The Saccharomyces cerevisiae ABC subfamily D transporter Pxa1/Pxa2p co‐imports CoASH into the peroxisome

Abstract

ATP‐binding cassette (ABC) subfamily D transporters are important for the uptake of fatty acids and other beta‐oxidation substrates into peroxisomes. Genetic and biochemical evidence indicates that the transporters accept fatty acyl‐coenzyme A that is cleaved during the transport cycle and then re‐esterified in the peroxisomal lumen. However, it is not known whether free coenzyme A (CoA) is released inside or outside the peroxisome. Here we have used Saccharomyces cerevisiae and isolated peroxisomes to demonstrate that free CoA is released in the peroxisomal lumen. Thus, ABC subfamily D transporter provide an import pathway for free CoA that controls peroxisomal CoA homeostasis and tunes metabolism according to the cell’s demands.

Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis

“…Our results also provide evidence for a partially overlapping function of ACAA1 and SCPx in DCA β-oxidation, with ACAA1 being more important in the β-oxidation of medium-chain DCAs. We speculate that additional players involved in DCA β-oxidation are a dicarboxylyl-CoA synthetase needed for the activation of DCAs into DCA-CoAs (ACSL1, acyl-CoA synthetase long chain family member 1) and subsequent uptake by peroxisomes as well as CROT (peroxisomal carnitine O-octanoyltransferase) and ACOT4 (Houten et al 2012, 2020; Hunt et al 2006; Vamecq et al 1985; van Roermund et al 2020; Westin et al 2005). The role of these enzymes in DCA metabolism should be addressed in future studies.…”

Peroxisomal ABC Transporters: An Update

“…After expressing human His-tagged ABCD1 in methylotrophic yeast, they directly demonstrated that ABCD1 transports the FA moiety after the hydrolysis of VLCFA-CoA and that acyl-CoA synthetase is required before the β-oxidation of VLCFA-CoA within the peroxisomes. When it comes to the fate of the free CoA, they are released in the peroxisomal lumen, as revealed using isolated peroxisomes from Saccharomyces cerevisiae [ 75 ].…”

“…The yeast model expresses only two peroxisomal ABC transporters, called Pxa1p and Pxa2p, which function as a strict heterodimer to import fatty acyl-CoAs into the peroxisomal matrix [ 107 , 108 , 109 ]. Functional assays and functional complementation experiments of pxa1/pxa2Δ yeast mutants with mammalian peroxisomal ABC transporters were particularly important in studying their transport mechanism and substrate specificity [ 26 , 65 , 75 ].…”

Peroxisomal ATP uptake is managed by the ABC transporters and two adenine nucleotide transporters

“…As reported previously and confirmed in our proteoliposome uptake studies, Ant1p most probably functions as an ATP/AMP antiporter 27,28 . Surprisingly, we found that the remaining peroxisomal ATP uptake capacity is mediated by the ABC transporter protein complex Pxa1p/Pxa2p, which most probably functions as an ATP uniporter, and Aac2p, a predominantly mitochondrial ATP/ADP antiporter 33,38,39,40 , which we here showed to be partly localized in peroxisomes. Our finding that heterodimeric Pxa1p/Pxa2p, as well as the human orthologues HsABCD1, HsABCD2 and HsABCD3 as homodimers, can also mediate peroxisomal uptake of nonhydrolyzed ATP in addition to fatty acyl-CoAs was unexpected and is very intriguing.…”