Molecular Classification
Enzyme, Mitochondrial multienzyme complex, Oxidoreductase (specifically, a member of the mitochondrial α-ketoacid dehydrogenase family)
Other Names
Branched-chain alpha-ketoacid dehydrogenase complex, BCKDH complex, Branched-chain 2-oxo acid dehydrogenase complex, Branched-chain ketoacid dehydrogenase complex
Disease Roles
Maple syrup urine disease (MSUD), due to genetic defects in subunits or regulatory proteinsMetabolic disorders involving elevated branched-chain amino acids or their ketoacids, which are implicated in heart failure, type 2 diabetes mellitus, and nonalcoholic fatty liver disease when dysregulated

Branched-chain alpha-keto acid dehydrogenase complex Overview

The Branched-chain alpha-keto acid dehydrogenase complex is a large mitochondrial multienzyme assembly responsible for catalyzing the irreversible oxidative decarboxylation step in the breakdown pathway for three essential branched-chain amino acids: leucine, isoleucine, and valine. The reaction products feed into energy metabolism pathways such as gluconeogenesis and lipogenesis. The enzyme consists primarily of three components: * E1 component*: A thiamin-dependent decarboxylase encoded by BCKDHA/BCKDHB, forming an α₂β₂ heterotetramer. * E2 component*: A lipoate-dependent dihydrolipoyl transacylase encoded by DBT, transferring acyl groups onto coenzyme A. * E3 component*: A FAD-dependent dihydrolipoyl dehydrogenase encoded by DLD, transferring electrons from reduced lipoamide onto NAD⁺. Activity is tightly regulated through reversible phosphorylation mediated by branched chain ketoacid dehydrogenase kinase (BCKDK)—which inhibits—and phosphatases like PP2Cm—which activate it. Dysfunction due to genetic mutations leads directly to maple syrup urine disease—a severe metabolic disorder characterized by accumulation of toxic metabolites with neurological consequences if untreated. Pharmacological modulation focuses on inhibiting BCKDK rather than directly targeting the core catalytic subunits; several small molecules including certain antihypertensives have been shown preclinically to enhance residual enzymatic function via this route.

Mechanism of Action

Drugs targeting this molecule typically act by inhibiting its negative regulator (BCKDK), leading to dephosphorylation and activation of the enzyme complex. This increases catabolism of branched-chain amino acids and reduces their plasma concentrations.

Biological Functions

Catabolism of branched-chain amino acids (leucine, isoleucine, valine)
Energy production via conversion of amino acids into TCA cycle intermediates
Regulation of metabolic flux in response to nutritional and physiological states

Disease Associations

Maple syrup urine disease (MSUD), due to genetic defects in subunits or regulatory proteins
Metabolic disorders involving elevated branched-chain amino acids or their ketoacids, which are implicated in heart failure, type 2 diabetes mellitus, and nonalcoholic fatty liver disease when dysregulated

Safety Considerations

  • Overactivation can lead to excessive depletion of essential branched-chain amino acids.

Interacting Drugs

BT2 (3,6-dichlorobenzo[b]thiophene‑2‑carboxylic acid) and analogs such as BT2F and BT3—these are inhibitors of the regulatory kinase BCKDK that indirectly activate BCKDC by preventing its phosphorylation/inactivation
Angiotensin receptor blocker class antihypertensive drugs have been identified as potent inhibitors of the regulatory kinase BCKDK; this may indirectly increase activity of the BCKDC itself by reducing inhibitory phosphorylation

Associated Biomarkers

Biomarker
Plasma levels of branched-chain amino acids (leucine, isoleucine, valine) and their corresponding ketoacids serve as biomarkers for monitoring efficacy or dysfunction related to this enzyme's activity. Elevated levels indicate reduced function or inhibition; normalization suggests restored activity.