FIGURE 10.

Link between PMP34 and peroxisomal phytol degradation. Schematically shown are the different steps involved in phytol breakdown and their (presumed) subcellular sites. Cofactors involved in intraperoxisomal reactions are highlighted in blue; enzymatic steps are drawn with solid black arrows; transport processes are shown with dotted lines, black for known or accepted ones, ochre-brown for non-characterized or putative ones, orange for (hypothesized) PMP34 related ones. The areas depicting reactions related to α- and β-oxidation are tinted darker. Compounds (or their hydrolysis product) depicted in red accumulate in phytol treated PMP34 knockout mice. Likely, different phytol derivatives can enter peroxisomes (phytol, 2-phytenal, 2-phytenic acid, phytanic acid, 2-phytenoyl-CoA, phytanoyl-CoA, phytanic acid), the CoA-esters presumably via ABCD3, but whether or not hydrolysis occurs during this transport is not specified. Activation of phytanic acid by ACSVL1 requires intraperoxisomal ATP/CoA (and export of generated AMP, perhaps via PMP34), but phytanic acid could also be activated at the cytosolic side of the peroxisomal membrane by ACSL4/1. In the α-oxidation process, ATP stimulates PHYH but is not required for its activity. Before pristanic acid, produced by α-oxidation, can enter the β-oxidation spiral, it needs to be activated to its CoA-ester, a CoA/ATP-dependent step which could be carried out in the peroxisomal lumen by ACSVL1 (AMP export not depicted) or in the cytosol by ACSL4/1, followed by transport via ABCD3. Subsequently, pristanoyl-CoA is degraded by three β-oxidation cycles (individual reactions are not shown) whereby the produced 4,8-dimethylnonanoyl-CoA (4,8-DM-C9-CoA) is presumed to be exported either as carnitine ester or acid, both reactions producing CoA. Similarly, the other β-oxidation products acetyl- and propionyl-CoA can be converted to carnitine esters (by CRAT) or hydrolyzed (by ACOT8/12) and result in CoA formation (not shown). CoA is not formed when 4,8-dimethylnonanoyl-CoA is cleaved by nudix hydrolases (NUDT), instead adenosine-3′,5′-diphosphate (PAP) and 4,8-dimethylnonanoyl-phosphopantetheine (4,8-DM-C9-PP) are generated. These NUDT enzymes can also act on CoA, producing phosphopantetheine (PP) and PAP. These products (MW 358, respectively 423 Da), being negatively charged, might not leak out via PMP22, but could rely on PMP34. Given the presence of shortened branched acyl-CoAs, activation of phytanic/pristanic acid is not a major issue if PMP34 is absent. Inadequate import of CoA (orange arrow), required for the SCPx reactions of the β-oxidation spiral, can explain the build-up of the upstream intermediates. Inability to export CoA, formed by the above mentioned ACOT/CROT/CRAT reactions, could reverse these reactions and slow down β-oxidation. If the CROT/ACOT8 reactions are to sluggish to handle an exces of 4,8-dimethyl-C9-CoA, PMP34-mediated export of this CoA-ester would offer another explanation for the observed metabolic phenotype. Inability to remove PAP could impact phytol degradation as well, if this compound is inhibitory to some oxidation enzymes. DM-, dimethyl-; TM-, trimethyl-; ER, endoplasmic reticulum.