Affinage

SLC25A17

Peroxisomal membrane protein PMP34 · UniProt O43808

Length
307 aa
Mass
34.6 kDa
Annotated
2026-04-28
11 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC25A17 (PMP34) is a peroxisomal integral membrane transporter that sustains peroxisomal metabolism by importing CoA, FAD, and NAD+ into the peroxisomal matrix in counter-exchange for intraperoxisomally generated PAP, FMN, and AMP (PMID:22185573). Peroxisomal targeting depends on basic residues within the loop between transmembrane segments 4 and 5 flanked by hydrophobic domains, and both termini face the cytosol (PMID:11121399). Loss of SLC25A17 specifically impairs branched-chain fatty acid (phytanic/pristanic acid) oxidation through limiting peroxisomal CoA availability and shifts the peroxisomal glutathione redox couple toward a more reductive state (PMID:32266253, PMID:38159891). SLC25A17 protein stability is regulated by interaction with PEX3 and by MARCH1-mediated ubiquitination and proteasomal degradation (PMID:40885408, PMID:41758657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 Medium

    Establishing that PMP34 is a peroxisomal membrane protein in the mitochondrial carrier family resolved its subcellular localization and placed it as a candidate peroxisomal solute transporter.

    Evidence GFP-fusion transfection in HepG2 and fibroblasts with co-localization to peroxisomal thiolase; mislocalization in PEX5-KO fibroblasts

    PMID:9874197

    Open questions at the time
    • Transport substrate unknown
    • Endogenous protein expression pattern not characterized
    • Single-lab study without independent confirmation
  2. 2000 High

    Determining PMP34's transmembrane topology (both termini cytosolic) and identifying the basic loop between TM4–TM5 as the peroxisomal targeting signal established how the protein is directed to peroxisomes.

    Evidence Differential permeabilization, epitope-tagged deletion/substitution mutants in CHO-K1 cells

    PMID:11121399

    Open questions at the time
    • Targeting receptor not identified
    • Whether the same signal operates in all cell types untested
  3. 2002 High

    Reconstitution of purified PMP34 in proteoliposomes demonstrated direct adenine nucleotide transport, and complementation of yeast ANT1 mutants confirmed functional equivalence, establishing PMP34 as a peroxisomal adenine nucleotide transporter.

    Evidence Proteoliposome transport assays with purified protein; genetic complementation in S. cerevisiae ant1Δ

    PMID:12445829

    Open questions at the time
    • Full substrate specificity and kinetic parameters not yet determined
    • In vivo substrates in mammalian cells unresolved
  4. 2012 High

    Comprehensive kinetic characterization revealed that SLC25A17 operates as a counter-exchange transporter importing CoA, FAD, and NAD+ while exporting PAP, FMN, and AMP, defining its physiological role in peroxisomal cofactor supply.

    Evidence Recombinant protein reconstituted into liposomes with saturation kinetics, inhibitor profiling (pyridoxal 5'-phosphate), and substrate competition assays

    PMID:22185573

    Open questions at the time
    • Relative contribution of each substrate pair in vivo unknown
    • Structural basis for substrate selectivity not resolved
  5. 2019 Medium

    In vivo rescue of slc25a17-knockdown zebrafish by CoA but not NAD+ injection identified CoA import as the primary physiological function, narrowing the substrate hierarchy observed in vitro.

    Evidence Morpholino knockdown in zebrafish with metabolite-specific rescue of swim bladder phenotype

    PMID:31187491

    Open questions at the time
    • Morpholino off-target effects not fully excluded
    • Whether FAD transport contributes to other tissue-specific phenotypes untested
    • Single-lab study
  6. 2020 High

    PMP34-deficient mice showed selective impairment of branched-chain fatty acid (phytanic/pristanic acid) oxidation while other peroxisomal pathways were intact, demonstrating pathway-specific dependence on SLC25A17-mediated CoA import.

    Evidence Gene-trap KO mice with dietary phytol challenge, acyl-CoA and bile acid profiling, fibroblast β-oxidation assays

    PMID:32266253

    Open questions at the time
    • Whether compensatory transporters exist for other peroxisomal pathways not identified
    • Neurological phenotypes not assessed
  7. 2023 High

    Demonstrating that SLC25A17 loss shifts the peroxisomal glutathione redox state toward reduction — rescuable by yeast orthologue Pmp47 — established SLC25A17 as a maintainer of peroxisomal redox homeostasis beyond fatty acid oxidation.

    Evidence CRISPR KO in HEK-293, HeLa, and MEFs with genetically encoded redox biosensors; rescue with C. boidinii Pmp47

    PMID:38159891

    Open questions at the time
    • Which transported cofactor (NAD+, FAD, or CoA) mediates the redox effect not dissected
    • In vivo redox consequences in animal models not assessed
  8. 2025 Medium

    Identification of PEX3 as a stabilizer of SLC25A17 protein and USF2 as a transcriptional driver of PEX3 revealed an upstream regulatory axis controlling SLC25A17 abundance, linked to JAK2/STAT3 signaling in lung adenocarcinoma.

    Evidence Co-immunoprecipitation (PEX3–SLC25A17), ChIP (USF2–PEX3 promoter), JAK2 inhibitor AG490, xenograft model in lung adenocarcinoma cells

    PMID:40885408

    Open questions at the time
    • Mechanism by which PEX3 stabilizes SLC25A17 unknown
    • Whether this regulatory axis operates in non-cancer cells not tested
    • Single-lab study
  9. 2026 Medium

    MARCH1 was identified as the E3 ubiquitin ligase that ubiquitinates SLC25A17 and targets it for proteasomal degradation, establishing a post-translational mechanism controlling transporter turnover.

    Evidence Co-immunoprecipitation, in vivo ubiquitination assay, SLC25A17 overexpression rescue of MARCH1 effects in lung adenocarcinoma cells

    PMID:41758657

    Open questions at the time
    • Ubiquitination site(s) on SLC25A17 not mapped
    • Whether MARCH1-mediated regulation occurs in non-cancer tissues unknown
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of SLC25A17 exists, and the molecular basis for its substrate selectivity among CoA, FAD, NAD+, and their exchange partners remains unresolved; whether SLC25A17 deficiency underlies a human Mendelian peroxisomal disorder has not been established.
  • No crystal or cryo-EM structure
  • No human disease-causing mutations reported
  • Tissue-specific functions beyond liver and lung adenocarcinoma unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005777 peroxisome 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-382551 Transport of small molecules 2
Partners
MARCH1PEX3

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Human PMP34 (SLC25A17) was identified as a peroxisomal integral membrane protein belonging to the mitochondrial solute carrier family, with six membrane-spanning domains. Its peroxisomal localization was established by fluorescence microscopy of HePG2 cells and mouse fibroblasts transfected with HsPMP34/GFP fusion protein, which colocalized with peroxisomal thiolase. In PEX5 knockout fibroblasts lacking functional peroxisomes, the fusion protein distributed to larger, less-abundant structures, confirming peroxisomal targeting. GFP fusion protein transfection, indirect immunofluorescence, co-localization with peroxisomal marker European journal of biochemistry Medium 9874197
2000 Transmembrane topology of PMP34 (SLC25A17) was determined: both N- and C-terminal parts face the cytosol, opposite to PMP47. The basic residue-containing loop between transmembrane segments 4 and 5 is required for peroxisome targeting (Ala substitution of basic residues abrogated activity), and three flanking hydrophobic transmembrane segments are essential for membrane integration into peroxisomes. Differential permeabilization, immunofluorescence of epitope-tagged variants, deletion mutagenesis, GFP fusion expression in CHO-K1 cells The Journal of biological chemistry High 11121399
2002 PMP34 (SLC25A17) was identified as a peroxisomal adenine nucleotide transporter. Purified PMP34 reconstituted in proteoliposomes directly transported adenine nucleotides. Functional rescue of defective medium-chain fatty acid oxidation in S. cerevisiae ANT1-disrupted cells (lacking the peroxisomal adenine nucleotide carrier) by human PMP34 provided genetic epistasis evidence. Protein reconstitution in proteoliposomes, transport assay, genetic complementation in yeast ANT1 mutant Biochemical and biophysical research communications High 12445829
2012 Recombinant SLC25A17 reconstituted into liposomes transports CoA, FAD, FMN, and AMP, and to a lesser extent NAD+, PAP, and ADP, functioning almost exclusively by counter-exchange mechanism. Kinetic parameters were determined; transport was saturable and inhibited by pyridoxal 5'-phosphate and other mitochondrial carrier inhibitors. The primary physiological role is import of free CoA, FAD, and NAD+ into peroxisomes in exchange for intraperoxisomally generated PAP, FMN, and AMP. Recombinant protein expression, reconstitution into liposomes, transport assays, kinetic characterization, inhibitor studies The Biochemical journal High 22185573
2019 In zebrafish, slc25a17 knockdown compromised peroxisome function and altered lipid composition. Injection of CoA, but not NAD+, rescued the defective swim bladder phenotype caused by slc25a17 knockdown, establishing CoA transport as the primary in vivo function of Slc25a17. Morpholino knockdown in zebrafish, metabolite rescue experiments, lipid composition analysis Journal of cellular physiology Medium 31187491
2020 PMP34-deficient mice (Slc25a17 gene trap) showed impaired degradation of phytanic and pristanic acid upon dietary phytol administration, with hepatomegaly, liver inflammation, and accumulation of phytanic acid, pristanic acid, and their CoA esters. Other peroxisomal pathways (bile acid formation, plasmalogen synthesis, VLCFA metabolism) were unaffected, indicating that PMP34 specifically supports peroxisomal CoA availability for branched-chain fatty acid oxidation. Gene-trap knockout mice, dietary challenge, lipid metabolite analysis (acyl-CoA profiling, bile acid analysis), fibroblast fatty acid oxidation assays Frontiers in cell and developmental biology High 32266253
2023 Inactivation of SLC25A17 in HEK-293, HeLa, and MEF cells shifted the glutathione redox couple toward a more reductive state (GSSG/GSH ratio decreased) and affected peroxisomal NADPH metabolism, establishing SLC25A17 as a maintainer of peroxisomal redox homeostasis. This phenotype was rescued by expression of Candida boidinii Pmp47 (orthologue). The redox changes were not due to altered antioxidant enzyme expression, catalase activity, H2O2 permeability, or mitochondrial fitness. CRISPR KO, redox biosensors, rescue with yeast orthologue Pmp47, catalase activity assay, H2O2 permeability assay Free radical biology & medicine High 38159891
2025 PEX3 interacts with SLC25A17 protein to upregulate its stability, and USF2 drives PEX3 transcriptional activation by directly binding the PEX3 promoter. This USF2-PEX3-SLC25A17 axis promotes JAK2/STAT3 pathway activation and abnormal lipid metabolism in lung adenocarcinoma cells. Co-immunoprecipitation (PEX3-SLC25A17 interaction), chromatin binding assay (USF2-PEX3 promoter), rescue experiments, JAK2 inhibitor (AG490), xenograft model Toxicology and applied pharmacology Medium 40885408
2026 MARCH1 E3 ubiquitin ligase directly ubiquitinates SLC25A17, promoting its proteasomal degradation. Loss of SLC25A17 stability via MARCH1 attenuates M2 macrophage polarization and cisplatin resistance in lung adenocarcinoma. Co-immunoprecipitation, ubiquitination assay, rescue experiments with SLC25A17 overexpression, flow cytometry, Western blotting Integrative biology : quantitative biosciences from nano to macro Medium 41758657

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+. The Biochemical journal 127 22185573
2002 Identification of human PMP34 as a peroxisomal ATP transporter. Biochemical and biophysical research communications 84 12445829
1998 Identification and characterization of human PMP34, a protein closely related to the peroxisomal integral membrane protein PMP47 of Candida boidinii. European journal of biochemistry 54 9874197
2000 Topogenesis of peroxisomal membrane protein requires a short, positively charged intervening-loop sequence and flanking hydrophobic segments. study using human membrane protein PMP34. The Journal of biological chemistry 51 11121399
2020 Slc25a17 Gene Trapped Mice: PMP34 Plays a Role in the Peroxisomal Degradation of Phytanic and Pristanic Acid. Frontiers in cell and developmental biology 21 32266253
2019 Slc25a17 acts as a peroxisomal coenzyme A transporter and regulates multiorgan development in zebrafish. Journal of cellular physiology 21 31187491
2024 SLC25A17 inhibits autophagy to promote triple-negative breast cancer tumorigenesis by ROS-mediated JAK2/STAT3 signaling pathway. Cancer cell international 16 38402166
2021 Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration-resistant prostate cancer. Molecular carcinogenesis 14 34939235
2023 The solute carrier SLC25A17 sustains peroxisomal redox homeostasis in diverse mammalian cell lines. Free radical biology & medicine 4 38159891
2025 USF2 regulates the JAK2/STAT3 pathway through PEX3-mediated SLC25A17 upregulation to affect lipid metabolism and promote the progression of lung adenocarcinoma. Toxicology and applied pharmacology 2 40885408
2026 MARCH1 attenuates lung adenocarcinoma by blocking macrophage M2 polarization and cisplatin resistance through reducing SLC25A17 stability. Integrative biology : quantitative biosciences from nano to macro 0 41758657