Affinage

NUDT7

Peroxisomal coenzyme A diphosphatase NUDT7 · UniProt P0C024

Length
238 aa
Mass
26.9 kDa
Annotated
2026-04-29
14 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUDT7 is a peroxisome-resident Nudix hydrolase that regulates intracellular coenzyme A homeostasis and downstream lipid metabolism. It catalyzes the Mg²⁺/Mn²⁺-dependent diphosphohydrolysis of CoA, acyl-CoAs, and oxidized CoA to 3',5'-ADP and 4'-(acyl)phosphopantetheine, with kinetic parameters of Km ~240 µM and kcat ~3.8 s⁻¹ for free CoA (PMID:11415433, PMID:29378847). In vivo, hepatic NUDT7 activity controls the size and composition of the peroxisomal short-chain and medium-chain acyl-CoA pool, thereby modulating peroxisomal fatty acid β-oxidation, bile acid conjugation, and cholesterol excretion (PMID:30846528, PMID:36436558). Loss of NUDT7 causes palmitic acid and acetyl-CoA accumulation that activates PPARγ-dependent de novo lipogenesis, Wnt/β-catenin signaling in colorectal tumorigenesis, and FOXM1-driven chondrocyte senescence linked to osteoarthritis (PMID:36185359, PMID:32131398, PMID:30143643, PMID:37908734).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 High

    Establishing the enzymatic identity of NUDT7 as a peroxisomal CoA diphosphatase resolved the question of which enzyme degrades CoA within peroxisomes and defined its kinetic parameters and cofactor requirements.

    Evidence Recombinant enzyme kinetics, product identification, and RFP-fusion peroxisomal localization in HeLa cells

    PMID:11415433

    Open questions at the time
    • Human NUDT7 kinetic parameters not directly measured in this study
    • Physiological substrates in vivo not determined
    • No structural information on active site
  2. 2018 High

    Comparative enzymology with NUDT19 defined the distinct catalytic determinants and inhibitor sensitivities of the two mammalian CoA diphosphatases, establishing that their Nudix and CoA-binding motifs are functionally non-interchangeable.

    Evidence Domain-swap mutagenesis and competitive inhibitor binding assays with purified recombinant enzymes

    PMID:29378847

    Open questions at the time
    • Crystal structure of NUDT7 with bound substrate not available
    • Relative contributions of NUDT7 vs NUDT19 to tissue-level CoA regulation unclear
  3. 2018 High

    Demonstration that NUDT7 loss disrupts lipid homeostasis and causes apoptotic chondrocyte death via PGAM1 upregulation established the first in vivo phenotypic consequence and a defined downstream effector pathway.

    Evidence Nudt7⁻/⁻ mouse model and siRNA knockdown in human chondrocytes with PGAM1 epistasis rescue

    PMID:30143643

    Open questions at the time
    • Mechanism linking CoA depletion to PGAM1 transcription not defined
    • Whether chondrocyte phenotype is peroxisome-autonomous not tested
  4. 2019 High

    Liver-specific overexpression demonstrated that NUDT7 directly modulates the hepatic peroxisomal CoA pool in vivo, reducing short-chain acyl-CoAs, bile acid content, and peroxisomal fatty acid oxidation rate.

    Evidence AAV-driven hepatic Nudt7 overexpression in mice with targeted/untargeted metabolomics and hepatocyte fatty acid oxidation assays

    PMID:30846528

    Open questions at the time
    • Loss-of-function metabolomics not yet performed at this stage
    • Effects on extra-hepatic tissues not assessed
  5. 2020 Medium

    Connecting NUDT7 loss to Wnt/β-catenin activation in a carcinogen-driven colorectal cancer model revealed that palmitic acid accumulation from peroxisomal dysfunction feeds into oncogenic signaling.

    Evidence Nudt7⁻/⁻ mice treated with AOM/DSS; palmitic acid-chitosan colonic application phenocopying β-catenin upregulation

    PMID:32131398

    Open questions at the time
    • Direct molecular target of palmitic acid in Wnt activation not identified
    • Human CRC relevance not validated
    • Single laboratory finding
  6. 2022 High

    Global Nudt7 knockout under Western diet conditions revealed sex-specific accumulation of medium-chain dicarboxylic acyl-CoAs and demonstrated that NUDT7 controls bile acid pool hydrophobicity and fecal cholesterol excretion, broadening its metabolic roles beyond simple CoA degradation.

    Evidence Nudt7⁻/⁻ mice on Western diet with hepatic CoA, bile acid, and fecal cholesterol metabolomics

    PMID:36436558

    Open questions at the time
    • Mechanism of sex-specific dicarboxylic acyl-CoA accumulation not elucidated
    • Whether phenotype is peroxisome-autonomous vs. secondary to bile acid changes unclear
  7. 2022 Medium

    Heterozygous Nudt7 deletion linked palmitic acid accumulation to epigenetic activation (H3K4me3) of PPARγ promoters and de novo lipogenesis, providing a chromatin-level mechanism for how peroxisomal CoA hydrolase deficiency drives hepatic steatosis.

    Evidence Nudt7⁺/⁻ mouse with RNA-seq, ChIP for H3K4me3, PPARγ reporter assays, and lipogenesis measurement

    PMID:36185359

    Open questions at the time
    • How palmitic acid increases H3K4me3 at PPARγ promoters mechanistically unresolved
    • Single lab; independent replication lacking
    • Haploinsufficiency model may not reflect complete loss
  8. 2023 Medium

    Double knockout of Acot12 and Nudt7 demonstrated that combined disruption of peroxisomal CoA metabolism drives acetyl-CoA accumulation, FOXM1 upregulation, and chondrocyte senescence, extending the cartilage phenotype to a senescence pathway.

    Evidence Acot12⁻/⁻Nudt7⁻/⁻ double-knockout mouse with acetyl-CoA measurement, microarray, and immunohistochemistry

    PMID:37908734

    Open questions at the time
    • Individual contribution of Nudt7 vs. Acot12 to acetyl-CoA accumulation not deconvoluted
    • FOXM1 as direct transcriptional target of acetyl-CoA not mechanistically proven
  9. 2026 Medium

    During PRRSV infection, NUDT7 was found to interact with UBA52, promoting its proteasomal degradation and thereby stabilizing SREBF1 to drive lipid droplet formation and viral replication, revealing a non-enzymatic protein-protein interaction function.

    Evidence Co-immunoprecipitation, ubiquitination assays, and viral replication assays in cell culture

    PMID:41608635

    Open questions at the time
    • Whether UBA52 interaction depends on NUDT7 hydrolase activity not tested
    • Relevance to non-viral physiological contexts unknown
    • Single laboratory, not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the crystal structure of NUDT7 with substrate, the mechanism by which CoA/acyl-CoA changes are transduced to nuclear epigenetic and transcriptional outputs, and whether NUDT7's protein-protein interaction with UBA52 is physiologically relevant outside viral infection.
  • No high-resolution structure of NUDT7
  • Signal transduction from peroxisomal CoA pool to chromatin not mechanistically defined
  • Tissue-specific and sex-specific regulation of NUDT7 expression poorly understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4
Localization
GO:0005777 peroxisome 2
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
ACOT12NUDT19PGAM1UBA52

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Mouse NUDT7α (Nudt7) is a peroxisomal CoA diphosphatase that hydrolyzes CoA, CoA esters, and oxidized CoA, yielding 3',5'-ADP and the corresponding 4'-phosphopantetheine derivative. Kinetic parameters: Km = 240 µM and kcat = 3.8 s⁻¹ with CoA; activity is optimal at pH 8.0 with 5 mM Mg²⁺ or Mn²⁺; fluoride inhibits with IC₅₀ = 20 µM. Transfection of HeLa cells with RFP-Nudt7α confirmed peroxisomal localization. In vitro enzymatic assay of recombinant thioredoxin-fusion protein expressed in E. coli; product identification; live-cell imaging of RFP-fusion in HeLa cells The Biochemical journal High 11415433
2018 Nudt19 and Nudt7 both hydrolyze the diphosphate bond of free CoA and acyl-CoAs to form 3',5'-ADP and 4'-(acyl)phosphopantetheine, but differ in regulation and inhibitor sensitivity. Chenodeoxycholic acid specifically inhibits Nudt19 by competing with CoA but does not bind Nudt7. Exchange of Nudix and CoA signature motifs between the two isoforms dramatically decreased their kcat, and substitution of conserved residues within these motifs identified amino acids playing different roles in CoA binding and hydrolysis in each isoform. In vitro enzymatic assay; active-site mutagenesis and domain-swap experiments; competitive inhibitor binding assays The Journal of biological chemistry High 29378847
2019 Liver-specific overexpression of Nudt7 in mice decreases the concentration of short-chain acyl-CoAs and choloyl-CoA in fasted livers, reduces hepatic bile acid content, and reduces the rate of peroxisomal fatty acid oxidation, as measured by targeted/untargeted metabolomics and fatty acid oxidation assays in intact hepatocytes, demonstrating that Nudt7 activity modulates the peroxisomal CoA pool and peroxisomal lipid metabolism in vivo. In vivo overexpression in mouse liver; targeted and untargeted metabolomics; fatty acid oxidation assay in isolated hepatocytes Journal of lipid research High 30846528
2018 Knockdown of NUDT7 in normal human chondrocytes disrupts lipid homeostasis. Nudt7⁻/⁻ mice accumulate lipids via peroxisomal dysfunction, upregulate IL-1β, and undergo apoptotic chondrocyte death. Genome-wide analysis identifies PGAM1 as a downstream target; PGAM1 overexpression phenocopies NUDT7 loss, and co-introduction of NUDT7 rescues the PGAM1-driven phenotype, placing NUDT7 upstream of PGAM1 in a pathway controlling chondrocyte lipid homeostasis and survival. siRNA knockdown in human chondrocytes; Nudt7⁻/⁻ mouse model; overexpression of PGAM1; rescue experiment with co-expression of NUDT7; microarray; apoptosis assays; lipid staining Nature communications High 30143643
2022 Deletion of Nudt7 in male mice fed a Western diet increases total liver CoA levels, driven by male-specific accumulation of medium-chain dicarboxylic acyl-CoAs from β-oxidation of dicarboxylic fatty acids. Under conditions of elevated chenodeoxycholic acid synthesis, Nudt7 deletion promotes tauromuricholic acid production, decreasing the hydrophobicity index of the intestinal bile acid pool and increasing fecal cholesterol excretion. Nudt7⁻/⁻ mouse model; targeted metabolomics of hepatic CoA and bile acid pools; fecal cholesterol measurement The Journal of biological chemistry High 36436558
2022 Heterozygous deletion of Nudt7 in mice causes accumulation of palmitic acid, which increases H3K4me3 on PPARγ promoters, activates PPARγ, and drives de novo lipogenesis in hepatocytes, linking peroxisomal CoA hydrolase activity to an epigenetic-transcriptional mechanism controlling hepatic lipid synthesis. Nudt7⁺/⁻ mouse model; RNA sequencing; IPA/KEGG pathway analysis; ChIP for H3K4me3; PPARγ reporter/activity assays; de novo lipogenesis measurement iScience Medium 36185359
2020 Loss of Nudt7 in AOM/DSS-treated mice increases lipid accumulation and activates Wnt/β-catenin signaling (elevated β-catenin, Myc, Ccnd1, Nos2). Palmitic acid accumulation in Nudt7⁻/⁻ colons is implicated as the driver; direct application of palmitic acid-conjugated chitosan to mouse colon phenocopies β-catenin upregulation, placing NUDT7-dependent peroxisomal lipid metabolism upstream of Wnt signaling in Kras-driven CRC. Nudt7⁻/⁻ mouse model + AOM/DSS carcinogen treatment; xenograft of Nudt7-overexpressing cancer cells; microarray; palmitic acid treatment experiment; Western blot for Wnt pathway components Cancers Medium 32131398
2023 Double knockout of Acot12 and Nudt7 in mice leads to accumulation of acetyl-CoA, upregulation of FOXM1, and induction of chondrocyte senescence and cartilage breakdown, linking peroxisomal CoA metabolism to a FOXM1-driven senescence pathway in osteoarthritis. Acot12⁻/⁻Nudt7⁻/⁻ double-knockout mouse; microarray; immunohistochemistry; qRT-PCR; apoptosis/proliferation assays; acetyl-CoA measurement Theranostics Medium 37908734
2010 Overexpression of pig NUDT7 in rat L6 myoblasts significantly reduces heme content (14.2 vs. 63.9 pmol/10⁵ cells), consistent with NUDT7-mediated hydrolysis of succinyl-CoA reducing substrate availability for heme biosynthesis. Transfection of NUDT7 expression vector into rat L6 myoblasts; heme content measurement at multiple time points Meat science Low 20619544
2022 In zebrafish, nudt7 gene products are localized to the peroxisome during early embryogenesis. CRISPR/Cas9 depletion of nudt7 decreases transcription rate at zygotic genome activation (ZGA) and correlates with a genome-wide decrease in H3K27ac levels, suggesting a role for peroxisomal Nudt7 in regulating active chromatin formation during early development. Computational localization prediction confirmed by reporter; CRISPR/Cas9 knockout in zebrafish; RNA-seq; H3K27ac ChIP-seq Journal of biochemistry Low 36270274
2026 During PRRSV infection, NUDT7 protein interacts with and promotes proteasomal degradation of the ubiquitin-ribosomal fusion protein UBA52. This blocks UBA52-mediated K11/K27/K48 polyubiquitination of SREBF1, stabilizing SREBF1 and driving lipid droplet formation that supports PRRSV replication. NUDT7 also inhibits type I interferon signaling to facilitate viral immune evasion. Co-immunoprecipitation; overexpression and knockdown in cells; ubiquitination assay; lipid droplet staining; viral replication assay; interferon signaling reporter International journal of biological sciences Medium 41608635

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Salicylic acid-independent ENHANCED DISEASE SUSCEPTIBILITY1 signaling in Arabidopsis immunity and cell death is regulated by the monooxygenase FMO1 and the Nudix hydrolase NUDT7. The Plant cell 406 16531493
2001 The mouse Nudt7 gene encodes a peroxisomal nudix hydrolase specific for coenzyme A and its derivatives. The Biochemical journal 79 11415433
2018 Dysregulation of the NUDT7-PGAM1 axis is responsible for chondrocyte death during osteoarthritis pathogenesis. Nature communications 58 30143643
2012 The ammonium/nitrate ratio is an input signal in the temperature-modulated, SNC1-mediated and EDS1-dependent autoimmunity of nudt6-2 nudt7. The Plant journal : for cell and molecular biology 30 23004358
2018 Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform. The Journal of biological chemistry 29 29378847
2019 Overexpression of Nudt7 decreases bile acid levels and peroxisomal fatty acid oxidation in the liver. Journal of lipid research 18 30846528
2023 Upregulated FOXM1 stimulates chondrocyte senescence in Acot12-/-Nudt7-/- double knockout mice. Theranostics 10 37908734
2020 NUDT7 Loss Promotes Kras CRC Development. Cancers 10 32131398
2009 Fine mapping of quantitative trait loci for meat color on Sus scrofa chromosome 6: analysis of the swine NUDT7 gene. Journal of animal science 10 19749013
2022 NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet. The Journal of biological chemistry 9 36436558
2010 Overexpression of NUDT7, a candidate quantitative trait locus for pork color, downregulates heme biosynthesis in L6 myoblasts. Meat science 9 20619544
2022 Deficiency of peroxisomal NUDT7 stimulates de novo lipogenesis in hepatocytes. iScience 3 36185359
2022 nudt7 gene depletion causes transcriptomic change in early development of zebrafish. Journal of biochemistry 1 36270274
2026 NUDT7 Modulates the UBA52-SREBF1 Signaling Axis to Promote PRRSV Replication via Lipid Synthesis. International journal of biological sciences 0 41608635