Dihydrolipoamide dehydrogenase

Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an is_associated_with::enzyme that in humans is encoded by the DLD is_associated_with::gene. DLD is a is_associated_with::flavoprotein enzyme that oxidizes is_associated_with::dihydrolipoamide to is_associated_with::lipoamide.

Dihydrolipoamide dehydrogenase (DLD) is a mitochondrial enzyme that plays a vital role in energy metabolism in eukaryotes. This enzyme is required for the complete reaction of at least five different multi-enzyme complexes. Additionally, DLD is a flavoenzyme is_associated_with::oxidoreductase that contains a reactive is_associated_with::disulfide bridge and a FAD cofactor that are directly involved in catalysis. The enzyme associates into tightly bound is_associated_with::homodimers required for its enzymatic activity.

Structure
The protein encoded by the DLD gene comes together with another protein to form a dimer in the is_associated_with::central metabolic pathway. Several is_associated_with::amino acids within the catalytic pocket have been identified as important to DLD function, including R281 and N473. Although the overall fold of the human is_associated_with::enzyme is similar to that of is_associated_with::yeast, the human structure is different in that it has two loops that extend from the general protein structure and into the is_associated_with::FAD binding sites. When bound the NAD+ molecule, required for catalysis, is not close to the FAD moiety. However, when is_associated_with::NADH is bound instead, it is stacked directly op top of the FAD central structure. The current hE3 structures show directly that the disease-causing is_associated_with::mutations occur at three locations in the human enzyme: the is_associated_with::dimer interface, the is_associated_with::active site, and the FAD and NAD(+)-binding sites.

Function
The DLD homodimer functions as the E3 component of the is_associated_with::pyruvate, is_associated_with::α-ketoglutarate, and branched-chain amino acid-is_associated_with::dehydrogenase complexes and the glycine cleavage system, all in the mitochondrial matrix. In these complexes, DLD converts dihydrolipoic acid and NAD+ into lipoic acid and NADH. DLD also has is_associated_with::diaphorase activity, being able to catalyze the oxidation of is_associated_with::NADH to NAD+ by using different electron acceptors such as O2, labile is_associated_with::ferric iron, is_associated_with::nitric oxide, and is_associated_with::ubiquinone. DLD is thought to have a pro-oxidant role by reducing oxygen to a is_associated_with::superoxide or ferric to is_associated_with::ferrous iron, which then catalyzes production of is_associated_with::hydroxyl radicals. Diaphorase activity of DLD may have an antioxidant role through its ability to scavenge nitric oxide and to reduce ubiquinone to ubiquinol. The dihyrolipamide dehydrogenase gene is known to have multiple splice variants.

Moonlighting function
Certain DLD mutations can simultaneously induce the loss of a primary metabolic activity and the gain of a moonlighting proteolytic activity. The moonlighting proteolytic activity of DLD is revealed by conditions that destabilize the DLD homodimer and decrease its DLD activity. Acidification of the mitochondrial matrix, as a result of ischemia-reperfusion injury, can disrupt the quaternary structure of DLD leading to decreased is_associated_with::dehydrogenase activity and increased is_associated_with::diaphorase activity. The moonlighting proteolytic activity of DLD could also arise under pathological conditions. Proteolytic activity can further complicate the reduction in energy metabolism and an increase in oxidative damage as a result of decreased DLD activity and an increase in diaphorase activity respectively. With its proteolytic function, DLD removes a functionally vital domain from the N-terminus of frataxin, a mitochondrial protein involved in iron metabolism and antioxidant protection.

Clinical significance
In humans, mutations in DLD are linked to a severe disorder of infancy with is_associated_with::failure to thrive, is_associated_with::hypotonia, and is_associated_with::metabolic acidosis. DLD deficiency manifests itself in a great degree of variability, which has been attributed to varying effects of different DLD mutations on the stability of the protein and its ability to dimerize or interact with other components of the three α-ketoacid dehydrogenase complexes. With its proteolytic function, DLD causes a deficiency in is_associated_with::frataxin, which leads to the neurodegenerative and cardiac disease, is_associated_with::Friedreich ataxia. Future research hopes to assess how the proteolytic activity of DLD contributes to the symptoms of DLD deficiency, Friedreich ataxia, and ischemia reperfusion injury and whether this activity could be a target for therapy for these conditions.

Enzyme regulation
This protein may use the is_associated_with::morpheein model of is_associated_with::allosteric regulation.