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Target intelligence / Profile preview
ATP-dependent (S)-NAD(P)H-hydrate dehydratase (NAXD)
- Target
- NAXD
- Molecular classification
- Enzyme, Metabolite repair enzyme, Mitochondrial protein
01
Overview
ATP-dependent (S)-NAD(P)H-hydrate dehydratase (NAXD) is a highly conserved enzyme critical for cellular repairing of damaged NADH and NADPH cofactors, specifically the hydrated forms NAD(P)HX, which are redox-inactive and can inhibit various dehydrogenases essential for energy metabolism[2][6]. NAXD catalyzes the dehydration of the S-form of NAD(P)HX, restoring functional NAD(P)H to sustain essential metabolic pathways, particularly in mitochondria. Loss-of-function mutations in NAXD result in toxic metabolite accumulation, mitochondrial dysfunction, and severe multisystem disease, primarily affecting the heart, brain, and muscles. Clinical presentations typically follow physical or febrile stress, reflecting the enzyme's essential role in metabolite repair during increased metabolic demand. Deficiency is classified as a metabolite repair disorder with rapid, devastating consequences and limited therapeutic options[1][2][3][6].
- Other names
- ATP-dependent NAD(P)HX dehydrataseCarbohydrate kinase domain-containing proteinCARKDLP3298PEBEL2FLJ10769NAD(P)HX dehydratase
02
Mechanism of action
Niacin: increases overall NAD levels as a compensatory mechanism for defective NAD(P)HX repair in NAXD deficiency
03
Biological functions
Metabolite repair (removal of damaged NAD(P)H derivatives)Maintenance of cellular and mitochondrial NAD(P)H poolsSupports energy metabolism (glycolysis, TCA cycle, fatty acid β-oxidation, electron transport chain, pentose phosphate pathway, fatty acid synthesis)Prevention of toxic metabolite accumulationCell survival
04
Disease associations
Inborn errors of metabolism (IEM)Mitochondrial diseaseCardiomyopathy and heart failureMyopathySevere psychomotor regressionNeurodegenerationSkin lesionsSudden death after febrile illness
05
Safety considerations
Severe, rapid deterioration after febrile illnessEarly childhood deathMulti-organ failure, especially heart and brainNo established targeted therapies beyond experimental niacin supplementationHigh metabolic vulnerability of multiple tissues
06
Interacting drugs
Niacin
07
Biomarkers
Elevated lactic acidIncreased muscle enzymesReduced plasma nicotinamide metabolitesAltered TCA cycle intermediatesIncreased branched-chain amino acid levelsReduced plasmalogen, phosphatidylcholine, and sphingomyelin plasma levelsImpaired mitochondrial complex I and IV subunit expression
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