2-oxoisovalerate dehydrogenase

From Proteopedia

Human 2-oxoisovalerate dehydrogenase α (deepskyblue and cyan) and β (coral and orangered) subunit with phosphorylated Ser residue complex with thiamine diphosphate, glycerol, K+ ion (purple), Cl- ion (green) and Mn+2 ion (PDB code 1x80)

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1 Function
2 Disease
3 Structural highlights
4 3D structures of 2-oxoisovalerate dehydrogenase

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

References

↑ Aevarsson A, Seger K, Turley S, Sokatch JR, Hol WG. Crystal structure of 2-oxoisovalerate and dehydrogenase and the architecture of 2-oxo acid dehydrogenase multienzyme complexes. Nat Struct Biol. 1999 Aug;6(8):785-92. PMID:10426958 doi:10.1038/11563
↑ Wang YP, Qi ML, Li TT, Zhao YJ. Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD). Gene. 2012 Apr 25;498(1):112-5. doi: 10.1016/j.gene.2012.01.082. Epub 2012 Feb 3. PMID:22326532 doi:10.1016/j.gene.2012.01.082
↑ Wynn RM, Kato M, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT. Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation. Structure. 2004 Dec;12(12):2185-96. PMID:15576032 doi:10.1016/j.str.2004.09.013