Abstract
The biological significance of the DHTKD1-encoded 2-oxoadipate dehydrogenase (OADH) remains obscure due to its catalytic redundancy with the ubiquitous OGDH-encoded 2-oxoglutarate dehydrogenase (OGDH). In this work, metabolic contributions of OADH and OGDH are discriminated by exposure of cells/tissues with different DHTKD1 expression to the synthesized phosphonate analogues of homologous 2-oxodicarboxylates. The saccharopine pathway intermediates and phosphorylated sugars are abundant when cellular expressions of DHTKD1 and OGDH are comparable, while nicotinate and non-phosphorylated sugars are when DHTKD1 expression is order(s) of magnitude lower than that of OGDH. Using succinyl, glutaryl and adipoyl phosphonates on the enzyme preparations from tissues with varied DHTKD1 expression reveals the contributions of OADH and OGDH to oxidation of 2-oxoadipate and 2-oxoglutarate in vitro. In the phosphonates-treated cells with the high and low DHTKD1 expression, adipate or glutarate, correspondingly, are the most affected metabolites. The marker of fatty acid β-oxidation, adipate, is mostly decreased by the shorter, OGDH-preferring, phosphonate, in agreement with the known OGDH dependence of β-oxidation. The longest, OADH-preferring, phosphonate mostly affects the glutarate level. Coupled decreases in sugars and nicotinate upon the OADH inhibition link the perturbation in glucose homeostasis, known in OADH mutants, to the nicotinate-dependent NAD metabolism.
Highlights
The biological significance of the dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1)-encoded 2-oxoadipate dehydrogenase (OADH) remains obscure due to its catalytic redundancy with the ubiquitous OGDH-encoded 2-oxoglutarate dehydrogenase (OGDH)
Transcriptomics (Fig. 2E) and proteomics (Fig. 2F) data indicate that in all the tissues the expression of E2o and E3 is comparable to the expression of the OGDH gene, and does not significantly increase when the DHTKD1 expression approaches that of OGDH
At very similar expressions of the OGDH, dihydrolipoamide succinyltransferase (DLST), and dihydrolipoamide dehydrogenase (DLD) transcripts (Fig. 2E) and proteins (Fig. 2F), the fully solubilized oxoglutarate dehydrogenase complex (OGDHC) activity in liver is an order of magnitude lower than that in skeletal muscles. This is obviously due to the stronger competition between the OGDH and DHTKD1-encoded proteins for E2o in the liver, where the expression of the two proteins is comparable, than in the skeletal muscles, where OGDH is expressed much more than DHTKD1 (Fig. 2E,F)
Summary
The biological significance of the DHTKD1-encoded 2-oxoadipate dehydrogenase (OADH) remains obscure due to its catalytic redundancy with the ubiquitous OGDH-encoded 2-oxoglutarate dehydrogenase (OGDH). The DHTKD1-knockout mice show the expected tissue-specific accumulation of 2-oxoadipate and its transamination product, 2-aminoadipate, especially upon the dietary intake of lysine, which is degraded via the OADHC-comprising pathway[24]. In good accord with such a complexity, the phenotypes and adaptations of human and animal organisms to the DHTKD1 mutations in vivo are highly conditional, obscuring specific molecular mechanisms linking the OADH-catalysed reaction to the decreased organismal fitness. No metabolic alterations other than the immediate and expected consequences of the downregulated OADH reaction are described Both DHTKD1 knockout animals and mutant patients may show accumulation of 2-oxoadipate, 2-aminoadipate and 2-hydroxyadipate in urine and/or plasma[11,12,13,23]. D/O is the ratio between the expression of DHTKD1 and OGDH + OGDHL genes at the mRNA and protein levels. n.d. – Not determined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
