Enzymes
UniProtKB help_outline | 3 proteins |
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- Name help_outline (24R,25R)-3α,7α,12α,24-tetrahydroxy-5β-cholestan-26-oyl-CoA Identifier CHEBI:59807 Charge -4 Formula C48H76N7O21P3S InChIKeyhelp_outline PXHZOQNODUPJKC-MTLGCJAASA-J SMILEShelp_outline [H][C@@](C)(CC[C@@H](O)[C@@H](C)C(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP([O-])(=O)OP([O-])(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1OP([O-])([O-])=O)n1cnc2c(N)ncnc12)[C@@]1([H])CC[C@@]2([H])[C@]3([H])[C@H](O)C[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])C[C@H](O)[C@]12C 2D coordinates Mol file for the small molecule Search links Involved in 3 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline (24E)-3α,7α,12α-trihydroxy-5β-cholest-24-en-26-oyl-CoA Identifier CHEBI:59879 Charge -4 Formula C48H74N7O20P3S InChIKeyhelp_outline QVDPWQVOSKJUES-JMOYVIBVSA-J SMILEShelp_outline [H][C@@](C)(CC\C=C(/C)C(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP([O-])(=O)OP([O-])(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1OP([O-])([O-])=O)n1cnc2c(N)ncnc12)[C@@]1([H])CC[C@@]2([H])[C@]3([H])[C@H](O)C[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])C[C@H](O)[C@]12C 2D coordinates Mol file for the small molecule Search links Involved in 2 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H2O Identifier CHEBI:15377 (Beilstein: 3587155; CAS: 7732-18-5) help_outline Charge 0 Formula H2O InChIKeyhelp_outline XLYOFNOQVPJJNP-UHFFFAOYSA-N SMILEShelp_outline [H]O[H] 2D coordinates Mol file for the small molecule Search links Involved in 6,048 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
RHEA:18933 | RHEA:18934 | RHEA:18935 | RHEA:18936 | |
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Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
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Publications
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Recombinant 2-enoyl-CoA hydratase derived from rat peroxisomal multifunctional enzyme 2: role of the hydratase reaction in bile acid synthesis.
Qin Y.M., Haapalainen A.M., Conry D., Cuebas D.A., Hiltunen J.K., Novikov D.K.
Rat liver peroxisomes contain two multifunctional enzymes: (1) perMFE-1 [2-enoyl-CoA hydratase 1/Delta3,Delta2-enoyl-CoA isomerase/(S)-3-hydroxyacyl-CoA dehydrogenase] and (2) perMFE-2 [2-enoyl-CoA hydratase 2/(R)-3-hydroxyacyl-CoA dehydrogenase]. To investigate the role of the hydratase activity ... >> More
Rat liver peroxisomes contain two multifunctional enzymes: (1) perMFE-1 [2-enoyl-CoA hydratase 1/Delta3,Delta2-enoyl-CoA isomerase/(S)-3-hydroxyacyl-CoA dehydrogenase] and (2) perMFE-2 [2-enoyl-CoA hydratase 2/(R)-3-hydroxyacyl-CoA dehydrogenase]. To investigate the role of the hydratase activity of perMFE-2 in beta-oxidation, a truncated version of perMFE-2 was expressed in Escherichia coli as a recombinant protein. The protein catalyses the hydration of straight-chain (2E)-enoyl-CoAs to (3R)-hydroxyacyl-CoAs, but it is devoid of hydratase 1 [(2E)-enoyl-CoA to (3S)-hydroxyacyl-CoA] and (3R)-hydroxyacyl-CoA dehydrogenase activities. The purified enzyme (46 kDa hydratase 2) can be stored as an active enzyme for at least half a year. The recombinant enzyme hydrates (24E)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA to (24R,25R)-3alpha,7alpha,12alpha, 24-tetrahydroxy-5beta-cholestanoyl-CoA, which has previously been characterized as a physiological intermediate in bile acid synthesis. The stereochemistry of the products indicates that the hydration reaction catalysed by the enzyme proceeds via a syn mechanism. A monofunctional 2-enoyl-CoA hydratase 2 has not been observed as a wild-type protein. The recombinant 46 kDa hydratase 2 described here survives in a purified form under storage, thus being the first protein of this type amenable to application as a tool in metabolic studies. << Less
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Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency.
van Grunsven E.G., van Berkel E., Ijlst L., Vreken P., de Klerk J.B.C., Adamski J., Lemonde H., Clayton P.T., Cuebas D.A., Wanders R.J.A.
Peroxisomes play an essential role in a number of different metabolic pathways, including the beta-oxidation of a distinct set of fatty acids and fatty acid derivatives. The importance of the peroxisomal beta-oxidation system in humans is made apparent by the existence of a group of inherited dise ... >> More
Peroxisomes play an essential role in a number of different metabolic pathways, including the beta-oxidation of a distinct set of fatty acids and fatty acid derivatives. The importance of the peroxisomal beta-oxidation system in humans is made apparent by the existence of a group of inherited diseases in which peroxisomal beta-oxidation is impaired. This includes X-linked adrenoleukodystrophy and other disorders with a defined defect. On the other hand, many patients have been described with a defect in peroxisomal beta-oxidation of unknown etiology. Resolution of the defects in these patients requires the elucidation of the enzymatic organization of the peroxisomal beta-oxidation system. Importantly, a new peroxisomal beta-oxidation enzyme was recently described called D-bifunctional protein with enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity primarily reacting with alpha-methyl fatty acids like pristanic acid and di- and trihydroxycholestanoic acid. In this patient we describe the first case of D-bifunctional protein deficiency as resolved by enzyme activity measurements and mutation analysis. The mutation found (Gly16Ser) is in the dehydrogenase coding part of the gene in an important loop of the Rossman fold forming the NAD+-binding site. The results show that the newly identified D-bifunctional protein plays an essential role in the peroxisomal beta-oxidation pathway that cannot be compensated for by the L-specific bifunctional protein. << Less
Proc. Natl. Acad. Sci. U.S.A. 95:2128-2133(1998) [PubMed] [EuropePMC]
This publication is cited by 1 other entry.
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Conjugation reactions catalyzed by bifunctional proteins related to beta-oxidation in bile acid biosynthesis.
Kurosawa T., Sato M., Nakano H., Fujiwara M., Murai T., Yoshimura T., Hashimoto T.
The conjugation reactions of hydration and dehydrogenation catalyzed by the dehydratase and dehydrogenase activities of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (DBP) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase bifunctional protein (LBP) in ... >> More
The conjugation reactions of hydration and dehydrogenation catalyzed by the dehydratase and dehydrogenase activities of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (DBP) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase bifunctional protein (LBP) in the side chain degradation step of bile acid biosynthesis were investigated using chemically synthesized C27-bile acid CoA esters as substrates. The hydration catalyzed by DBP showed high diastereoselectivity for (24E)-3alpha,7alpha,12alpha-trihydroxy- and (24E)-3alpha,7alpha-dihydroxy-5beta-cholest-24-en-26-oyl CoA to give (24R,25R)-3alpha,7alpha,12alpha,24-tetrahydroxy- and (24R,25R)-3alpha,7alpha,24-trihydroxy-5beta-cholestan-26-oyl CoAs, respectively, and the dehydrogenation catalyzed by DBP also showed high stereospecificity for the above (24R,25R)-isomers to give 3alpha,7alpha,12alpha-trihydroxy- and 3alpha,7alpha-dihydroxy-24-oxo-5beta-cholestan-26-oyl CoAs, respectively. On the other hand, the dehydratase activity of LBP displayed a different diastereoselectivity producing the (24S,25S)-isomer, and dehydrogenase activity of LBP was stereospecific for the (24S,25R)-isomer to give the above 24-oxo-derivative. The hydration and dehydrogenation reactions catalyzed by DBP were effectively conjugated to convert (24E)-5beta-cholestenoyl CoA to 24-oxo-5beta-cholestanoyl CoA. However, the reactions catalyzed by LBP were not conjugated. These results indicate that DBP plays an important role in the biosynthesis of bile acid. << Less
Steroids 66:107-114(2001) [PubMed] [EuropePMC]
This publication is cited by 2 other entries.
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The enzymes, regulation, and genetics of bile acid synthesis.
Russell D.W.
The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps ... >> More
The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps that accomplish this transformation also confer detergent properties to the bile acid, which are exploited by the body to facilitate the secretion of cholesterol from the liver. This role in the elimination of cholesterol is counterbalanced by the ability of bile acids to solubilize dietary cholesterol and essential nutrients and to promote their delivery to the liver. The synthesis of a full complement of bile acids requires 17 enzymes. The expression of selected enzymes in the pathway is tightly regulated by nuclear hormone receptors and other transcription factors, which ensure a constant supply of bile acids in an ever changing metabolic environment. Inherited mutations that impair bile acid synthesis cause a spectrum of human disease; this ranges from liver failure in early childhood to progressive neuropathy in adults. << Less
Annu. Rev. Biochem. 72:137-174(2003) [PubMed] [EuropePMC]
This publication is cited by 13 other entries.
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Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein X (SCPx). Activity measurements in liver and fibroblasts using a newly developed method.
Ferdinandusse S., Denis S., van Berkel E., Dacremont G., Wanders R.J.
Sterol carrier protein X (SCPx) plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids. To investigate whether patients with an unresolved defect in peroxisomal beta-oxidation are deficient for SCPx, we developed a novel and specific assay to measure the activity of SCPx i ... >> More
Sterol carrier protein X (SCPx) plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids. To investigate whether patients with an unresolved defect in peroxisomal beta-oxidation are deficient for SCPx, we developed a novel and specific assay to measure the activity of SCPx in both liver and fibroblast homogenates. The substrate used in the assay, 3alpha, 7alpha,12alpha-trihydroxy-24-keto-5beta-cholestanoy l-CoA (24-keto-THC-CoA), is produced by preincubating the enoyl-CoA of the bile acid intermediate THCA with a lysate from the yeast Saccharomyces cerevisiae expressing human D-bifunctional protein. After the preincubation period, liver or fibroblast homogenate is added plus CoASH, and the production of choloyl-CoA is determined by HPLC. The specificity of the assay was demonstrated by the finding of a full deficiency in fibroblasts from an SCPx knock-out mouse. In addition to SCPx activity measurements in fibroblasts from patients with a defect in peroxisomal beta-oxidation of unresolved etiology, we studied the stability and activity of SCPx in fibroblasts from patients with Zellweger syndrome, which lack functional peroxisomes. We found that SCPx is not only stable in the cytosol, but displays a higher activity in fibroblasts from patients with Zellweger syndrome than in control fibroblasts. Furthermore, in all patients studied with a defect in peroxisomal beta-oxidation of unknown origin, SCPx was found to be normally active, indicating that human SCPx deficiency remains to be identified. << Less
J. Lipid Res. 41:336-342(2000) [PubMed] [EuropePMC]
This publication is cited by 2 other entries.
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The reactions catalyzed by the inducible bifunctional enzyme of rat liver peroxisomes cannot lead to the formation of bile acids.
Xu R., Cuebas D.A.
The ability of the bifunctional 2-enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase from rat liver peroxisomes to metabolize (24E)-3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA, a presumed intermediate during the beta-oxidative degradation of the steroid side chain in the formati ... >> More
The ability of the bifunctional 2-enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase from rat liver peroxisomes to metabolize (24E)-3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA, a presumed intermediate during the beta-oxidative degradation of the steroid side chain in the formation of cholic acid, was investigated. The bifunctional enzyme efficiently hydrated the above compound specifically to (24S,25S)-3alpha, 7alpha, 12alpha, 24-tetrahydroxy-5beta-cholestanoyl-CoA, but the dehydrogenase component of the enzyme was virtually inactive toward this product. In contrast, the bifunctional enzyme efficiently catalyzed the dehydrogenation of the (24S,25R) diastereomer of the above hydroxy intermediate to two products whose uv absorbance and chemical properties were consistent with those of alpha-methyl-beta-ketoacyl-CoAs. These results suggest that the bifunctional enzyme is not sufficient for the formation of a 24-keto intermediate in bile acid biosynthesis. << Less
Biochem Biophys Res Commun 221:271-278(1996) [PubMed] [EuropePMC]