The role of α-methylacyl-CoA racemase in bile acid synthesis

2002 ◽  
Vol 363 (3) ◽  
pp. 801-807 ◽  
Author(s):  
Dean A. CUEBAS ◽  
Christopher PHILLIPS ◽  
Werner SCHMITZ ◽  
Ernst CONZELMANN ◽  
Dmitry K. NOVIKOV
Keyword(s):  
Fatty Acids ◽  
Bile Acid ◽  
Alternative Pathway ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Side Chain ◽  
Multifunctional Enzyme ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Dehydrogenation Reactions ◽  
Enoyl Coa Hydratase

According to current views, the second peroxisomal β-oxidation pathway is responsible for the degradation of the side chain of bile acid intermediates. Peroxisomal multifunctional enzyme type 2 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(R)-3-hydroxyacyl-CoA dehydrogenase; MFE-2] catalyses the second (hydration) and third (dehydrogenation) reactions of the pathway. Deficiency of MFE-2 leads to accumulation of very-long-chain fatty acids, 2-methyl-branched fatty acids and C27 bile acid intermediates in plasma, but bile acid synthesis is not blocked completely. In this study we describe an alternative pathway, which allows MFE-2 deficiency to be overcome. The alternative pathway consists of α-methylacyl-CoA racemase and peroxisomal multifunctional enzyme type 1 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(S)-3-hydroxyacyl-CoA dehydrogenase; MFE-1]. (24E)-3α,7α,12α-Trihydroxy-5β-cholest-24-enoyl-CoA, the presumed physiological isomer, is hydrated by MFE-1 with the formation of (24S,25S)-3α,7α,12α,24-tetrahydroxy-5β-cholestanoyl-CoA [(24S,25S)-24-OH-THCA-CoA], which after conversion by a α-methylacyl-CoA racemase into the (24S,25R) isomer can again be dehydrogenated by MFE-1 to 24-keto-3α,7α,12α-trihydroxycholestanoyl-CoA, a physiological intermediate in cholic acid synthesis. The discovery of the alternative pathway of cholesterol side-chain oxidation will improve diagnosis of peroxisomal deficiencies by identification of serum 24-OH-THCA-CoA diastereomer profiles.

scholarly journals Evidence that multifunctional protein 2, and not multifunctional protein 1, is involved in the peroxisomal β-oxidation of pristanic acid

1997 ◽  
Vol 325 (2) ◽  
pp. 367-373 ◽  
Author(s):  
Martine DIEUAIDE-NOUBHANI ◽  
Stanny ASSELBERGHS ◽  
Guy P. MANNAERTS ◽  
Paul P. VAN VELDHOVEN
Keyword(s):  
Fatty Acids ◽  
Bile Acid ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Side Chain ◽  
Acid Oxidation ◽  
Synthetic Analogue ◽  
Pristanic Acid ◽  
Multifunctional Protein ◽  
Hydroxyacyl Coa Dehydrogenase

The second (enoyl-CoA hydratase) and third (3-hydroxyacyl-CoA dehydrogenase) steps of peroxisomal β-oxidation are catalysed by two separate multifunctional proteins (MFPs), MFP-1 being involved in the degradation of straight-chain fatty acids and MFP-2 in the β-oxidation of the side chain of cholesterol (bile acid synthesis). In the present study we determined which of the two MFPs is involved in the peroxisomal degradation of pristanic acid by using the synthetic analogue 2-methylpalmitic acid. The four stereoisomers of 3-hydroxy-2-methylpalmitoyl-CoA were separated by gas chromatography after hydrolysis, methylation and derivatization of the hydroxy group with (S)-2-phenylpropionic acid, and the stereoisomers were designated I–IV according to their order of elution from the column. Purified MFP-1 dehydrated stereoisomer IV but dehydrogenated stereoisomer III, so by itself MFP-1 is not capable of converting a branched enoyl-CoA into a 3-ketoacyl-CoA. In contrast, MFP-2 dehydrated and dehydrogenated the same stereoisomer (II), so it is highly probable that MFP-2 is involved in the peroxisomal degradation of branched fatty acids and that stereoisomer II is the physiological intermediate in branched fatty acid oxidation. By analogy with the results obtained with the four stereoisomers of the bile acid intermediate varanoyl-CoA, stereoisomer II can be assigned the 3R-hydroxy, 2R-methyl configuration.

scholarly journals Recombinant 2-enoyl-CoA hydratase derived from rat peroxisomal multifunctional enzyme 2: role of the hydratase reaction in bile acid synthesis

1997 ◽  
Vol 328 (2) ◽  
pp. 377-382 ◽  
Author(s):  
Yong-Mei QIN ◽  
M. Antti HAAPALAINEN ◽  
Demara CONRY ◽  
A. Dean CUEBAS ◽  
J. Kalervo HILTUNEN ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Hydration Reaction ◽  
Multifunctional Enzymes ◽  
Hydratase Activity ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Liver Peroxisomes ◽  
Enoyl Coa Hydratase

Rat liver peroxisomes contain two multifunctional enzymes: (1) perMFE-1 [2-enoyl-CoA hydratase 1/Δ3,Δ2-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 β-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)-3α,7α,12α-trihydroxy- 5β-cholest-24-enoyl-CoA to (24R,25R)-3α,7α,12α,24-tetrahydroxy-5β-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.

scholarly journals Identification and characterization of the 2-enoyl-CoA hydratases involved in peroxisomal β-oxidation in rat liver

1997 ◽  
Vol 321 (1) ◽  
pp. 253-259 ◽  
Author(s):  
Martine DIEUAIDE-NOUBHANI ◽  
Dmitry NOVIKOV ◽  
Joël VANDEKERCKHOVE ◽  
Paul P. Van VELDHOVEN ◽  
Guy P. MANNAERTS
Keyword(s):  
Rat Liver ◽  
Hydroxysteroid Dehydrogenase ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Side Chain ◽  
Multifunctional Protein ◽  
Hydratase Activity ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Enoyl Coa Hydratase

In this study we attempted to determine the number of 2-enoyl-CoA hydratases involved in peroxisomal β-oxidation. We therefore separated peroxisomal proteins from rat liver on several chromatographic columns and measured hydratase activities on the eluates with different substrates. The results indicate that rat liver peroxisomes contain two hydratase activities: (1) a hydratase activity associated with multifunctional protein 1 (MFP-1) (2-enoyl-CoA hydratase/Δ3,Δ2-enoyl-CoA isomerase/l-3-hydroxyacyl-CoA dehydrogenase) and (2) a hydratase activity associated with MFP-2 (17β-hydroxysteroid dehydrogenase/d-3-hydroxyacyl-CoA dehydrogenase/2-enoyl-CoA hydratase). MFP-1 forms and dehydrogenates l-3-hydroxyacyl-CoA species, whereas MFP-2 forms and dehydrogenates d-3-hydroxyacyl-CoA species. A portion of MFP-2 is proteolytically cleaved, most probably in the peroxisome, into a 34 kDa 17β-hydroxysteroid dehydrogenase/d-3-hydroxyacyl-CoA dehydrogenase and a 45 kDa d-specific 2-enoyl-CoA hydratase. Finally, the results confirm that MFP-1 is involved in the degradation of straight-chain fatty acids, whereas MFP-2 and its cleavage products seem to be involved in the degradation of the side chain of cholesterol (bile acid synthesis)

scholarly journals Transport of Cholesterol into Mitochondria Is Rate-limiting for Bile Acid Synthesis via the Alternative Pathway in Primary Rat Hepatocytes

2002 ◽  
Vol 277 (50) ◽  
pp. 48158-48164 ◽  
Author(s):  
William M. Pandak ◽  
Shunlin Ren ◽  
Dalila Marques ◽  
Elizabeth Hall ◽  
Kaye Redford ◽  
...  
Keyword(s):  
Bile Acid ◽  
Alternative Pathway ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Primary Rat Hepatocytes ◽  
Rate Limiting

Role of AMACR (α-methylacyl-CoA racemase) and MFE-1 (peroxisomal multifunctional enzyme-1) in bile acid synthesis in mice

2014 ◽  
Vol 461 (1) ◽  
pp. 125-135 ◽  
Author(s):  
Kaija J. Autio ◽  
Werner Schmitz ◽  
Remya R. Nair ◽  
Eija M. Selkälä ◽  
Raija T. Sormunen ◽  
...  
Keyword(s):  
Bile Acid ◽  
Mouse Models ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Wild Type ◽  
Multifunctional Enzyme

Bile acid analysis of wild-type, Mfe-1−/−, Amacr−/− and Amacr−/−Mfe-1−/− mouse models shows that peroxisomal multifunctional enzyme 1 can participate in bile acid synthesis in both AMACR-dependent and AMACR-independent pathways.

scholarly journals Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increased Cyp7a1 expression levels

2009 ◽  
Vol 297 (1) ◽  
pp. G144-G151 ◽  
Author(s):  
Katie T. Burke ◽  
Paul S. Horn ◽  
Patrick Tso ◽  
James E. Heubi ◽  
Laura A. Woollett
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Alternative Pathway ◽  
Newborn Infants ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Metabolism ◽  
Mrna Levels ◽  
Bile Acid Pool ◽  
Acid Pool

Intraluminal concentrations of bile acids are low in newborn infants and increase rapidly after birth, at least partly owing to increased bile acid synthesis rates. The expansion of the bile acid pool is critical since bile acids are required to stimulate bile flow and absorb lipids, a major component of newborn diets. The purpose of the present studies was to determine the mechanism responsible for the increase in bile acid synthesis rates and the subsequent enlargement of bile acid pool sizes (BAPS) during the neonatal period, and how changes in circulating hormone levels might affect BAPS. In the hamster, pool size was low just after birth and increased modestly until 10.5 days postpartum (dpp). BAPS increased more significantly (∼3-fold) between 10.5 and 15.5 dpp. An increase in mRNA and protein levels of cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting step in classical bile acid synthesis, immediately preceded an increase in BAPS. In contrast, levels of oxysterol 7α-hydroxylase (Cyp7b1), a key enzyme in bile acid synthesis by the alternative pathway, were relatively elevated by 1.5 dpp. farnesyl X receptor (FXR) and short heterodimeric partner (SHP) mRNA levels remained relatively constant at a time when Cyp7a1 levels increased. Finally, although simultaneous increases in circulating cortisol and Cyp7a1 levels occurred, precocious expression of Cyp7a1 could not be induced in neonatal hamsters with dexamethasone. Thus the significant increase in Cyp7a1 levels in neonatal hamsters is due to mechanisms independent of the FXR and SHP pathway and cortisol.

scholarly journals Differences in the Regulation of the Classical and the Alternative Pathway for Bile Acid Synthesis in Human Liver

2002 ◽  
Vol 277 (30) ◽  
pp. 26804-26807 ◽  
Author(s):  
Ingemar Björkhem ◽  
Zufan Araya ◽  
Mats Rudling ◽  
Bo Angelin ◽  
Curt Einarsson ◽  
...  
Keyword(s):  
Bile Acid ◽  
Human Liver ◽  
Alternative Pathway ◽  
Acid Synthesis ◽  
Bile Acid Synthesis

Tissue-specific Mechanisms of Bile Acid Homeostasis and Activation of FXR-FGF19 Signaling in Preterm and Term Neonatal Pigs

2021 ◽  
Author(s):  
Caitlin Vonderohe ◽  
Gregory Guthrie ◽  
Barbara Stoll ◽  
Shaji Chacko ◽  
Harry Dawson ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gestational Age ◽  
Molecular Mechanisms ◽  
Alternative Pathway ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Tissue Specific ◽  
Neonatal Pigs ◽  
Bile Acid Pool Size ◽  
Ileal Tissue

Background & Aims: The tissue specific molecular mechanisms involved in perinatal liver and intestinal FXR-FGF19 signaling are poorly defined. Our aim was to establish how gestational age and feeding status affect bile acid synthesis pathway, bile acid pool size, ileal response to bile acid stimulation, genes involved in bile acid-FXR-FGF19 signaling and plasma FGF19 in neonatal pigs. Methods Term (n=23) and preterm (n=33) pigs were born via cesarean section at 100% and 90% gestation, respectively. Plasma FGF19, hepatic bile acid and oxysterol profiles, and FXR target gene expression was assessed in pigs at birth and after a bolus feed on day 3 of life. Pig ileal tissue explants were used to measure signaling response to bile acids. Results Preterm pigs had smaller, more hydrophobic bile acid pools, lower plasma FGF19, and blunted FXR-mediated ileal response to bile acid stimulation than term pigs. GATA-4 expression was higher in jejunum than ileum, and was higher in preterm than term pig ileum. Hepatic oxysterol analysis suggested dominance of the alternative pathway of bile acid synthesis in neonates, regardless of gestational age and persists in preterm pigs after feeding on day 3. Conclusion These results highlight the tissue-specific molecular basis for the immature enterohepatic bile acid signaling via FXR-FGF19 in preterm pigs and may have implications for disturbances of bile acid homeostasis and metabolism in preterm infants.

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