Function
2-oxoisovalerate dehydrogenase (OIVD) or branched-chain α-keto acid decarboxylase or branched-chain α-keto acid dehedrogenase is part of a multienzyme complex metabolizing pyruvate, 2-oxogluterate and branched-chain 2-oxo acids. The multienzyme complex (BCKDC) contains three catalytic components: OIVD, lipoamide acyltransferase and lipoamide dehydrogenase, a kinase and a phosphatase. The active site of OIVD contains the cofactor thiamin diphosphate (ThDP)[1].
The BCKDC complex consists of three main components: E1 (branched-chain alpha-keto acid decarboxylase), E2 (dihydrolipoyl transacylase), and E3 (dihydrolipoamide dehydrogenase). 2-Oxoisovalerate dehydrogenase, or the E1 component of the complex, is responsible for the decarboxylation of 2-oxoisovalerate, which is the alpha-keto acid derived from isoleucine.
The reaction catalyzed by 2-oxoisovalerate dehydrogenase involves the removal of a carboxyl group from 2-oxoisovalerate, leading to the formation of isobutyryl-CoA. This reaction is coupled with the reduction of NAD+ to NADH. The resulting isobutyryl-CoA can then enter further metabolic pathways, such as the TCA cycle, to generate energy or participate in biosynthesis.
The activity of the BCKDC complex, including 2-oxoisovalerate dehydrogenase, is tightly regulated. Various factors, such as the availability of BCAAs, energy status, and hormonal signals, can influence the activity of the complex through allosteric regulation and reversible phosphorylation.
Deficiencies or dysfunction in the BCKDC complex, including 2-oxoisovalerate dehydrogenase, can lead to metabolic disorders known as maple syrup urine disease (MSUD). In MSUD, there is impaired metabolism of BCAAs, resulting in the accumulation of toxic branched-chain alpha-keto acids and their derivatives. This can cause neurological symptoms, including intellectual disability and developmental delays.
Understanding the function and regulation of 2-oxoisovalerate dehydrogenase and the BCKDC complex is important for studying BCAA metabolism and the associated metabolic disorders.
Disease
Mutations in OIVD result in maple syrup urine disease characterized by mental and physical retardation and feeding problems[2].
Structural highlights
. The structure of the phosphorylated human OIVD shows the (water molecules shown as red spheres). Phosphorylation of Ser292 of the α subunit interferes with ThDP binding[3].
3D structures of 2-oxoisovalerate dehydrogenase
2-oxoisovalerate dehydrogenase 3D structures
