Sterol Carrier Protein X (SCPx) Is a Peroxisomal Branched-Chain β-Ketothiolase Specifically Reacting with 3-Oxo-pristanoyl-CoA: A New, Unique Role for SCPx in Branched-Chain Fatty Acid Metabolism in Peroxisomes

Abstract

cholesterol in microsomes and also the acyltransferase One of the most important functions of peroxisomes, mediated esterification of intracellular cholesterol [1]. at least in humans, is the b-oxidation of a range of Moreover, in steroid hormone producing cells SCP2 is different fatty acids and fatty acid derivatives. Recent thought to facilitate the transport of cholesterol to mistudies have shown that the enzymatic machinery re-tochondria, where the first committed step in the forquired for the b-oxidations of these substrates, may mation of pregnenolone takes place [2][3][4][5].be much more complex as originally thought. We now SCP2 has been purified from a variety of sources report that the conventional peroxisomal thiolase and its structure appears to be highly conserved Firstly, the antibody raised not only for the functional organization of the peroxi-against SCP2 was found to crossreact with a higher somal b-oxidation system but also for studies dealing molecular mass protein of 58 kDa [6,7,[14][15][16]. In adwith the resolution of the underlying defect in patients dition, the livers of all mammalian species studied with some defect in peroxisomal b-oxidation. ᭧ 1997 contain SCP2-related transcripts encoding for larger Academic Pressproteins that were found to be identical to pre-SCP2 at their C-terminal domains [8-13; 18-21]. It is now clear that the 58 kDa protein called SCPx [1] and the 14.5 kDa pre-SCP2 are the products of different Sterol carrier protein 2 (SCP2), alternatively called mRNAs produced from the same gene which has two non-specific lipid transfer protein (nsLTP) is a small promoters [22]. Interestingly, significant sequence basic protein assumed to participate in the intracellu-homology was found between the first 400 amino acid lar transport of sterols and other lipids [1]. Indeed, residues of SCPx and both mitochondrial and peroxi-SCP2 has been found to promote the exchange of vari-somal 3-oxoacyl-CoA thiolase [11,18,23]. Direct activous lipids and sterols between membranes, stimulates ity measurements showed that SCPx, indeed, posthe enzymatic conversion of 7-dehydrocholesterol to sesses 3-oxoacyl-CoA thiolase activity next to its intrinsic sterol carrier protein and lipid transfer activity [24]. The substrate specificity of SCPx, how-

Genetic and chemical characterization of ibuprofen degradation by Sphingomonas Ibu-2

“…2) we hypothesize that IpfD and E are responsible for the acid side chain removal based on the role that related proteins play in acyl group transfer (Fig. 4) (Bangera & Thomashow, 1999;Kube et al, 2004;Kühner et al, 2005;Leuthner & Heider, 2000;Verhoeven & Jakobs, 2001;Wanders et al, 1997;Westin et al, 2007).…”

“…Detailed molecular analyses of mammalian SCPx family members have demonstrated their involvement in two specific metabolic reactions in eukaryotes, namely bile-acid synthesis (Takeuchi et al, 2004) and the b-oxidation of pristanoyl-CoA, a branchedchain fatty acid (Fig. 5) (Verhoeven & Jakobs, 2001;Wanders et al, 1997;Westin et al, 2007). In both cases, SCPx is specifically involved in the b-oxidation of an amethyl b-keto fatty acid.…”

Sexually dimorphic metabolism of branched-chain lipids in C57BL/6J mice

“…Studies with the SCP-x protein indicate that along with its inherent ability to transport lipids such as cholesterol (16), this protein has unique roles in the peroxisomal ␤ -oxidation of branched-chain fatty acids and in bile acid formation from cholesterol (17)(18)(19)(20). Although in vitro experiments show that SCP-x has the same substrate specificity for straight-chain fatty acids as that of the conventional peroxisomal thiolases, SCP-x also has a unique ability to catalyze the thiolytic cleavage of 3-oxoacyl-CoA esters of branched-chain molecules with methyl groups at the 2-position, such as pristanic acid (17,19,21) and cholestanoic acid (22).…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…With respect to their physiological role, it is now clear that the D-specific enzyme as encoded by HSD17B4 catalyzes the hydration and subsequent dehydrogenation of most peroxisomal beta-oxidation substrates including the enoyl-CoA esters of VLCFAs, pristanic acid and DHCA and THCA, whereas the L-specific enzyme appears to handle the dicarboxylic enoylCoA esters specifically (see Figure 4; Houten et al, 2012). Finally, with respect to the two thiolases, work on the isolated enzymes (Antonenkov et al, 1997;Wanders et al, 1997) as well as Sterol Carrier Protein X (SCPx)-deficient patients (Ferdinandusse et al, 2006) and mutant mice (Seedorf et al, 1998;Kannenberg et al, 1999) has shown that both peroxisomal 3-ketoacyl-CoA-thiolase 1 (ACAA1; pTH1) and SCPx (pTH2) encoded by ACAA1 and SCP2, respectively, are involved in the oxidation of VLCFAs, whereas the 3-ketoacyl-CoA esters of pristanic acid, DHCA and THCA are solely cleaved by SCPx. The redundancy of the two thiolases with respect the oxidation of VLCFAs may explain why peroxisomal 3-ketoacyl-CoA-thiolase1 (ACAA1)-deficiency has not been identified sofar.…”