Inactivation of the Peroxisomal Multifunctional Protein-2 in Mice Impedes the Degradation of Not Only 2-Methyl-branched Fatty Acids and Bile Acid Intermediates but Also of Very Long Chain Fatty Acids

Abstract

According to current views, peroxisomal ␤-oxidation is organized as two parallel pathways: the classical pathway that is responsible for the degradation of straight chain fatty acids and a more recently identified pathway that degrades branched chain fatty acids and bile acid intermediates. Multifunctional protein-2 (MFP-2), also called D-bifunctional protein, catalyzes the second (hydration) and third (dehydrogenation) reactions of the latter pathway. In order to further clarify the physiological role of this enzyme in the degradation of fatty carboxylates, MFP-2 knockout mice were generated. MFP-2 deficiency caused a severe growth retardation during the first weeks of life, resulting in the premature death of one-third of the MFP-2 ؊/؊ mice. Furthermore, MFP-2-deficient mice accumulated VLCFA in brain and liver phospholipids, immature C 27 bile acids in bile, and, after supplementation with phytol, pristanic and phytanic acid in liver triacylglycerols. These changes correlated with a severe impairment of peroxisomal ␤-oxidation of very long straight chain fatty acids (C 24 ), 2-methyl-branched chain fatty acids, and the bile acid intermediate trihydroxycoprostanic acid in fibroblast cultures or liver homogenates derived from the MFP-2 knockout mice. In contrast, peroxisomal ␤-oxidation of long straight chain fatty acids (C 16 ) was enhanced in liver tissue from MFP-2 ؊/؊ mice, due to the up-regulation of the enzymes of the classical peroxisomal ␤-oxidation pathway. The present data indicate that MFP-2 is not only essential for the degradation of 2-methyl-branched fatty acids and the bile acid intermediates di-and trihydroxycoprostanic acid but also for the breakdown of very long chain fatty acids.

Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

“…12 17HSD type 4 is identical to MFP-2, whose main role is associated with the peroxisomal ␤-oxidation of fatty acids. 30,31 It is therefore more likely that the decrease in oxidative activity converting E2 to E1 in the colon is the result of decreased 17HSD type 2 expression.…”

Overexpression of Peroxisome Proliferator-activated Receptor-α (PPARα)-regulated Genes in Liver in the Absence of Peroxisome Proliferation in Mice Deficient in both l- and d-Forms of Enoyl-CoA Hydratase/Dehydrogenase Enzymes of Peroxisomal β-Oxidation System

“…ϩ/Ϫ mice also generated D-PBE Ϫ/Ϫ mice at the expected ratio of ϳ25%, and these single nulls were indistinguishable at birth from their heterozygous and wild-type littermates (16,18). No detectable phenotype was noted in L-PBE Ϫ/Ϫ mice, which were viable and fertile (16), whereas, 30% of the D-PBE Ϫ/Ϫ mice died before postnatal day 12, and most of the remaining mice survived to adulthood (18).…”

Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 Å resolution 1 1Edited by R. Huber

“…The tunnel, with a diameter of 9 A Ê and a length of 18 A Ê , is large enough to accommodate ligands of the size of various fatty acids or their CoA derivatives such as 30 Crystal Structure of the SCP-2-like Domain of MFE-2 bile acid intermediates and straight-chain and branched-chain fatty acyl groups, all of which are known to be ligands of MFE-2. 10 The entrance of the tunnel is formed by the amino acid residues Gln90, Phe93, Leu98, Ala100, Ile104, Met105 and Gln108 in the helices D and E and b-strand V (Figures 2 and 6(b)). Parts of the side of the tunnel between the helices D and E are composed of the polar amino acids Gln90, Gln108, Gln111 and Lys115, where the oxygen and nitrogen atoms of the side-chains form a hydrogen bonding network.…”

“…4 ± 8 Analysis of accumulating metabolites in patients with MFE-2 de®ciency and`k nock-out'' mice, together with enzymatic properties observed in vitro, suggest that the physiological role of mammalian MFE-2 is the peroxisomal b-oxidation of very-long-chain fatty acids and 2-methyl-branched-chain fatty acids as well as di-and trihydroxycholestanoic acids. 9,10 (3R)-hydroxyacyl-CoA dehydrogenase, which catalyzes the third reaction of the b-oxidation pathway, is located to the N terminus of MFE-2, followed by the trans-2-enoyl-CoA hydratase 2 domain, responsible for the second reaction. Both domains were ®rst identi®ed experimentally in yeast MFE-2.…”