG2 did not. The ratio between PPARbeta/PPARalpha mRNAs was higher in HepG2 cells than in Morris cells (3.2 versus 1.9), pointing to an antagonizing effect of PPARbeta on PPARalpha activity. These results were obtained in untransfected cells expressing their own basal set of receptors. We also provide evidence of the translocation of PPARalpha from the cytosol to the nucleus upon activation by ciprofibrate.
Mol Pharmacol 2000 Jul
PMID:Differences in the formation of PPARalpha-RXR/acoPPRE complexes between responsive and nonresponsive species upon fibrate administration. 1086 Sep 41

The putative involvement of peroxisomal beta-oxidation in the biosynthetic pathway of docosahexaenoic acid (22:6n-3, DHA) synthesis is critically reviewed in light of experiments with two recently developed knockout mouse models for Zellweger syndrome, a peroxisomal disorder affecting brain development. These mice were generated by targeted disruption of the PEX2 and PEX5 peroxisomal assembly genes encoding targeting signal receptor peroxins for the recognition and transport of a set of peroxisomal enzymes, including those of peroxisomal beta-oxidation, to the peroxisomal matrix. Analysis of esterified 22:6n-3 concentrations in PEX2-/- and PEX5-/- mice do not support the hypothesized requirement of peroxisomal beta-oxidation in 22:6n-3 synthesis, as only brain, but not liver or plasma, 22:6n-3 levels were decreased. Supplementation of PEX5+/- dams with 22:6n-3, although restoring the levels of brain 22:6n-3 in total lipids to that of controls, did not normalize the phenotype. These decreased brain 22:6n-3 concentrations appear to be secondary to impaired plasmalogen (sn-1-alkyl-, alkenyl-2-acyl glycerophospholipids) synthesis, probably at the level of the dihydroxyacetonephosphate acyltransferase (DHAP-AT), a peroxisomal enzyme catalyzing the first step in the synthesis of 22:6n-3-rich plasmalogens. To diminish the confounding effects of impaired plasmalogen synthesis in the brains of these Zellweger syndrome mouse models, kinetic experiments with labeled precursors, such as 18:3n-3 or 20:5n-3, in liver or isolated hepatocytes, which have negligible amounts of plasmalogens, are suggested to establish the rates of 22:6n-3 biosynthesis and precursor-product relationships. Similar experiments using brain of the acyl-CoA oxidase knockout mouse model are proposed to confirm the lack of peroxisomal beta-oxidation involvement in 22:6n-3 synthesis, since this mutation would not impair plasmalogen synthesis.
Mol Genet Metab 2001 Jan
PMID:Zellweger syndrome knockout mouse models challenge putative peroxisomal beta-oxidation involvement in docosahexaenoic acid (22:6n-3) biosynthesis. 1116 22

Peroxisome proliferators (PPs) are potent tumor promoters in rodents. The mechanism of hepatocarcinogenesis requires the nuclear receptor peroxisome proliferator activated receptor-alpha (PPARalpha), but might also involve the PPARalpha independent alteration of signaling pathways that regulate cell growth. Here, we studied the effects of PPs on the mevalonate pathway, a critical pathway that controls cell proliferation. Liver X receptors (LXRs) are nuclear receptors that act as sterol sensors in the mevalonate pathway. In gene reporter assays in COS-7 cells, the basal activity of the LXR responsive reporter gene (LXRE-luc) was suppressed by 10 microM lovastatin and zaragozic acid A, suggesting that this activity was attributed to the activation of native LXRs, by endogenously produced mevalonate products. The potent PP and rodent tumor promoter, pirinixic acid (WY-14643) also inhibited LXR-mediated transcription in a dose related manner (approximate IC(50) of 100 microM). As did several other PPs including ciprofibric acid and mono-ethylhexylphthalate. Polyunsaturated and medium to long chain fatty acids at 100 microM were also potent inhibitors; the arachidonic acid analogue eicosatetraynoic acid being the most active (approximate IC(50) of 10 microM). Of the PPs and fatty acids tested, there was a strong correlation between the ability of these agents to suppress de novo sterol synthesis in a rat hepatoma cell line, H4IIEC3, and inhibit LXR-mediated transcription in COS-7 cells, but a discordance between these endpoints and PPARalpha activation and fatty acid acyl-CoA oxidase induction. Taken together, these results suggest that PPs and fatty acids negatively regulate the mevalonate pathway through a mechanism that is not entirely dependent on PPARalpha activation. Because of the importance of the mevalonate pathway in regulating cell proliferation, the modulation of this pathway by PPs and fatty acids might contribute to their actions on cell growth/differentiation.
J Steroid Biochem Mol Biol 2001 Apr
PMID:Peroxisome proliferators and fatty acids negatively regulate liver X receptor-mediated activity and sterol biosynthesis. 1135 75

The promoter regions of the genes encoding the first two enzymes of the peroxisomal beta-oxidation pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), contain transcriptional regulatory sequences termed peroxisome proliferator-response elements (PPRE) that are bound by the peroxisome proliferator-activated receptor alpha (PPARalpha) and 9-cis-retinoic acid receptor (RXRalpha) heterodimeric complex. In this study, the role of the short heterodimer partner (SHP) receptor in modulating PPARalpha-mediated gene transcription from the PPREs of the genes encoding AOx and HD was investigated both in vitro and in vivo. In vitro binding assays using glutathione-S-transferase-tagged chimeric receptors for PPARalpha and SHP were used to verify the interaction between PPARalpha and SHP. This interaction was unaffected by the presence of the peroxisome proliferator, Wy-14,643. SHP has been proposed to act as a negative regulator of nuclear hormone receptor activity, and SHP inhibited transcription by PPARalpha/RXRalpha heterodimers from the AOx-PPRE. Surprisingly, SHP potentiated transcription by PPARalpha/RXRalpha heterodimers from the HD-PPRE. This is the first demonstration of positive transcriptional activity attributable to SHP. Together, these results suggest that SHP can modulate PPARalpha/RXRalpha-mediated transcription in a response element-specific manner.
Mol Cell Endocrinol 2001 May 15
PMID:The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase. 1136 42

The first committed step in the beta-oxidation of fatty acids is catalyzed by the enzyme acyl-CoA oxidase (ACOX), which oxidizes a fatty acyl-CoA to a 2-trans-enoyl-CoA. To understand the role of beta-oxidation during seedling growth in soybean, two ACOX cDNAs were isolated by screening a seedling library with a DNA fragment obtained by RT-PCR by using degenerate oligonucleotides. The two cDNAs (ACX1;1 and ACX1;2) are 86% identical to each other at the nucleotide and the amino acid level. Their deduced amino acid sequences share significant homology with known acyl-CoA oxidases, including the conserved CGGHGY motif, a putative flavin mononucleotide binding site. In both sequences, the last three amino acids, ARL, represent a putative peroxisome targeting signal. The mRNA and protein of both cDNAs accumulated in all seedling tissues, with relatively stronger expression in the growing seedling axis and hypocotyl, and weaker expression in the cotyledon. Immunolocalization studies indicated that the two proteins were localized in the phloem cells of hypocotyl tissue. The two cDNAs were expressed in Escherichia coli and shown to possess acyl-CoA oxidase activity. With fatty acyl-CoA substrates of varying chain lengths, it was demonstrated that both ACX1;1 and ACX1;2 have broad substrate specificities (C8-C18). The stronger expression of ACX1;1 and ACX 1;2 in the axis and hypocotyl tissue, the weaker expression in the oil-rich cotyledon tissue, and the broad substrate specificities suggest that the two acyl-CoA oxidases might play a general house-keeping role during soybean seedling growth, such as the turnover of membrane lipids.
Plant Mol Biol 2001 Nov
PMID:Gene isolation and characterization of two acyl CoA oxidases from soybean with broad substrate specificities and enhanced expression in the growing seedling axis. 1166 77

Pex6p belongs to the AAA family of ATPases. Its CHO mutant, ZP92, lacks normal peroxisomes but contains peroxisomal membrane remnants, so called peroxisomal ghosts, which are detected with anti-70-kDa peroxisomal membrane protein (PMP70) antibody. No peroxisomal matrix proteins were detected inside the ghosts, but exogenously expressed green fluorescent protein (GFP) fused to peroxisome targeting signal-1 (PTS-1) accumulated in the areas adjacent to the ghosts. Electron microscopic examination revealed that PMP70-positive ghosts in ZP92 were complex membrane structures, rather than peroxisomes with reduced matrix protein import ability. In a typical case, a set of one central spherical body and two layers of double-membraned loops were observed, with endoplasmic reticulum present alongside the outer loop. In the early stage of complementation by PEX6 cDNA, catalase and acyl-CoA oxidase accumulated in the lumen of the double-membraned loops. Biochemical analysis revealed that almost all the peroxisomal ghosts were converted into peroxisomes upon complementation. Our results indicate that 1) Peroxisomal ghosts are complex membrane structures; and 2) The complex membrane structures become import competent and are converted into peroxisomes upon complementation with PEX6.
Mol Biol Cell 2002 Feb
PMID:Peroxisomes are formed from complex membrane structures in PEX6-deficient CHO cells upon genetic complementation. 1185 24

Extremely long chain polyunsaturated fatty acids (ELCPs) with >24 carbons and four or more double bonds are normally found in excitatory tissues but have no known function, and are greatly increased in brain and other tissues of humans with peroxisomal disorders. Straight-chain acyl-CoA oxidase (AOX) catalyzes the first, rate-limiting step of peroxisomal beta-oxidation of very-long-chain saturated and unsaturated fatty acids. We have studied the polyunsaturated fatty acid metabolism of AOX knockout mice (AOX-/- as a model of human AOX deficiency (pseudo-neonatal adrenoleukodystrophy), and as a genetic tool to test the putative peroxisomal beta-oxidation involvement in polyunsaturated fatty acid synthesis. Liver lipids of 26-day-old weanling AOX-/- mice livers accumulate n-3 and n-6 ELCPs from C24 to C30 with 5 and 6 double bonds, have 356 +/- 66 microg/g docosahexaenoic acid (22:6n-3), similar to congenic (AOX -/* = AOX+/+ and AOX+/-) controls (401 +/- 96 microg/g), but increased 22:5n-6 (22.4 +/- 3.7 vs 6.4 +/- 1.5 microg/g). AOX+/* mice injected intraperitoneally at 23 days with [U-(13)C]-18:3n-3 show strong labeling of 22:6n-3 after 72 h, whereas AOX -/- mice display less labeling of 22:6n-3 but strong tracer incorporation into 24:6n-3, 26:6n-3, and 28:6n-3, after the same period. These data suggest that ELCPs are natural runaway elongation by-products of 22:6n-3 and 22:5n-6 synthesis, which are normally disposed of by peroxisomal beta-oxidation. Under conditions with impaired peroxisomal beta-oxidation, such as Zellweger syndrome and adrenoleukodystrophies, ELCPs accumulate due to increased synthesis and impaired disposal. Two mechanisms for the formation of these runaway elongation by-products and the involvement of secondary carnitine deficiency in this process are proposed: n-3 ELCPs are synthesized by a carnitine-dependent multifunctional mitochondrial docosahexaenoic acid synthase (mtDHAS) which normally synthesizes primarily 22:6n-3, while n-6 ELCPs are synthesized by independent elongation enzymes in the endoplasmic reticulum.
Mol Genet Metab 2002 Feb
PMID:Straight-chain acyl-CoA oxidase knockout mouse accumulates extremely long chain fatty acids from alpha-linolenic acid: evidence for runaway carousel-type enzyme kinetics in peroxisomal beta-oxidation diseases. 1185 29

To determine whether the PPARalpha agonist fenofibrate regulates obesity and lipid metabolism with sexual dimorphism, we examined the effects of fenofibrate on body weight, white adipose tissue (WAT) mass, circulating lipids, and the expression of PPARalpha target genes in both sexes of high fat diet-fed C57BL/6J mice. Both sexes of mice fed a high-fat diet for 14 weeks exhibited increases in body weight, visceral WAT mass, as well as serum triglycerides and cholesterol, although these effects were more pronounced among males. Feeding a high fat diet supplemented with fenofibrate (0.05% w/w) reduced all of these effects significantly in males except serum cholesterol level. Females on a fenofibrate-enriched high fat diet had reduced serum triglyceride levels, albeit to a smaller extent compared to males, but did not exhibit decreases in body weight, WAT mass, and serum cholesterol. Fenofibrate treatment resulted in hepatic induction of PPARalpha target genes encoding enzymes for fatty acid beta-oxidation, the magnitudes of which were much higher in males compared to females, as evidenced by results for acyl-CoA oxidase, a first enzyme of the beta-oxidation system. These results suggest that observed sexually dimorphic effects on body weight, WAT mass and serum lipids by fenofibrate may involve sexually related elements in the differential activation of PPARalpha.
Exp Mol Med 2002 Dec 31
PMID:Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism. 1252 91


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