Peroxisomal fatty acid α- and β-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases

Abstract

Peroxisomes are subcellular organelles with an indispensable role in cellular metabolism. The importance of peroxisomes for humans is stressed by the existence of a group of genetic diseases in humans in which there is an impairment in one or more peroxisomal functions. Most of these functions have to do with lipid metabolism including the alpha- and beta-oxidation of fatty acids. Here we describe the current state of knowledge about peroxisomal fatty acid alpha- and beta-oxidation with particular emphasis on the following: (1) the substrates beta-oxidized in peroxisomes; (2) the enzymology of the alpha- and beta-oxidation systems; (3) the permeability properties of the peroxisomal membrane and the role of the different transporters therein; (4) the interaction with other subcellular compartments, including the mitochondria, which are the ultimate site of NADH re-oxidation and full degradation of acetyl-CoA to CO(2) and water; and (5) the different disorders of peroxisomal alpha- and beta-oxidation.

Investigation of the ligand spectrum of human sterol carrier protein 2 using a direct mass spectrometry assay

“…These assays demonstrated tight binding of a set of LCFA-CoAs, concurring with published data [14][15][16][17]. However, a set of LCFA-carnitines-a pool of which are present in the peroxisomal matrix [21,22]-were found not to bind to any SCP2 variant.…”

“…The physiological relevance of the lack of LCFA-carnitine binding capacity of SCP2 may relate to the dual role of the peroxisome and the mitochondrion in fatty acid b-oxidation. Peroxisomes take up LCFA-CoAs for several rounds of b-oxidation to produce chain shortened carnitine derivatives, which are used both as export substrates from the peroxisome to the cytoplasm and import substrates to the mitochondrion from the cytoplasm (reviewed in [22]). Thus a role for SCP2 can be envisaged in which it assists in retaining the pool of intraperoxisomal LCFA-CoAs for chain shortening but does not inhibit export of a b Fig.…”

Identification of a Substrate-binding Site in a Peroxisomal β-Oxidation Enzyme by Photoaffinity Labeling with a Novel Palmitoyl Derivative

“…Analyses of these peroxisomal diseases reflect the importance of the peroxisomal ␤-oxidation in organisms along with disclosing the enzymatic organization of the peroxisomal ␤-oxidation system. Peroxisomes are involved in the ␤-oxidation of VLCFAs, branched chain fatty acids such as pristanic acid, and bile acid intermediates such as dihydroxycholestanoic acid and trihydroxycholestanoic acid, which are incompatible with mitochondrial ␤-oxidation (6). Peroxisomal ␤-oxidation of fatty acids proceeds via a four-step pathway as in mitochondria, and multiple enzymes are involved in each step of the pathway.…”

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

“…pristanic acid that is generated after ␣-oxidation of the 3-methyl-branched fatty acid phytanic acid), prostanoids, dicarboxylic acids, and the C 27 bile acid intermediates di-and trihydroxycoprostanoic acids (1,2,4). The importance of peroxisomes and peroxisomal fatty acid ␤-oxidation for human health is underscored by the existence of peroxisomal biogenesis disorders such as Zellweger syndrome and other genetic diseases affecting peroxisomal ␤-oxidation (1,2) and by the ability of many structurally diverse chemicals designated as peroxisome proliferators to induce peroxisome proliferation and increase fatty acid oxidation in liver cells, leading to the development of liver tumors in rodents (5)(6)(7).…”