Affinage

ACADM

Medium-chain specific acyl-CoA dehydrogenase, mitochondrial · UniProt P11310

Length
421 aa
Mass
46.6 kDa
Annotated
2026-06-09
97 papers in source corpus 24 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACADM encodes the mitochondrial flavoenzyme MCAD, which catalyzes the rate-determining first dehydrogenation step of medium-chain fatty acid β-oxidation; in MCAD-deficient cells decanoyl-CoA is readily shortened to octanoyl-CoA but octanoyl-CoA cannot be further oxidized, producing the characteristic accumulation of octanoyl-, decanoyl-, and decenoylcarnitine (PMID:7551818). Catalysis proceeds through an FAD-dependent reductive half-reaction with octanoyl-CoA that generates kinetically distinct MCAD-FADH2–octenoyl-CoA charge-transfer complexes, and the enzyme's latent oxidase activity is suppressed while these charge-transfer species persist (PMID:7626613); electrons are relayed to electron-transferring flavoprotein (ETF), and disease variants can alter both substrate chain-length dependence and ETF interaction (PMID:37257730). Proper FAD incorporation is coupled to cofactor affinity, proteolytic and thermal stability, and correct tetramer assembly, with FAD supplementation able to structurally rescue some variants (PMID:37257730). Newly imported MCAD monomers are folded along an ATP-dependent chaperone pathway in which they first bind mitochondrial hsp70 and are then transferred to hsp60 before release as mature tetramers (PMID:7905878). The prevalent K304E (K329E) disease mutation does not impair import but introduces a charge that destabilizes the hsp60–MCAD complex against ATP-driven release and impairs subunit docking and tetramer stability; the neutral K304Q substitution restores far more activity, demonstrating that the glutamate negative charge is responsible (PMID:8104486, PMID:7905878, PMID:7730333). Systematic variant studies separate folding/assembly defects, which are rescuable by chaperonin co-overexpression or permissive temperature, from purely catalytic lesions such as R256T that yield well-folded but inactive enzyme (PMID:16128823, PMID:24966162), and a large class of ACADM disease alleles act not on protein but on pre-mRNA splicing, disrupting exonic splicing enhancers/silencers or activating cryptic splice sites to cause exon skipping and NMD-mediated transcript loss (PMID:17273963, PMID:23810226, PMID:15171999). Beyond classic β-oxidation, MCAD is transcriptionally repressed via the CAV1/SREBP1 axis in hepatocellular carcinoma (PMID:33975883), is phosphorylated downstream of PINK1 kinase in a pathway linking mitochondrial function to fatty acid metabolism (PMID:29563254), and re-oxidizes microbiota-derived phenylpropionic acid in a host-microbe co-metabolic pathway generating hippuric acid (PMID:36720857). Loss of MCAD impairs hepatic glucose homeostasis under metabolic stress (PMID:18459129).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1991 High

    Established the molecular basis of the most common ACADM disease allele by showing the 985A>G (K304E) substitution produces inactive enzyme through failure to form active tetramers, moving the field from genetic association to a defined protein defect.

    Evidence E. coli expression of mutant cDNA with activity assay and immunoblot, replicated across labs

    PMID:1363805 PMID:1684086 PMID:1902818

    Open questions at the time
    • Did not resolve whether the defect was in synthesis, import, folding, or stability
    • No structural mechanism for why the charge change blocks assembly
  2. 1992 High

    Resolved that K304E is a post-import instability defect rather than an import defect, by showing mutant protein is imported, processed, and assembled into tetramers in eukaryotic cells but is degraded faster and present at lower steady-state levels.

    Evidence EBV-based expression in COS-7 cells with pulse-chase, activity assay, and immunoblot

    PMID:1382617

    Open questions at the time
    • Did not identify the chaperone machinery handling the mutant
    • Did not localize the assembly step that fails
  3. 1994 High

    Defined the ordered ATP-dependent chaperone pathway for MCAD biogenesis (hsp70mit then hsp60 then tetramer release) and pinpointed the K304E lesion to an abnormally stable, ATP-resistant hsp60–MCAD intermediate, explaining the folding/assembly failure mechanistically.

    Evidence In vitro import into isolated rat liver mitochondria with gel filtration, anti-hsp60/anti-hsp70 immunoprecipitation, and ATP chase

    PMID:7905878

    Open questions at the time
    • Did not establish whether the same release step limits other folding variants
    • No structural model of the hsp60–MCAD complex
  4. 1995 High

    Distinguished the contributions of folding versus oligomer assembly across mutations, showing R28C is a pure folding defect fully rescuable by chaperonins/temperature while K304E additionally impairs assembly and tetramer thermostability, and assigned the assembly defect specifically to glutamate's negative charge via the K304Q control.

    Evidence E. coli expression with GroEL/GroES titration, temperature variation, thermal stability assays, and engineered K304Q/K304E-D346K controls

    PMID:7730333 PMID:8104486

    Open questions at the time
    • Did not quantify in vivo assembly kinetics in human mitochondria
    • Did not address cofactor loading during assembly
  5. 1995 High

    Defined the FAD-dependent catalytic mechanism, showing the reductive half-reaction with octanoyl-CoA forms kinetically distinct charge-transfer complexes that gate the enzyme's oxidase activity, providing the chemical basis of the dehydrogenase reaction.

    Evidence Stopped-flow kinetics with O2 monitoring on purified enzyme and defined substrate

    PMID:7626613

    Open questions at the time
    • Did not connect charge-transfer kinetics to ETF electron transfer in physiologic context
    • Did not address chain-length selectivity at the kinetic level
  6. 1995 Medium

    Confirmed the metabolic block in patient cells by isotope tracing, showing MCAD-deficient fibroblasts convert decanoyl-CoA to octanoyl-CoA but cannot oxidize octanoyl-CoA, establishing the diagnostic acylcarnitine signature independent of genotype.

    Evidence Stable isotope-labeled fatty acid incubation of patient fibroblasts with tandem MS acylcarnitine profiling

    PMID:7551818

    Open questions at the time
    • Ex vivo fibroblast model rather than in vivo flux
    • Did not quantify substrate chain-length boundaries precisely
  7. 2008 High

    Connected MCAD loss to systemic metabolism in vivo, showing MCAD-/- mice have impaired hepatic de novo glucose-6-phosphate synthesis and glucose output specifically under LPS-induced stress but not fasting alone, revealing condition-dependent metabolic vulnerability.

    Evidence MCAD-/- mice with stable-isotope flux measurements and microarray under fasting and LPS challenge

    PMID:18459129

    Open questions at the time
    • Did not identify the compensatory mechanism active during fasting
    • Mouse stress paradigm may not map directly to human crisis physiology
  8. 2007 High

    Reframed a class of ACADM disease alleles as splicing rather than protein defects, showing an exon 5 missense mutation acts by inactivating an exonic splicing enhancer to cause exon skipping, with a synonymous SNP modulating the outcome.

    Evidence Patient cell RNA analysis, minigene and in vitro splicing assays identifying ESE/ESS elements

    PMID:17273963

    Open questions at the time
    • Did not identify all trans-acting splicing factors involved
    • Generalizability to other exons not established here
  9. 2014 High

    Systematized genotype-to-function relationships across many variants, separating moderate chaperonin-rescuable folding variants from severe (<5% activity) lesions and mapping structural consequences, refining clinical interpretation.

    Evidence E. coli expression of 18 variants with multi-substrate activity assays, chaperonin rescue, temperature variation, cross-linking, and structure mapping

    PMID:24966162

    Open questions at the time
    • Heterologous system may not capture human mitochondrial folding fully
    • Did not measure cofactor occupancy systematically
  10. 2005 High

    Dissociated catalysis from folding at the residue level, showing R256T yields a well-folded, stable but catalytically dead enzyme while K364R is a chaperonin-rescuable folding mutant, identifying R256 as catalytically essential.

    Evidence E. coli expression with GroELS rescue, purification, activity, and thermostability assays

    PMID:16128823

    Open questions at the time
    • Did not define the precise catalytic role of R256 structurally
    • FAD depletion was not the explanation but cofactor coupling left open
  11. 2023 High

    Established FAD cofactor handling as a central determinant of variant stability and activity, correlating FAD content with affinity, proteolytic/thermal stability, assembly state, and ETF interaction, and showing FAD supplementation can structurally rescue some variants.

    Evidence Heterologous expression of 12 variants with FAD quantification, kinetics, thermostability, proteolysis, ETF binding, and native gels

    PMID:37257730

    Open questions at the time
    • Therapeutic FAD/riboflavin benefit not tested in patients here
    • Mechanism of dimer-only assembly for p.Y372N not structurally resolved
  12. 2018 Medium

    Placed MCAD in a regulatory phosphorylation pathway, identifying it as a PINK1 substrate whose phosphomimetic form rescues PINK1-null phenotypes and metabolic defects, linking mitochondrial kinase signaling to fatty acid metabolism.

    Evidence Unbiased phosphoproteomics in Drosophila with phosphomimetic transgene rescue and metabolic profiling

    PMID:29563254

    Open questions at the time
    • Drosophila model; human MCAD phosphosite and effect not demonstrated
    • Direct kinase-substrate biochemistry not shown
  13. 2021 Medium

    Identified transcriptional control of ACADM, showing the CAV1/SREBP1 axis represses ACADM to suppress fatty acid oxidation and promote hepatocellular carcinoma aggressiveness, extending MCAD biology into cancer metabolism.

    Evidence Loss/gain-of-function, SREBP1 inhibition, xenografts, lipid and motility assays

    PMID:33975883

    Open questions at the time
    • Direct SREBP1 binding to the ACADM promoter not shown in this entry
    • Single tumor context
  14. 2023 High

    Revealed a host-microbe co-metabolic role, showing host MCAD re-oxidizes bacterially derived phenylpropionic acid to generate hippuric acid and processes additional microbial metabolites, broadening MCAD substrate scope beyond dietary fatty acids.

    Evidence Germ-free MCAD-/- mice with gnotobiotic colonization, stable isotope tracing, and untargeted metabolomics

    PMID:36720857

    Open questions at the time
    • Full repertoire of microbial substrates not exhaustively defined
    • Physiologic significance of hippurate flux not quantified
  15. 2023 Medium

    Linked MCAD to antiviral lipid metabolism, showing it binds PEDV NSP4 and restricts viral replication by lowering free fatty acids and β-oxidation through suppression of AMPK-mediated lipophagy.

    Evidence IP-MS, reciprocal Co-IP, confocal colocalization, overexpression/knockdown viral replication and lipophagy assays

    PMID:39002673

    Open questions at the time
    • Single lab; interaction interface not mapped
    • Relevance to human coronaviruses not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether MCAD phosphorylation (PINK1-dependent and the post-translational modification inferred from 2D-gel pI shifts) directly regulates enzyme activity, assembly, or turnover in human mitochondria remains undefined.
  • Phosphosite identity and stoichiometry in human cells unknown
  • Functional consequence of the 2D-gel-observed modification not directly tested
  • Link between PINK1 signaling and MCAD regulation in mammals unconfirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016740 transferase activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 1
Partners
CAV1ETFHSPA9HSPD1PINK1SREBF1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The prevalent 985A→G mutation in MCAD causes a lysine-to-glutamate substitution at position 304 (K304E, also referred to as K329E in mature protein numbering) that results in inactive enzyme due to impaired ability to form active tetramers, demonstrated by expression of mutant MCAD cDNA in E. coli producing inactive protein. E. coli expression of mutant MCAD cDNA, enzyme activity assay, immunoblot Human genetics High 1363805 1684086 1902818
1992 Expression of K304E mutant MCAD in eukaryotic COS-7 cells showed that mutant protein is synthesized and transported into mitochondria in similar amounts to wild-type, achieves correct mature protein size, adopts tetrameric structure, but is present at consistently lower steady-state levels than wild-type and is degraded more readily, indicating post-import instability rather than import defect. EBV-based eukaryotic expression in COS-7 cells, immunoblot, enzyme activity assay, pulse-chase labeling Biochimica et biophysica acta High 1382617
1993 Co-overexpression of bacterial chaperonins GroEL/GroES partially rescues solubility and tetramer formation of K304E MCAD expressed in E. coli, but even soluble K304E tetramers show reduced amounts relative to wild-type, indicating the K304E mutation primarily impairs the rate of polypeptide folding and subunit assembly. Neutral substitution K304Q restores more activity than K304E, demonstrating that the negative charge of glutamate specifically impairs subunit docking. E. coli co-overexpression with GroEL/GroES, native PAGE, enzyme activity assay, Western blot Biochimica et biophysica acta High 8104486
1993 The R28C mutation (T157C in cDNA) in MCAD primarily affects polypeptide folding; based on the known 3D structure of MCAD, it is proposed to destroy a salt bridge between arginine-28 and glutamate-86. Expression in COS-7 cells confirmed impaired formation of enzymatically active protein. COS-7 cell expression of mutant MCAD cDNA, enzyme activity assay, structural inference from 3D structure American journal of human genetics Medium 8102510
1994 In vitro import of MCAD into isolated rat liver mitochondria demonstrated that: (1) newly imported MCAD first forms a transient complex with mitochondrial hsp70 (hsp70mit), (2) is then transferred to hsp60 (a ~700 kDa high-molecular-weight complex), and (3) subsequently released as mature tetramer in an ATP-dependent manner. K304E MCAD binds hsp70mit and transfers to hsp60 normally, but the hsp60–K304E complex is abnormally stable and resistant to ATP-driven release, indicating the folding/release step from hsp60 is impaired. In vitro import into isolated mitochondria, gel filtration, specific antibody immunoprecipitation (anti-hsp60, anti-hsp70), ATP chase experiment The Journal of biological chemistry High 7905878
1995 The R28C and K304E mutations in MCAD have distinct molecular effects: R28C predominantly affects folding (amounts of active enzyme can be modulated from undetectable to 100% of wild-type by chaperonin co-overexpression and low growth temperature), while K304E affects both folding and oligomer assembly/stability (active enzyme cannot exceed ~50% of wild-type even under optimal chaperonin conditions), and K304E assembled tetramers show decreased thermal stability. E. coli expression with and without GroEL/GroES co-overexpression, enzyme activity assay, thermal stability assay, Western blot The Journal of biological chemistry High 7730333
1994 Two-dimensional gel electrophoresis of MCAD expressed in eukaryotic cells revealed two spots for mature MCAD with different isoelectric points, demonstrating that MCAD undergoes post-translational modification in mitochondria after transit peptide removal. The pI shift is compatible with phosphorylation of one aspartic acid residue per monomer. The modified form accumulates over time relative to the unmodified form, indicating the modification is time-dependent. The K304E mutant shows a higher ratio of unmodified form, suggesting the modification efficiency or stability of the modified form is impaired by K304E. 2D gel electrophoresis, pulse labeling, expression in E. coli and COS-7 cells Biochemical medicine and metabolic biology Medium 7917465
1995 The reductive half-reaction of MCAD with octanoyl-CoA as substrate generates two kinetically distinct forms of the reduced enzyme (MCAD-FADH2)–octenoyl-CoA charge-transfer complexes. Octenoyl-CoA dissociates from the more stable complex (CT2) via two pathways: a 'facile' pathway involving reversal of the reductive half-reaction (releasing octanoyl-CoA), and a 'restricted' pathway involving direct slow dissociation of octenoyl-CoA yielding MCAD-FADH2. The oxidase activity of MCAD is suppressed as long as reduced enzyme remains in charge-transfer complex form, emerging concomitantly with conversion of CT2 to the MCAD-FADH2–octenoyl-CoA Michaelis complex. Stopped-flow kinetics, in vitro enzymatic assay with O2 monitoring Biochemistry High 7626613
2001 The 199T→C mutation in MCAD (Y67H) is a mild folding mutation: overexpression experiments showed that it exhibits decreased levels of enzyme activity only under stringent conditions (i.e., impaired folding is partially compensated under permissive conditions), distinguishing it from the severe K304E mutation. Overexpression experiments in E. coli, enzyme activity assay under varying conditions American journal of human genetics Medium 11349232
2005 The R256T mutation in MCAD results in a well-folded, stable protein that is completely devoid of catalytic activity, identifying R256 as critical for catalysis rather than folding. The K364R mutation by contrast causes a folding defect (protein is only active when GroELS chaperonin is co-overexpressed and shows reduced thermostability). Neither mutant shows marked FAD depletion. E. coli overexpression with and without GroELS, enzyme activity assay, protein purification, thermostability assay, Western blot The FEBS journal High 16128823
2007 A missense mutation in MCAD exon 5 primarily causes disease by inactivating an exonic splicing enhancer (ESE), leading to exon skipping rather than by direct protein dysfunction. The ESE functions by antagonizing a juxtaposed exonic splicing silencer (ESS) to define a suboptimal 3′ splice site. A synonymous polymorphic variant in exon 5 inactivates the ESS and renders splicing immune to the deleterious ESE mutation, demonstrating context-dependent SNP effects on pre-mRNA splicing. Patient cell RNA analysis, minigene splicing assays, in vitro splicing assays American journal of human genetics High 17273963
2013 A synonymous SNP c.1161A>G in ACADM exon 11 affects pre-mRNA splicing efficiency. The c.1161A allele is associated with exon 11 missplicing; the c.1161G allele corrects this missplicing, apparently by altering the relative binding of splicing regulatory proteins SRSF1 and hnRNP A1, resulting in higher levels of full-length MCAD protein from the G allele. Minigene splicing assays, RNA-seq analysis, splicing factor binding inference Molecular genetics and metabolism Medium 23810226
2018 PINK1 kinase mediates phosphorylation of MCAD in vivo in Drosophila, identified by unbiased phosphoproteomic screen. Mimicking MCAD phosphorylation in a PINK1-null background rescued climbing, flight, thorax, and wing defects of PINK1 null flies, and partially corrected metabolic disruptions in acylcarnitines and amino acids, placing MCAD downstream of PINK1 in a pathway relevant to mitochondrial function and fatty acid metabolism. Unbiased phosphoproteomic screen in Drosophila, phosphomimetic transgene rescue, metabolic profiling (acylcarnitines and amino acids) Molecular biology of the cell Medium 29563254
2021 SREBP1 acts as a negative transcriptional regulator of ACADM in hepatocellular carcinoma. CAV1 (caveolin-1) was found to inhibit fatty acid oxidation by enhancing nuclear accumulation of SREBP1, which in turn suppresses ACADM expression and activity, promoting HCC cell aggressiveness. ACADM suppression led to elevated triglyceride, phospholipid, and lipid droplet levels and increased HCC cell motility. Loss-of-function and gain-of-function experiments, SREBP1 inhibitor treatment, in vivo xenograft model, lipid assays, cell motility assays Cancer research Medium 33975883
2023 MCAD (encoded by ACADM) participates in a host-microbe co-metabolic pathway for hippuric acid generation: gut bacteria reduce phenylalanine to phenylpropionic acid, and the host re-oxidizes phenylpropionic acid via MCAD (β-oxidation). This was demonstrated using MCAD-/- germ-free mice colonized with specific bacteria combined with stable isotope tracing and untargeted metabolomics, which also identified additional microbial metabolites processed by MCAD in host circulation. Stable isotope tracing, germ-free MCAD-/- mouse model, gnotobiotic colonization, untargeted metabolomics Nature communications High 36720857
2023 ACADM interacts with the NSP4 protein of porcine epidemic diarrhea virus (PEDV), identified by immunoprecipitation-mass spectrometry. The interaction was confirmed by co-immunoprecipitation and laser confocal co-localization. ACADM overexpression inhibits PEDV replication while knockdown facilitates it. Mechanistically, ACADM reduces cellular free fatty acid levels and β-oxidation by hindering AMPK-mediated lipophagy, thereby suppressing PEDV replication. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, laser confocal microscopy, overexpression/knockdown functional assays, viral replication assays, lipophagy assays The Journal of biological chemistry Medium 39002673
2023 Multiple MCAD missense variants alter FAD cofactor incorporation: half of studied variants showed FAD content <65% of wild-type. A correlation was established between FAD content and cofactor affinity, proteolytic stability, thermostability, and thermal inactivation rate. The p.Y372N variant assembles predominantly as dimers rather than tetramers. Some variants show altered substrate chain-length dependence and altered interaction with electron-transferring-flavoprotein (ETF). FAD supplementation structurally rescued some variants, suggesting mitochondrial FAD availability can modulate variant MCAD levels. Heterologous expression, FAD content measurement, enzyme kinetics with varied substrates, thermal stability assay, proteolytic stability assay, ETF interaction assay, native gel analysis Biochimica et biophysica acta. Molecular basis of disease High 37257730
2014 Functional characterization of 18 ACADM missense variants by heterologous E. coli overexpression identified three variants (Y42H, E18K, R6H) with moderate impairment (22–47% residual octanoyl-CoA oxidation activity, normal temperature sensitivity, activity rescued to 100% by chaperonin co-overexpression), while 15 others showed severely reduced residual activities (<5%). Cross-linking experiments and 3D structure mapping were used to infer structural consequences. E. coli heterologous expression, enzyme activity assay with multiple substrates, GroEL/GroES co-overexpression, temperature variation assay, cross-linking experiments, 3D structure mapping Journal of inherited metabolic disease High 24966162
2004 A novel splice mutation IVS3-1G>C in MCAD leads to deletion of 7 bp and introduction of a premature stop codon through complete missplicing of MCAD mRNA. The misspliced mRNA is reduced in abundance due to nonsense-mediated mRNA decay (NMD), resulting in total absence of functional MCAD enzyme. This was the first functionally characterized splice mutation in the MCAD gene. RT-PCR analysis of patient mRNA, sequence analysis, functional characterization of splice products Molecular genetics and metabolism Medium 15171999
2015 A novel splice site mutation c.600-18G>A in ACADM activates a cryptic splice site that competes with the natural splice site, producing three transcripts, two of which result in truncated non-functional MCAD protein. Only partial missplicing occurs, leaving sufficient functional MCAD for a mild deficiency phenotype. The degree of missplicing was found to be temperature-sensitive, with octanoyl-CoA oxidation rate decreasing during febrile infection. RT-PCR and mRNA analysis in granulocytes and monocytes, enzyme activity measurement (octanoyl-CoA oxidation) before and during febrile infection BMC medical genetics Medium 26223887
2008 MCAD-deficient (MCAD-/-) mice show specific alterations in hepatic carbohydrate management under metabolic stress: during lipopolysaccharide-induced acute phase response, de novo glucose-6-phosphate synthesis was significantly decreased (-20%) and newly formed G6P was preferentially directed toward glycogen, leading to decreased hepatic glucose output. During fasting alone, de novo G6P synthesis was not affected, suggesting compensatory mechanisms exist under that condition. MCAD-/- knockout mice, quantitative flux measurements with stable isotopes, microarray gene expression analysis, metabolic challenge (fasting, LPS) Hepatology High 18459129
1995 In vitro incubation of MCAD-deficient human fibroblasts with stable isotope-labeled fatty acid probes produced acylcarnitine profiles characteristic of MCAD deficiency regardless of the underlying DNA mutation: elevated octanoyl-, decanoyl-, and decenoylcarnitine with specific octanoylcarnitine-to-decanoylcarnitine ratios, indicating that MCAD-deficient cells readily convert decanoyl-CoA to octanoyl-CoA but cannot further oxidize octanoyl-CoA. Stable isotope-labeled fatty acid incubation with human fibroblasts, tandem mass spectrometry analysis of acylcarnitine intermediates Biochemical and molecular medicine Medium 7551818

Source papers

Stage 0 corpus · 97 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. American journal of human genetics 181 11349232
1993 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: diagnosis by acylcarnitine analysis in blood. American journal of human genetics 145 8488845
2007 Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. American journal of human genetics 123 17273963
1997 The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype? Human molecular genetics 104 9158144
2021 Suppression of ACADM-Mediated Fatty Acid Oxidation Promotes Hepatocellular Carcinoma via Aberrant CAV1/SREBP1 Signaling. Cancer research 102 33975883
2005 Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Human mutation 92 15832312
1991 Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium-chain Acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency. American journal of human genetics 90 1684086
1991 Specific diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in dried blood spots by a polymerase chain reaction (PCR) assay detecting a point-mutation (G985) in the MCAD gene. Clinica chimica acta; international journal of clinical chemistry 79 1769118
1995 Effects of two mutations detected in medium chain acyl-CoA dehydrogenase (MCAD)-deficient patients on folding, oligomer assembly, and stability of MCAD enzyme. The Journal of biological chemistry 78 7730333
1991 Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329 to glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli. Human genetics 75 1902818
1993 Co-overexpression of bacterial GroESL chaperonins partly overcomes non-productive folding and tetramer assembly of E. coli-expressed human medium-chain acyl-CoA dehydrogenase (MCAD) carrying the prevalent disease-causing K304E mutation. Biochimica et biophysica acta 70 8104486
1992 Mutations in the medium chain acyl-CoA dehydrogenase (MCAD) gene. Human mutation 67 1363805
2023 Host-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid. Nature communications 66 36720857
1993 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe. Human heredity 65 7904584
2003 Adult presentation of MCAD deficiency revealed by coma and severe arrythmias. Intensive care medicine 60 12897989
1994 Intramitochondrial folding and assembly of medium-chain acyl-CoA dehydrogenase (MCAD). Demonstration of impaired transfer of K304E-variant MCAD from its complex with hsp60 to the native tetramer. The Journal of biological chemistry 60 7905878
2001 Molecular and functional characterisation of mild MCAD deficiency. Human genetics 50 11409868
2010 Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Molecular genetics and metabolism 48 20434380
2009 Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Molecular genetics and metabolism 47 20036593
2008 Neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in The Netherlands: the importance of enzyme analysis to ascertain true MCAD deficiency. Journal of inherited metabolic disease 44 18188679
1993 A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD). American journal of human genetics 39 8102510
2012 MCAD deficiency in Denmark. Molecular genetics and metabolism 36 22542437
1992 Expression of wild-type and mutant medium-chain acyl-CoA dehydrogenase (MCAD) cDNA in eucaryotic cells. Biochimica et biophysica acta 34 1382617
2004 Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency. Brain research 33 15567346
2009 Medium-chain fatty acids accumulating in MCAD deficiency elicit lipid and protein oxidative damage and decrease non-enzymatic antioxidant defenses in rat brain. Neurochemistry international 31 19428797
2008 Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice. Hepatology (Baltimore, Md.) 31 18459129
2005 Genotypic differences of MCAD deficiency in the Asian population: novel genotype and clinical symptoms preceding newborn screening notification. Genetics in medicine : official journal of the American College of Medical Genetics 31 15915086
2006 PGC-1beta down-regulation is associated with reduced ERRalpha activity and MCAD expression in skeletal muscle of senescence-accelerated mice. The journals of gerontology. Series A, Biological sciences and medical sciences 29 16912093
2023 Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer. BMC cancer 27 37612627
2014 Differential Expression of PPARγ, FASN, and ACADM Genes in Various Adipose Tissues and Longissimus dorsi Muscle from Yanbian Yellow Cattle and Yan Yellow Cattle. Asian-Australasian journal of animal sciences 27 25049920
2019 A nationwide retrospective observational study of population newborn screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the Netherlands. Journal of inherited metabolic disease 25 31012112
2016 miR-224 Affects Mammary Epithelial Cell Apoptosis and Triglyceride Production by Downregulating ACADM and ALDH2 Genes. DNA and cell biology 24 27918674
2013 A synonymous polymorphic variation in ACADM exon 11 affects splicing efficiency and may affect fatty acid oxidation. Molecular genetics and metabolism 24 23810226
1995 Investigation of beta-oxidation intermediates in normal and MCAD-deficient human fibroblasts using tandem mass spectrometry. Biochemical and molecular medicine 24 7551818
2004 Homozygosity for a severe novel medium-chain acyl-CoA dehydrogenase (MCAD) mutation IVS3-1G > C that leads to introduction of a premature termination codon by complete missplicing of the MCAD mRNA and is associated with phenotypic diversity ranging from sudden neonatal death to asymptomatic status. Molecular genetics and metabolism 22 15171999
2016 Screening of MCAD deficiency in Japan: 16years' experience of enzymatic and genetic evaluation. Molecular genetics and metabolism 21 27856190
2012 Sequencing from dried blood spots in infants with "false positive" newborn screen for MCAD deficiency. Molecular genetics and metabolism 21 23151387
1995 Facile and restricted pathways for the dissociation of octenoyl-CoA from the medium-chain fatty acyl-CoA dehydrogenase (MCAD)-FADH2-octenoyl-CoA charge-transfer complex: energetics and mechanism of suppression of the enzyme's oxidase activity. Biochemistry 21 7626613
2019 Quantitative Proteomics of Th-MYCN Transgenic Mice Reveals Aurora Kinase Inhibitor Altered Metabolic Pathways and Enhanced ACADM To Suppress Neuroblastoma Progression. Journal of proteome research 20 31560547
2007 Oxidative stress induction by cis-4-decenoic acid: relevance for MCAD deficiency. Free radical research 20 17987455
2020 Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review. Orphanet journal of rare diseases 19 31937333
2012 [Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management]. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 19 22244319
2006 Acute liver failure in pregnancy associated with maternal MCAD deficiency. Journal of inherited metabolic disease 19 17186412
1996 Prevalence of carriers of the most common medium-chain acyl-CoA dehydrogenase (MCAD) deficiency mutation (G985A) in The Netherlands. Human genetics 18 8682492
1993 Scottish frequency of the common G985 mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene and the role of MCAD deficiency in sudden infant death syndrome (SIDS). Journal of inherited metabolic disease 18 8127075
2023 Fenofibrate Attenuates Renal Tubular Cell Apoptosis by Up-Regulating MCAD in Diabetic Kidney Disease. Drug design, development and therapy 17 37223723
2000 A successful strategy for preimplantation diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Prenatal diagnosis 17 10913960
2022 Chaetomorpha linum polysaccharides alleviate NAFLD in mice by enhancing the PPARα/CPT-1/MCAD signaling. Lipids in health and disease 16 36529726
2010 A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report. Orphanet journal of rare diseases 16 20923556
2008 Newborn screening for MCAD deficiency: experience of the first three years in British Columbia, Canada. Canadian journal of public health = Revue canadienne de sante publique 16 18767270
2015 Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening. BMC medical genetics 15 26223887
2007 Assessment of the prevalence of the 985A>G MCAD mutation in the French-Canadian population using allele-specific PCR. Clinical genetics 15 17539907
1993 Three RFLPs defining a haplotype associated with the common mutation in human medium-chain acyl-CoA dehydrogenase (MCAD) deficiency occur in Alu repeats. American journal of human genetics 15 8099254
2023 A gene therapy targeting medium-chain acyl-CoA dehydrogenase (MCAD) did not protect against diabetes-induced cardiac pathology. Journal of molecular medicine (Berlin, Germany) 14 37987775
2015 Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan. Molecular genetics and metabolism 14 26947917
2021 Genotype and residual enzyme activity in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: Are predictions possible? Journal of inherited metabolic disease 13 33580884
2018 Phosphorylation of MCAD selectively rescues PINK1 deficiencies in behavior and metabolism. Molecular biology of the cell 13 29563254
2017 Establishing core outcome sets for phenylketonuria (PKU) and medium-chain Acyl-CoA dehydrogenase (MCAD) deficiency in children: study protocol for systematic reviews and Delphi surveys. Trials 13 29258568
2005 Newborns with C8-acylcarnitine level over the 90th centile have an increased frequency of the common MCAD 985A>G mutation. Journal of inherited metabolic disease 13 15902558
1992 Identification of a new mutation in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. American journal of human genetics 13 1729890
2024 ACADM inhibits AMPK activation to modulate PEDV-induced lipophagy and β-oxidation for impairing viral replication. The Journal of biological chemistry 11 39002673
2014 Functional studies of 18 heterologously expressed medium-chain acyl-CoA dehydrogenase (MCAD) variants. Journal of inherited metabolic disease 11 24966162
1994 Molecular genetic characterization and urinary excretion pattern of metabolites in two families with MCAD deficiency due to compound heterozygosity with a 13 base pair insertion in one allele. Journal of inherited metabolic disease 11 7967471
2012 Sudden unexpected infant death (SUDI) in a newborn due to medium chain acyl CoA dehydrogenase (MCAD) deficiency with an unusual severe genotype. Italian journal of pediatrics 10 23095120
1995 Prenatal diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in a family with a previous fatal case of sudden unexpected death in childhood. Prenatal diagnosis 10 7740006
1994 Characterization of wild-type human medium-chain acyl-CoA dehydrogenase (MCAD) and mutant enzymes present in MCAD-deficient patients by two-dimensional gel electrophoresis: evidence for post-translational modification of the enzyme. Biochemical medicine and metabolic biology 10 7917465
2000 Preimplantation genetic diagnosis for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Molecular human reproduction 9 11101700
2013 Regional differences in the frequency of the c.985A>G ACADM mutation: findings from a meta-regression of genotyping and screening studies. Clinical genetics 8 23574375
2022 MCAD activation by empagliflozin promotes fatty acid oxidation and reduces lipid deposition in NASH. Journal of molecular endocrinology 7 35900373
2005 Two novel variants of human medium chain acyl-CoA dehydrogenase (MCAD). K364R, a folding mutation, and R256T, a catalytic-site mutation resulting in a well-folded but totally inactive protein. The FEBS journal 6 16128823
2024 MiR-26a Inhibits Porcine Adipogenesis by Regulating ACADM and ACSL1 Genes and Cell Cycle Progression. Animals : an open access journal from MDPI 5 39682455
2009 Mutation screening of the medium-chain acyl-CoA dehydrogenase (MCAD) and the ornithine transcarbamylase (OTC) genes by multiplex PCR amplification and sequencing. Clinical chemistry and laboratory medicine 5 19055470
2001 Public health explores expanding newborn screening for cystic fibrosis, congenital adrenal hyperplasia, and medium-chain acyl coenzyme A dehydrogenase deficiency (MCAD). The Journal of the Oklahoma State Medical Association 5 11392180
2018 Medium-chain acyl-CoA dehydrogenase deficiency: Two novel ACADM mutations identified in a retrospective screening. The Journal of international medical research 4 29350094
1995 [Screening of A985 to G mutation of medium-chain acyl-CoA dehydrogenase (MCAD) gene in Normandy. Evaluation of the role of MCAD deficiency in sudden infant death]. Comptes rendus des seances de la Societe de biologie et de ses filiales 4 8590228
2023 Classical Swine Fever Virus Structural Glycoprotein E2 Interacts with Host Protein ACADM during the Virus Infectious Cycle. Viruses 3 37243123
2022 ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency. Genes 3 36292732
2015 Intermediate MCAD Deficiency Associated with a Novel Mutation of the ACADM Gene: c.1052C>T. Case reports in genetics 3 26798524
2004 [Deficiency of the fatty-acid oxidising enzyme medium-chain acyl-CoA dehydrogenase (MCAD) in an adult, detected during a neonatal screening programme]. Nederlands tijdschrift voor geneeskunde 3 15559414
1997 Rapid testing for the MCAD G583A mutation, by PCR-mediated site directed mutagenesis, in an Australian population of SIDS patients. Disease markers 3 9160189
2025 NRF2-REGγ-ACADM/KLF15 Signaling Pathway Regulates the Browning of White Adipose Tissue to Modulate Obesity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 40971725
2023 Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase. Biochimica et biophysica acta. Molecular basis of disease 2 37257730
2012 Macro-AST: misleading finding in an adolescent with MCAD-deficiency. BMC gastroenterology 2 22935320
2000 Mutation 985A>G in the MCAD gene shows low incidence in Estonian population. Human mutation 2 10679947
1999 Prevalence of the 985A>G mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in Sweden. Scandinavian journal of clinical and laboratory investigation 2 10463467
1992 [Medium chain acyl-CoA dehydrogenase (MCAD) deficiency: a life-threatening defect of fatty acid oxidation]. Ugeskrift for laeger 2 1539377
2023 [Analysis of clinical characteristics and ACADM gene variants in four children with Medium chain acyl-CoA dehydrogenase deficiency]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 37368378
2023 [Diosgenin alleviates NAFLD induced by a high-fat diet in rats via mTOR/SREBP-1c/HSP60/MCAD/SCAD signaling pathway]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 1 38114120
2013 A Large Intragenic Deletion in the ACADM Gene Can Cause MCAD Deficiency but is not Detected on Routine Sequencing. JIMD reports 1 23546811
2009 A985G mutation incidence in the medium-chain acyl-CoA dehydrogenase (MCAD) gene in Brazil. Genetics and molecular research : GMR 1 19551636
2026 Tachycardiomyopathy-like presentation in neonatal MCAD deficiency: A novel cardiac phenotype. European journal of medical genetics 0 41611076
2026 Exploring Deleterious Nonsynonymous SNPs in the ACADM Gene: Insights Into Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) via In Silico Analysis. Genetics research 0 41767627
2026 ACADM-mediated fatty acid β-oxidation pathway in atherosclerosis and abdominal aortic aneurysm. European heart journal 0 42247143
2025 [Down-regulation of ACADM-mediated lipotoxicity inhibits invasion and metastasis of estrogen receptor-positive breast cancer cells]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 40579130
2025 Transcriptomic and single-cell insights into mitochondrial genes NDUFA8, ECI2, and ACADM in acute myocardial infarction. Gene 0 40619072
1999 Screening of the most common medium-chain acyl CoA dehydrogenase (MCAD) deficiency mutation (K329E) in the Czech newborn population. The Southeast Asian journal of tropical medicine and public health 0 11400780
1988 [Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in 2 patients with symptoms of Reye syndrome]. Tijdschrift voor kindergeneeskunde 0 3046055

Missed literature

Know a paper Affinage missed for ACADM? Flag it for the maintainers and the community.

No submissions yet.