The human 2-oxoadipate dehydrogenase complex (OADHc) in L-lysine catabolism is involved
in the oxidative decarboxylation of 2-oxoadipate (OA) to glutaryl-CoA and NADH (+H+).
Genetic findings have linked the DHTKD1 encoding 2-oxoadipate dehydrogenase (E1a),
the first component of the OADHc, to pathogenesis of AMOXAD, eosinophilic esophagitis
(EoE), and several neurodegenerative diseases. A multipronged approach, including
circular dichroism spectroscopy, Fourier Transform Mass Spectrometry, and computational
approaches, was applied to provide novel insight into the mechanism and functional
versatility of the OADHc. The results demonstrate that E1a oxidizes a non-cognate
substrate 2-oxopimelate (OP) as well as OA through the decarboxylation step, but the
OADHc was 100-times less effective in reactions producing adipoyl-CoA and NADH from
the dihydrolipoamide succinyltransferase (E2o) and dihydrolipoamide dehydrogenase
(E3). The results revealed that the E2o is capable of producing succinyl-CoA, glutaryl-CoA,
and adipoyl-CoA. The important conclusions are the identification of: (i) the functional
promiscuity of E1a and (ii) the ability of the E2o to form acyl-CoA products derived
from homologous 2-oxo acids with five, six, and even seven carbon atoms. The findings
add to our understanding of both the OADHc function in the L-lysine degradative pathway
and of the molecular mechanisms leading to the pathogenesis associated with DHTKD1
variants.
