Affinage

DHTKD1

2-oxoadipate dehydrogenase complex component E1 · UniProt Q96HY7

Length
919 aa
Mass
103.1 kDa
Annotated
2026-04-28
18 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DHTKD1 is the E1 (thiamine diphosphate-dependent dehydrogenase) component of a mitochondrial 2-oxoadipate dehydrogenase complex that catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA, the penultimate step in lysine and tryptophan catabolism (PMID:23141293, PMID:32695416). DHTKD1 assembles with DLST (E2) and DLD (E3) into a megacomplex and also forms a hybrid complex with OGDH, which explains residual glutaryl-CoA production in DHTKD1-deficient cells (PMID:32160276, PMID:32695416). Crystal structures reveal an active site adapted from the OGDH scaffold to accommodate the longer 2-oxoadipate substrate, and disease-associated missense variants disrupt folding, thermal stability, or DLST interaction (PMID:32695416, PMID:32633484). Loss of function causes mitochondrial energy deficits, ROS accumulation, and Charcot–Marie–Tooth type 2-like peripheral neuropathy in mice, driven in part by 2-aminoadipic acid and 2-ketoadipic acid accumulation that dysregulates insulin secretion and myelin gene expression in Schwann cells (PMID:29661920, PMID:32169121, PMID:23141294).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2012 High

    Identification of DHTKD1 as the enzyme catalyzing oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA resolved the last unassigned step in the lysine degradation pathway.

    Evidence Lentiviral complementation of patient fibroblasts with wild-type DHTKD1 normalized 2-oxoadipate levels; deuterium-labeled substrate tracing confirmed the enzymatic step

    PMID:23141293

    Open questions at the time
    • Recombinant enzyme kinetics not yet determined at this point
    • Complex partners not identified
    • In vivo validation in animal models absent
  2. 2012 Medium

    Demonstrating that DHTKD1 haploinsufficiency impairs mitochondrial energy output established that the gene is rate-limiting for NAD+/NADH homeostasis, not just lysine catabolism.

    Evidence Transfection of heterozygous nonsense mutant into cells showed decreased ATP, NAD+, and NADH; nonsense-mediated mRNA decay confirmed by UPF1 silencing rescue

    PMID:23141294

    Open questions at the time
    • Single overexpression system; endogenous KO not performed
    • Contribution of substrate accumulation versus direct energy deficit not separated
  3. 2013 Medium

    Knockdown studies broadened DHTKD1's role beyond lysine catabolism by showing it is required for mitochondrial biogenesis, ROS homeostasis, and cell survival.

    Evidence siRNA knockdown in cultured cells caused impaired mitochondrial biogenesis, elevated ROS, growth retardation, and increased apoptosis

    PMID:24076469

    Open questions at the time
    • Whether these phenotypes are direct or secondary to metabolite accumulation was not resolved
    • In vivo confirmation lacking at this stage
  4. 2017 High

    Genetic epistasis in double-knockout mice placed DHTKD1 upstream of GCDH in lysine catabolism but revealed an alternative, DHTKD1-independent source of glutaryl-CoA in brain and liver.

    Evidence Dhtkd1−/−/Gcdh−/− mice still accumulated glutaric acid at levels comparable to Gcdh−/− single knockouts

    PMID:28545977

    Open questions at the time
    • Identity of the alternative enzyme producing glutaryl-CoA remains unknown
    • Tissue-specific contributions of DHTKD1 versus OGDH not quantified
  5. 2018 Medium

    A disease mechanism for DHTKD1-associated peripheral neuropathy was delineated: accumulated substrates 2-AAA and 2-KAA stimulate insulin secretion, which upregulates Egr2 in Schwann cells to alter myelin gene expression and cause axonal degeneration.

    Evidence Dhtkd1−/− mice developed CMT2-like neuropathy; metabolite feeding experiments and gene expression analysis in Schwann cells traced the signaling chain

    PMID:29661920

    Open questions at the time
    • Whether insulin-mediated Schwann cell damage is the sole neuropathy mechanism is untested
    • Human patient nerve pathology not examined
    • Rescue by metabolite reduction not demonstrated
  6. 2018 Medium

    DHTKD1 loss links mitochondrial ROS to inflammatory signaling through viperin induction, extending its functional relevance to mucosal immunity.

    Evidence shRNA knockdown in esophageal epithelial cells and patient fibroblasts increased ROS and viperin expression

    PMID:29669943

    Open questions at the time
    • Viperin induction mechanism (direct ROS effect or secondary) not determined
    • Relevance to eosinophilic esophagitis pathogenesis not causally established
  7. 2020 High

    Discovery that DHTKD1 forms a hybrid complex with OGDH, DLST, and DLD explained why DHTKD1-null cells retain partial 2-oxoadipate oxidation capacity, as OGDH can partially substitute.

    Evidence Co-immunoprecipitation in HEK-293 cells and CRISPR-KO lines showed physical interaction; glutarylcarnitine biomarker persisted in DHTKD1-KO cells

    PMID:32160276

    Open questions at the time
    • Stoichiometry and regulation of the hybrid versus homomeric complex not defined
    • Whether hybrid complex formation occurs in all tissues is unknown
  8. 2020 High

    Crystal structures of DHTKD1 at near-atomic resolution revealed the structural basis for 2-oxoadipate preference over 2-oxoglutarate and showed how disease variants impair folding, stability, or complex assembly.

    Evidence X-ray crystallography at 1.9 Å and 2.25 Å with ThDP cofactor; cryo-EM of DLST 24-mer core; activity and thermal stability assays of >10 missense variants

    PMID:32633484 PMID:32695416

    Open questions at the time
    • No structure of the intact megacomplex (DHTKD1–DLST–DLD)
    • Catalytic mechanism of the reductive acylation step not structurally resolved
    • Inhibitor binding modes not co-crystallized
  9. 2020 Medium

    A knock-in mouse model carrying a patient nonsense variant confirmed that DHTKD1 loss of function causes sensory defects, reduced large-axon diameter, and myelination abnormalities in peripheral nerves, consolidating the CMT2Q disease model.

    Evidence Dhtkd1Y486* knock-in mice phenotyped by histopathology, electron microscopy, behavioral testing, and metabolic assays

    PMID:32169121

    Open questions at the time
    • Gene therapy or substrate-reduction rescue not attempted
    • Whether the truncated 70-kDa isoform retains partial function in vivo is untested
  10. 2021 Medium

    DHTKD1 knockout impairs mitochondrial respiration but cells maintain proliferation through compensatory Akt/p38/ERK signaling, revealing homeostatic adaptation to chronic DHTKD1 loss.

    Evidence CRISPR-KO in HAP-1 cells with Seahorse respirometry and signaling pathway profiling

    PMID:34484123

    Open questions at the time
    • Whether compensatory signaling occurs in differentiated neurons or Schwann cells is unknown
    • Direct versus indirect activation of Akt/p38/ERK not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the alternative enzyme producing glutaryl-CoA in brain, the full structure and stoichiometry of the DHTKD1–DLST–DLD megacomplex, the tissue-specific balance between DHTKD1 and OGDH for 2-oxoadipate oxidation, and whether substrate-reduction therapy can rescue peripheral neuropathy.
  • Alternative glutaryl-CoA source in brain unidentified
  • Full megacomplex structure unavailable
  • No therapeutic rescue demonstrated in animal models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016829 lyase activity 3
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 5
Partners
DLDDLSTOGDH
Complex memberships
2-oxoadipate dehydrogenase complex (DHTKD1–DLST–DLD)Hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase complex (OGDH–DHTKD1–DLST–DLD)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 DHTKD1 encodes the enzyme that catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA, representing the last unresolved step in the L-lysine degradation pathway. Lentiviral expression of wild-type DHTKD1 normalized elevated 2-oxoadipate in patient-derived fibroblasts, and deuterium-labeled 2-oxoadipate accumulated only in non-complemented cells. Lentiviral complementation in patient fibroblasts, isotope-labeled metabolite tracing American journal of human genetics High 23141293
2012 DHTKD1 deficiency caused by a heterozygous nonsense mutation leads to impaired mitochondrial energy production, evidenced by decreased ATP, total NAD+, NADH, and NADH levels in transfected cells. Mutant mRNA and truncated protein are degraded by nonsense-mediated mRNA decay, rescued by UPF1 silencing. In vitro transfection, NMD inhibition by UPF1 silencing, ATP/NAD measurement American journal of human genetics Medium 23141294
2013 DHTKD1 suppression in cells leads to impaired mitochondrial biogenesis, increased reactive oxygen species (ROS), retarded cell growth, and increased apoptosis, demonstrating a role in mitochondrial biogenesis and function maintenance. siRNA knockdown, mitochondrial biogenesis assay, ROS measurement, apoptosis assay FEBS letters Medium 24076469
2017 Genetic epistasis in Dhtkd1-/-/Gcdh-/- double-knockout mice demonstrated that DHTKD1 acts upstream of glutaryl-CoA dehydrogenase (GCDH) in lysine degradation. Despite Dhtkd1 inhibition, glutaric acid still accumulated in brain and liver at levels similar to Gcdh-/- mice, revealing an alternative (unknown) enzymatic source of glutaryl-CoA. Double-knockout mouse model, metabolite quantification in brain and liver Biochimica et biophysica acta. Molecular basis of disease High 28545977
2018 Loss of DHTKD1 in Dhtkd1-/- mice causes CMT2-like peripheral neuropathy. Mechanistically, accumulated substrates 2-ketoadipic acid (2-KAA) and 2-aminoadipic acid (2-AAA) stimulate insulin biosynthesis and secretion; elevated insulin upregulates Egr2 in Schwann cells, which regulates myelin protein zero (Mpz) transcription, leading to myelin structure damage and axonal degeneration. Knockout mouse model, metabolite feeding experiments, gene expression analysis in Schwann cells Molecular and cellular biology Medium 29661920
2018 DHTKD1 loss-of-function increases ROS production and induces expression of viperin (a gene involved in Th2 cytokine production) in esophageal epithelial cells, linking mitochondrial dysfunction to inflammatory signaling. shRNA knockdown in esophageal epithelial cells and patient fibroblasts, ROS assay, gene expression JCI insight Medium 29669943
2020 DHTKD1 interacts with OGDH (oxoglutarate dehydrogenase), dihydrolipoyl succinyltransferase (DLST), and dihydrolipoamide dehydrogenase (DLD) to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex. OGDH can also use 2-oxoadipic acid as a substrate, explaining residual glutarylcarnitine production in DHTKD1-deficient cells. Co-immunoprecipitation, CRISPR-KO HEK-293 cells, glutarylcarnitine biomarker measurement Human molecular genetics High 32160276
2020 Crystal structure of human DHTKD1 at 1.9 Å resolution in complex with thiamine diphosphate cofactor reveals how the DHTKD1 active site is adapted from the 2-oxoglutarate dehydrogenase (OGDH) scaffold to preferentially accommodate the longer substrate 2-oxoadipate (2OA). A 4.7 Å cryo-EM reconstruction of the DLST catalytic core shows a 24-mer cubic scaffold for assembling DHTKD1 and DLD into a megacomplex. Disease-associated DHTKD1 missense variants disrupt complex formation either directly (DLST interaction) or indirectly (protein destabilization). X-ray crystallography (1.9 Å), single-particle electron microscopy (4.7 Å), interaction studies with disease variants IUCrJ High 32695416
2020 Crystal structure of DHTKD1 at 2.25 Å in complex with thiamine diphosphate identifies the active site architecture. Screening identified adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors. Ten disease-associated missense variants were found to cause impaired folding, reduced thermal stability, or absent/reduced enzyme activity, while three variants showed no abnormalities. X-ray crystallography (2.25 Å), high-throughput inhibitor screening, thermal stability assay, enzyme activity assay of variants ACS chemical biology High 32633484
2020 Two DHTKD1 protein isoforms (~130 kDa and ~70 kDa) exist in animal tissues but are not produced when human DHTKD1 is expressed in bacterial or yeast systems, suggesting animal-specific posttranslational modifications or processing. The 70-kDa isoform is N-terminally truncated but retains the active site; as the N-terminal domain of OGDH is required for multienzyme complex formation, the 70-kDa isoform may catalyze non-oxidative transformation of 2-oxo acids independently of the complex. Immunoblotting, mass spectrometry, heterologous expression in bacterial and yeast systems, phylogenetic analysis Biochemistry. Biokhimiia Medium 33045952
2020 Dhtkd1Y486* knock-in mice display sensory defects, reduced large axon diameter, abnormal myelination in peripheral nerves, mitochondrial accumulation, and elevated energy metabolism. Dhtkd1 expression in sciatic nerve was significantly lower in knock-in mice than wild-type, confirming loss of function. Knock-in mouse model, histopathology, electron microscopy, behavioral testing, metabolic assays Acta neuropathologica communications Medium 32169121
2021 DHTKD1 knockout in HAP-1 cells impairs mitochondrial structure and function (reduced respiration, less ATP production) while normal cell proliferation is maintained through compensatory mechanisms including increased mitochondrial content and activation of Akt, p38, and ERK signaling. CRISPR-KO (HAP-1 cells), mitochondrial respiration assay (Seahorse), signaling pathway analysis Frontiers in endocrinology Medium 34484123
2023 circDHTKD1 (a circular RNA derived from the DHTKD1 locus) directly sponges miR-338-3p in bronchial epithelial cells, thereby de-repressing ETS1 and activating ERK signaling to promote inflammatory cytokine production in an LPS-induced asthma model. Dual-luciferase reporter assay, siRNA knockdown, miRNA mimic/inhibitor transfection, cytokine ELISA Experimental and therapeutic medicine Low 37273760

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 83 23141293
2012 A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree. American journal of human genetics 60 23141294
2013 DHTKD1 is essential for mitochondrial biogenesis and function maintenance. FEBS letters 54 24076469
2018 Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis. JCI insight 45 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 27 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 11 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