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2-oxoadipate dehydrogenase complex
The 2-oxoadipate dehydrogenase complex (OADHC, OADHc) or α-ketoadipate dehydrogenase complex is a mitochondrial, multienzyme complex, most commonly known for its role in the degradation of lysine, tryptophan and hydroxylysine. It belongs to the 2-oxoacid dehydrogenase complex family.
The enzymatic activity of the 2-oxoadipate dehydrogenase complex can be summarized by the following reaction:
The OADHC can also process 2-oxopimelate, a non-native substrate, but does so over 100 times less efficiently than its natural substrate, 2-oxoadipate.
The OADHC consists of three distinct enzymatic components:
E1a is the E1 enzyme specific to 2-oxoadipate ("a"), while E2o is the E2 subunit shared by some 2-oxoacid ("o") complexes, such as the OADHC and the 2-oxoglutarate dehydrogenase complex (OGDC), but not by others like the pyruvate dehydrogenase complex (PDHC) or branched-chain α-ketoacid dehydrogenase complex (BCKDC).
OADHC catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA in the lysine and tryptophan degradation pathway. Glutaryl-CoA can act as an acyl group donor for lysine glutarylation, a non-enzymatic post-translational modification. OADHC itself has been shown to undergo autoglutarylation, which may inhibit its activity and create a feedback regulatory loop. The mitochondrial sirtuin SIRT5 can remove glutaryl groups in a NAD+-dependent manner.
The OADHC produces superoxide and hydrogen peroxide at levels comparable to the flavin site of Complex I, a known source of mitochondrial reactive oxygen species (ROS). However, its activity is much lower than that of other related enzymes—approximately sevenfold lower than the 2-oxoglutarate dehydrogenase complex (OGDC), fourfold lower than the pyruvate dehydrogenase complex (PDC), and about half that of the branched-chain α-ketoacid dehydrogenase complex (BCKDC).
ROS production increases when the NAD(P)H to NAD(P)+ ratio is high, but only during the forward reaction where 2-oxoadipate is converted into glutaryl-CoA. In contrast, reverse electron flow through isolated E3 with NADH does not generate ROS, indicating that full substrate turnover by the intact complex is required.
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2-oxoadipate dehydrogenase complex
The 2-oxoadipate dehydrogenase complex (OADHC, OADHc) or α-ketoadipate dehydrogenase complex is a mitochondrial, multienzyme complex, most commonly known for its role in the degradation of lysine, tryptophan and hydroxylysine. It belongs to the 2-oxoacid dehydrogenase complex family.
The enzymatic activity of the 2-oxoadipate dehydrogenase complex can be summarized by the following reaction:
The OADHC can also process 2-oxopimelate, a non-native substrate, but does so over 100 times less efficiently than its natural substrate, 2-oxoadipate.
The OADHC consists of three distinct enzymatic components:
E1a is the E1 enzyme specific to 2-oxoadipate ("a"), while E2o is the E2 subunit shared by some 2-oxoacid ("o") complexes, such as the OADHC and the 2-oxoglutarate dehydrogenase complex (OGDC), but not by others like the pyruvate dehydrogenase complex (PDHC) or branched-chain α-ketoacid dehydrogenase complex (BCKDC).
OADHC catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA in the lysine and tryptophan degradation pathway. Glutaryl-CoA can act as an acyl group donor for lysine glutarylation, a non-enzymatic post-translational modification. OADHC itself has been shown to undergo autoglutarylation, which may inhibit its activity and create a feedback regulatory loop. The mitochondrial sirtuin SIRT5 can remove glutaryl groups in a NAD+-dependent manner.
The OADHC produces superoxide and hydrogen peroxide at levels comparable to the flavin site of Complex I, a known source of mitochondrial reactive oxygen species (ROS). However, its activity is much lower than that of other related enzymes—approximately sevenfold lower than the 2-oxoglutarate dehydrogenase complex (OGDC), fourfold lower than the pyruvate dehydrogenase complex (PDC), and about half that of the branched-chain α-ketoacid dehydrogenase complex (BCKDC).
ROS production increases when the NAD(P)H to NAD(P)+ ratio is high, but only during the forward reaction where 2-oxoadipate is converted into glutaryl-CoA. In contrast, reverse electron flow through isolated E3 with NADH does not generate ROS, indicating that full substrate turnover by the intact complex is required.