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Showing DHTKD1 — E1A is a alias.

DHTKD1

2-oxoadipate dehydrogenase complex component E1 · UniProt Q96HY7

Length
919 aa
Mass
103.1 kDa
Annotated
2026-06-09
18 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DHTKD1 encodes the E1 component (2-oxoadipate dehydrogenase) that catalyzes the last unresolved step of L-lysine and tryptophan catabolism — the thiamine diphosphate (ThDP)-dependent oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA — established by functional complementation in patient fibroblasts where loss-of-function mutations cause accumulation of deuterium-labeled 2-oxoadipate that wild-type DHTKD1 restoration normalizes (PMID:23141293). Crystal structures of human DHTKD1 bound to ThDP define an active site modeled on 2-oxoglutarate dehydrogenase but specifically remodeled to accommodate the longer 2-oxoadipate substrate, and most disease-associated missense variants act by impairing protein folding/thermal stability or by disrupting partner interaction rather than by abolishing catalysis directly (PMID:32695416, PMID:32633484). Rather than acting alone, DHTKD1 assembles into a hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase megacomplex with OGDH, DLST, and DLD, with OGDH providing a redundant route to glutaryl-CoA from 2-oxoadipate when DHTKD1 is absent (PMID:32160276); this functional redundancy is reinforced in vivo, where DHTKD1 loss fails to rescue glutaric aciduria type I, indicating an alternative enzymatic source of glutaryl-CoA (PMID:28545977). Loss of DHTKD1 broadly compromises mitochondrial energetics — reducing ATP and respiration, impairing mitochondrial biogenesis, and elevating ROS (PMID:23141294, PMID:24076469, PMID:34484123). In peripheral nerve, DHTKD1 deficiency causes a CMT2Q-like neuropathy through a defined cascade in which accumulated 2-aminoadipate and 2-oxoadipate stimulate insulin secretion, elevating EGR2 in Schwann cells and dysregulating myelin protein zero (Mpz) to drive demyelination and axonal degeneration (PMID:29661920, PMID:32169121).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2012 High

    Identified the enzyme responsible for the previously unresolved oxidative decarboxylation of 2-oxoadipate, completing the L-lysine degradation pathway and assigning DHTKD1 a defined metabolic function.

    Evidence Lentiviral complementation in patient fibroblasts with deuterium-labeled metabolite tracing and exome sequencing

    PMID:23141293

    Open questions at the time
    • Did not resolve enzymatic mechanism or cofactor requirement directly
    • Did not establish complex membership or partner enzymes
  2. 2012 Medium

    Linked the catabolic defect to a bioenergetic consequence, showing DHTKD1 is required for mitochondrial energy production.

    Evidence siRNA knockdown in cells with biochemical measurement of ATP, NAD+, and NADH

    PMID:23141294

    Open questions at the time
    • Knockdown rather than clean genetic null
    • Mechanistic link between metabolite block and respiratory chain impairment not defined
  3. 2013 Medium

    Extended the bioenergetic phenotype to mitochondrial biogenesis and oxidative stress, connecting DHTKD1 loss to ROS, impaired growth, and apoptosis.

    Evidence siRNA knockdown with ATP, ROS, mitochondrial morphology, growth, and apoptosis assays

    PMID:24076469

    Open questions at the time
    • Single-lab knockdown without rescue
    • Causal ordering of ROS versus mitochondrial dysfunction unresolved
  4. 2017 High

    Tested whether blocking glutaryl-CoA production via DHTKD1 could rescue glutaric aciduria type I, revealing an alternative, DHTKD1-independent source of glutaryl-CoA.

    Evidence Dhtkd1-/-/Gcdh-/- double knockout mice with metabolite quantification in brain and liver

    PMID:28545977

    Open questions at the time
    • Did not identify the alternative enzyme producing glutaryl-CoA
    • Tissue-specific contribution of the redundant route not quantified
  5. 2018 High

    Defined the molecular cascade by which DHTKD1 loss causes CMT2Q peripheral neuropathy, linking substrate accumulation to a signaling axis controlling myelination.

    Evidence Dhtkd1 knockout mouse with electrophysiology, metabolite/insulin assays, Schwann cell Mpz/Egr2 analysis, and 2-AAA feeding rescue

    PMID:29661920

    Open questions at the time
    • Mechanism by which 2-AAA/2-KAA stimulate insulin secretion not defined
    • Relative contribution of metabolic versus signaling damage to axonal degeneration unclear
  6. 2018 Medium

    Showed DHTKD1 loss compromises mitochondrial function in additional epithelial cell contexts and links to viperin/Th2 cytokine biology.

    Evidence shRNA knockdown in esophageal epithelial cells and patient fibroblasts with mitochondrial function, ROS, and viperin readouts

    PMID:29669943

    Open questions at the time
    • Mechanism connecting DHTKD1 to viperin induction not established
    • Knockdown approach without genetic rescue
  7. 2020 High

    Established that DHTKD1 functions within a hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase megacomplex and that OGDH provides redundant 2-oxoadipate processing.

    Evidence Co-immunoprecipitation and CRISPR KO in HEK-293 cells with glutarylcarnitine quantification

    PMID:32160276

    Open questions at the time
    • Stoichiometry and architecture of the hybrid complex not fully resolved by this study
    • Conditions favoring DHTKD1 versus OGDH usage in vivo unknown
  8. 2020 High

    Provided atomic-resolution structural basis for DHTKD1 substrate preference and explained how disease variants act.

    Evidence X-ray crystallography of DHTKD1-ThDP (1.9 Å) plus EM of DLST core and disease-variant interaction studies

    PMID:32695416

    Open questions at the time
    • Full assembled megacomplex structure not solved at high resolution
    • Catalytic cycle intermediates not visualized
  9. 2020 High

    Confirmed substrate preference structurally, dissected the variant-folding/activity relationship, and identified the first DHTKD1 inhibitors.

    Evidence X-ray crystallography (2.25 Å), compound screening, enzyme activity, and thermal stability assays on a 10-variant panel

    PMID:32633484

    Open questions at the time
    • Three variants with no biochemical abnormality remain mechanistically unexplained
    • In vivo efficacy/selectivity of identified inhibitors not established
  10. 2020 Medium

    Identified animal-specific DHTKD1 isoforms and proposed a complex-independent role for an N-terminally truncated form.

    Evidence Partial purification, immunoblotting, mass spectrometry, recombinant expression, and structural peptide mapping

    PMID:33045952

    Open questions at the time
    • Functional role of the 70 kDa isoform inferred, not directly demonstrated
    • Post-translational mechanism generating the truncated form unknown
  11. 2020 Medium

    Validated a patient-relevant point mutation in vivo, recapitulating peripheral neuropathy with abnormal myelination and altered nerve mitochondria.

    Evidence Dhtkd1Y486* knock-in mouse with histopathology, nerve conduction, behavior, and mitochondrial morphology

    PMID:32169121

    Open questions at the time
    • Did not independently confirm the insulin/EGR2/Mpz cascade
    • Mitochondrial accumulation versus dysfunction relationship in nerve unresolved
  12. 2021 Medium

    Characterized cellular compensation to DHTKD1 loss, showing mitochondrial dysfunction is buffered by increased mitochondrial content and survival signaling.

    Evidence CRISPR KO in HAP-1 cells with Seahorse respiration, ATP, mitochondrial content, and Akt/p38/ERK signaling analysis

    PMID:34484123

    Open questions at the time
    • Trigger linking metabolic defect to Akt/p38/ERK activation not defined
    • Relevance of compensation to neuronal cell types not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the DHTKD1-independent enzyme producing glutaryl-CoA, the signal coupling 2-oxoadipate accumulation to insulin secretion and survival kinase activation, and the in vivo function of the truncated isoform remain unresolved.
  • Alternative glutaryl-CoA source unidentified
  • Sensor coupling substrate accumulation to insulin/EGR2 signaling unknown
  • Physiological role of 70 kDa isoform untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016829 lyase activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 2
Partners
DLDDLSTOGDH
Complex memberships
2-oxoglutarate/2-oxoadipate dehydrogenase hybrid complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 DHTKD1 encodes the enzyme mediating the last unresolved step in the L-lysine degradation pathway — oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA. Patient-derived fibroblasts with DHTKD1 loss-of-function mutations accumulated deuterium-labeled 2-oxoadipate, and lentiviral restoration of wild-type DHTKD1 normalized elevated 2-oxoadipate levels. Lentiviral complementation in patient fibroblasts, stable-isotope (deuterium-labeled) metabolite tracing, exome sequencing American journal of human genetics High 23141293
2012 DHTKD1 is required for mitochondrial energy production; silencing DHTKD1 in cells significantly decreased ATP, total NAD+, NADH, and NADH levels, consistent with impaired mitochondrial respiratory chain activity. siRNA knockdown of DHTKD1 in transfected cells; biochemical measurement of ATP, NAD+, and NADH American journal of human genetics Medium 23141294
2013 DHTKD1 knockdown impairs mitochondrial biogenesis and increases reactive oxygen species (ROS) production, leading to retarded cell growth and increased apoptosis; DHTKD1 expression level correlates directly with ATP production. siRNA knockdown; measurement of ATP, ROS, mitochondrial morphology, cell growth, and apoptosis assays FEBS letters Medium 24076469
2018 Loss of DHTKD1 in a mouse knockout model causes CMT2-like peripheral neuropathy phenotypes (progressive distal weakness, motor and sensory dysfunction, decreased nerve conduction velocity). Mechanistically, accumulated substrates 2-ketoadipic acid (2-KAA) and 2-aminoadipic acid (2-AAA) stimulate insulin secretion, and elevated insulin upregulates EGR2 in Schwann cells, which drives transcription of myelin protein zero (Mpz), leading to myelin damage and axonal degeneration. 2-AAA feeding reproduced CMT2Q-like phenotypes. Dhtkd1 knockout mouse model; electrophysiology; metabolite measurement in urine; insulin secretion assay; Schwann cell culture with Mpz/Egr2 expression analysis; 2-AAA feeding experiment Molecular and cellular biology High 29661920
2018 DHTKD1 loss reduces mitochondrial function in esophageal epithelial cells and patient fibroblasts; loss of DHTKD1 increases ROS production and induces viperin expression, a gene involved in Th2 cytokine production. shRNA knockdown in esophageal epithelial cells; patient fibroblasts; mitochondrial function assays; ROS measurement; viperin expression analysis JCI insight Medium 29669943
2020 DHTKD1 forms a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex with OGDH (oxoglutarate dehydrogenase), DLST (dihydrolipoyl succinyltransferase), and DLD (dihydrolipoamide dehydrogenase). In glutaryl-CoA dehydrogenase-deficient HEK-293 cells, DHTKD1 loss reduces glutarylcarnitine 2-fold, while OGDH accounts for the remaining production, demonstrating substrate overlap between DHTKD1 and OGDH for 2-oxoadipate. Co-immunoprecipitation in HEK-293 cells; CRISPR KO; glutarylcarnitine measurement; hybrid complex characterization Human molecular genetics High 32160276
2020 Crystal structure of human DHTKD1 solved at 1.9 Å resolution in complex with thiamine diphosphate (ThDP) cofactor. The active site is modeled on 2-oxoglutarate dehydrogenase but specifically engineered to preferentially accommodate the longer substrate 2-oxoadipate over 2-oxoglutarate. Disease-associated missense variants disrupt either DLST interaction or DHTKD1 protein stability. X-ray crystallography (1.9 Å); single-particle electron microscopy (4.7 Å reconstruction of DLST core); interaction studies with disease variants IUCrJ High 32695416
2020 Crystal structure of DHTKD1 with ThDP at 2.25 Å; identification of adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors. Most disease-associated missense variants showed impaired folding or reduced thermal stability combined with absent or reduced enzyme activity; three variants showed no biochemical abnormality. X-ray crystallography (2.25 Å); high-throughput and targeted compound screening; enzyme activity assays; thermal stability assays on 10 disease-associated variants ACS chemical biology High 32633484
2020 Two DHTKD1 isoforms (~130 kDa and ~70 kDa) were identified in animal tissues by immunoblotting and mass spectrometry. The 70 kDa isoform is truncated at the N-terminus but retains the active site. These isoforms were not produced upon recombinant expression of human DHTKD1 in bacterial or yeast systems, suggesting animal-specific post-translational regulation. The N-terminal domain (absent in the 70 kDa form) is required for multienzyme complex assembly, implying the 70 kDa form may catalyze non-oxidative decarboxylation independently of the complex. Partial purification of animal OADH; immunoblotting; mass spectrometry; recombinant expression in bacterial and yeast systems; peptide mapping on protein structure Biochemistry. Biokhimiia Medium 33045952
2020 A knock-in mouse model with the Dhtkd1Y486* mutation shows reduced DHTKD1 expression in sciatic nerve, peripheral neuropathy with reduced large axon diameter, abnormal myelination, sensory defects, mitochondrial accumulation in peripheral nerves, and elevated energy metabolic state. Knock-in mouse model (Dhtkd1Y486* point mutation); histopathology; nerve conduction studies; sensory/motor behavioral testing; mitochondrial morphology analysis Acta neuropathologica communications Medium 32169121
2021 DHTKD1 knockout in HAP-1 cells impairs mitochondrial structure and function (reduced mitochondrial respiration, less ATP production). Compensatory mechanisms include increased mitochondrial content and activation of Akt, p38, and ERK signaling pathways, allowing maintenance of normal cell proliferation despite metabolic impairment. CRISPR KO in HAP-1 cells; Seahorse mitochondrial respiration assay; ATP measurement; Western blot for signaling pathways; mitochondrial content quantification Frontiers in endocrinology Medium 34484123
2017 In Dhtkd1-/-/Gcdh-/- double knockout mice, DHTKD1 inhibition alone does not rescue the glutaric aciduria type I (GA-I) phenotype; double knockouts show similar glutaric acid accumulation in brain and liver as Gcdh-/- single knockouts, indicating an alternative enzymatic source of glutaryl-CoA independent of DHTKD1. Double knockout mouse model; metabolite quantification in brain and liver; behavioral phenotyping Biochimica et biophysica acta. Molecular basis of disease High 28545977

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. American journal of human genetics 88 23141293
2012 A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree. American journal of human genetics 59 23141294
2013 DHTKD1 is essential for mitochondrial biogenesis and function maintenance. FEBS letters 55 24076469
2018 Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis. JCI insight 46 29669943
2017 Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism. Biochimica et biophysica acta. Molecular basis of disease 44 28545977
2015 New Cases of DHTKD1 Mutations in Patients with 2-Ketoadipic Aciduria. JIMD reports 29 26141459
2018 DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice. Molecular and cellular biology 28 29661920
2020 DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo. Human molecular genetics 26 32160276
2021 Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk. Frontiers in endocrinology 20 34484123
2020 Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism. IUCrJ 20 32695416
2020 Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex. ACS chemical biology 14 32633484
2020 CMT2Q-causing mutation in the Dhtkd1 gene lead to sensory defects, mitochondrial accumulation and altered metabolism in a knock-in mouse model. Acta neuropathologica communications 12 32169121
2021 Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients. Genes 9 35052424
2020 Isoforms of the DHTKD1-Encoded 2-Oxoadipate Dehydrogenase, Identified in Animal Tissues, Are not Observed upon the Human DHTKD1 Expression in Bacterial or Yeast Systems. Biochemistry. Biokhimiia 8 33045952
2019 A Chinese pedigree with a novel mutation in GJB1 gene and a rare variation in DHTKD1 gene for diverse Charcot‑Marie‑Tooth diseases. Molecular medicine reports 6 30896807
2023 Circular RNA DHTKD1 targets miR‑338‑3p/ETS1 axis to regulate the inflammatory response in human bronchial epithelial cells. Experimental and therapeutic medicine 5 37273760
2021 Atypical presentation of Charcot-Marie-Tooth disease type 2Q by mutations on DHTKD1 and NTRK2 genes. Boletin medico del Hospital Infantil de Mexico 2 34571524
2023 A novel DHTKD1 gene mutation with ALS like presentation: a case report. Amyotrophic lateral sclerosis & frontotemporal degeneration 0 37880984

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