The moonlighting activities of dihydrolipoamide dehydrogenase: Biotechnological and biomedical applications

Abstract

Dihydrolipoamide dehydrogenase (DLDH) is a homodimeric flavin-dependent enzyme that catalyzes the NAD + -dependent oxidation of dihydrolipoamide. The enzyme is part of several multi-enzyme complexes such as the Pyruvate Dehydrogenase system that transforms pyruvate into acetyl-co-A. Concomitantly with its redox activity, DLDH produces Reactive Oxygen Species (ROS), which are involved in cellular apoptotic processes. DLDH possesses several moonlighting functions. One of these is the capacity to adhere to metal-oxides surfaces. This was first exemplified by the presence of an exocellular form of the enzyme on the cell-wall surface of Rhodococcus ruber. This capability was evolutionarily conserved and identified in the human, mitochondrial, DLDH. The enzyme was modified with Arg-Gly-Asp (RGD) groups, which enabled its interaction with integrin-rich cancer cells followed by "integrin-assisted-endocytosis." This allowed harnessing the enzyme for cancer therapy. Combining the TiO 2 -binding property with DLDH's ROS-production, enabled us to develop several medical applications including improving oesseointegration of TiO 2 -based implants and photodynamic treatment for melanoma. The TiO 2 -binding sites of both the bacterial and human DLDH's were identified on the proteins' molecules at regions that overlap with the binding site of E3-binding protein (E3BP). This protein is essential in forming the multiunit structure of PDC. Another moonlighting activity of DLDH, which is described in this Review, is its DNA-binding capacity that may affect DNA chelation and shredding leading to apoptotic processes in living cells. The typical ROS-generation by DLDH, which occurs in association with its enzymatic activity and its implications in cancer and apoptotic cell death are also discussed.

High expression of cuproptosis-related gene DLD in relation to good prognosis and immune cells infiltration in colon cancer

“…The DLD gene encodes a member of the class I pyridine nucleotide-disul de oxidoreductase family that plays multiple roles in the decarboxylation of pyruvate and the oxidation of dihydrolipoamide and is involved in constituting α-keto acid dehydrogenase complexes (e.g. α-ketoglutarate dehydrogenase, αketoadipate dehydrogenase and glycine decarboxylase) 6, [23][24][25] .DLD is a mitochondrial respiration-dependent copper ion carrier induced novel regulated positive regulators of cell death that regulate copper-dependent cell death by affecting the tumor TCA cycle and the underlying biosynthetic processes that support tumor growth, which may provide new ideas for the therapeutic action of certain cancer-targeted drugs 5,26 . Previous studies have found that DLD is involved in constituting pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex, which are associated with several fatal metabolic diseases and have been identi ed as important metabolic targets in cancer [27][28][29][30] .…”

The cuproptosis related genes signature predicts the prognosis and correlates with the immune status of clear cell renal cell carcinoma

“…FDX1 may modulate TP73 tumor suppressor through IRP2 to regulate tumor suppression ( Zhang et al, 2020a ), and FDX1 may be a gene related to KIRC ( Khouja et al, 2022 ). DLD is a homodimeric flavin-dependent enzyme that catalyzes NAD + -dependent oxidation of dihydrolipoamide and participates in the TCA cycle to convert pyruvate to acetyl-CoA ( Fleminger and Dayan, 2021 ). DLD may destroy cancer cells by producing ROS and by chelation with DNA ( Dayan et al, 2019 ).…”

Hybrid Metabolic Activity-Related Prognostic Model and Its Effect on Tumor in Renal Cell Carcinoma

“…The dihydrolipoamide dehydrogenase encoded by the DLD gene is a homologous flavin-dependent enzyme that catalyses NAD + -dependent dihydrolipoamide oxidation. It is involved in regulating apoptosis by producing ROS, and its enzyme activity is associated with tumor and apoptotic cell death [ 27 ]. We hypothesised that higher expression of the DLD gene in the high-risk group might indicate more ROS production.…”