DLD - dismech genes

Normal function · from ai-gene-review (P09622, commit 79fe13b38970) · AI-generated, not KB evidence

DLD encodes dihydrolipoyl dehydrogenase (E3; dihydrolipoamide dehydrogenase, EC 1.8.1.4), a mitochondrial FAD-dependent, NAD+-linked flavoenzyme that functions as a homodimer with one FAD per subunit and a redox-active active-site disulfide. Its enzymatic role is to reoxidize the reduced (dihydro)lipoyl groups carried on the lipoyl-bearing domains of the E2/H components of several 2-oxoacid dehydrogenase systems, passing the electrons to NAD+ via FAD (regenerating the oxidized lipoyl cofactor for another catalytic cycle). DLD is a shared subunit: it serves as the common E3 component of the pyruvate dehydrogenase complex (PDH), the 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase complex (OGDH), the branched-chain alpha-ketoacid dehydrogenase complex (BCKDH), and the 2-oxoadipate dehydrogenase complex (OADH), and it is also the L protein of the mitochondrial glycine cleavage system. Through these complexes DLD contributes to pyruvate decarboxylation to acetyl-CoA, the tricarboxylic acid cycle, branched-chain amino acid catabolism, and lysine degradation. It resides mainly in the mitochondrial matrix, with a small nuclear pool of the 2-oxoglutarate dehydrogenase complex that supplies succinyl-CoA for KAT2A-mediated histone succinylation. Because the enzyme is shared across multiple complexes, loss-of-function variants cause dihydrolipoamide dehydrogenase (E3) deficiency, a combined disorder with features of maple syrup urine disease together with lactic acidosis and alpha-ketoglutaric aciduria.

Dihydrolipoyl dehydrogenase (E3) activity - the shared, defining function of DLD. As a FAD-dependent, NAD+-linked flavoenzyme homodimer, DLD reoxidizes the dihydrolipoyl groups on the lipoyl-bearing E2/H components of mitochondrial 2-oxoacid dehydrogenase complexes and the glycine cleavage system, transferring electrons to NAD+ via FAD. This single activity is used by the pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain alpha-ketoacid dehydrogenase and 2-oxoadipate dehydrogenase complexes.

molecular function: dihydrolipoyl dehydrogenase (NADH) activity · directly involved in: pyruvate decarboxylation to acetyl-CoA; 2-oxoglutarate decarboxylation to succinyl-CoA; branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA; glycine decarboxylation via glycine cleavage system · locations: mitochondrial matrix

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Pyruvate Dehydrogenase Deficiency	causative germline	mechanism: DLD-associated E3 hepatic and branched-chain ketoacid dysfunction; PDH complex component or phosphatase deficiency subtype: E3 deficiency scoped to subtype: E3 deficiency
Maple Syrup Urine Disease	untyped Causative	mechanism: Branched-Chain Alpha-Ketoacid Dehydrogenase Complex Deficiency scoped to subtype: Type III

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
pyruvate dehydrogenase E3 deficiency MONDO:0009529	AR	Definitive 2019-03-08	Pyruvate Dehydrogenase Deficiency causative
Leigh syndrome MONDO:0009723	AR	Definitive 2021-03-11	Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 1 not named Leigh Syndrome not named

Mechanism modules · computed from kb/

metabolic_intoxication_decompensation via Maple Syrup Urine Disease