The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+

Abstract

The essential cofactors CoA, FAD and NAD+ are synthesized outside the peroxisomes and therefore must be transported into the peroxisomal matrix where they are required for important processes. In the present study we have functionally identified and characterized SLC25A17 (solute carrier family 25 member 17), which is the only member of the mitochondrial carrier family that has previously been shown to be localized in the peroxisomal membrane. Recombinant and purified SLC25A17 was reconstituted into liposomes. Its transport properties and kinetic parameters demonstrate that SLC25A17 is a transporter of CoA, FAD, FMN and AMP, and to a lesser extent of NAD+, PAP (adenosine 3',5'-diphosphate) and ADP. SLC25A17 functioned almost exclusively by a counter-exchange mechanism, was saturable and was inhibited by pyridoxal 5'-phosphate and other mitochondrial carrier inhibitors. It was expressed to various degrees in all of the human tissues examined. Its main function is probably to transport free CoA, FAD and NAD+ into peroxisomes in exchange for intraperoxisomally generated PAP, FMN and AMP. The present paper is the first report describing the identification and characterization of a transporter for multiple free cofactors in peroxisomes.

Peroxisomes in cardiomyocytes and the peroxisome / peroxisome proliferator-activated receptor-loop

“…The elevation in Pex11β expression, as well as the substantial increase in number, size and the structural alteration of peroxisomes in heart tissue of Pex11α -/-mice, suggest a compensation of peroxisome growth and fission by PEX11β in the absence of PEX11α. In line with peroxisomal proliferation and elevated protein abundance of ABCD3 and PEX14p, ACOX1-3, the enzymes catalysing the first step of peroxisomal β-oxidation (▶ Figure 1) and PMP34, a putative peroxisomal Coenzyme A carrier (89), are upregulated in the heart of the Pex11α -/-mouse (▶ Figure 4 P and Q).…”

The peroxisome: an update on mysteries

“…Recently, however, two membrane transporters for CoA and FAD, PXN for NAD ? in plants (Bernhardt et al 2012) and the previously mentioned PMP34/SLC25A17 in animals (Agrimi et al 2011), have been described, which may provide peroxisomes with the corresponding cofactors, especially under proliferative conditions. Taken together, in the last few years, much light has been shed on the bimodal transport system combining unselective channels for small metabolites with specific transporters for bulky ones, thus forming the basis for the unique permeability properties of peroxisomes.…”

Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform

“…3), thus suggesting a specific role for Nudt19 in peroxisomal metabolism. In the peroxisomes, free CoA and acyl-CoAs are imported through dedicated transporters (45,46) and participate in several processes including the α-and β-oxidation of fatty acids that are not substrates for the mitochondrial oxidative machinery, the synthesis of ether phospholipids and, in the liver, the final steps in bile acid synthesis and conjugation. Additionally, since imported CoA species and other molecules >400 Da cannot freely exit the peroxisomes, the Nudix-mediated hydrolysis of CoA species to 3',5'-ADP and 4'-(acyl)phosphopantetheine likely prevents CoA buildup in this organelle (32,33).…”