A <i>Tetrahymena thermophila</i> G4-DNA Binding Protein with Dihydrolipoamide Dehydrogenase Activity

Kee, Kehkooi; Niu, Luming; Henderson, Eric

doi:10.1021/bi9716377

Cited by 20 publications

(11 citation statements)

References 30 publications

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“…36 E3 proteins isolated from pig heart and cow intestine bind to G4‐DNA of tetrahymina thermophila. 37 Binding of E3 to human or other mammalian DNA has not been described. E3 from yeast has been crystallized.…”

Section: Enzymology Of Kgdhc and Its Componentsmentioning

confidence: 99%

The α‐Ketoglutarate Dehydrogenase Complex

Sheu

Blass

1999

Annals of the New York Academy of Sciences

102

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The alpha-ketoglutarate dehydrogenase complex (KGDHC) is an important mitochondrial constituent, and deficiency of KGDHC is associated with a number of neurological disorders. KGDHC is composed of three proteins, each encoded on a different and well-characterized gene. The sequences of the human proteins are known. The organization of the proteins into a large, ordered multienzyme complex (a "metabolon") has been well studied in prokaryotic and eukaryotic species. KGDHC catalyzes a critical step in the Krebs tricarboxylic acid cycle, which is also a step in the metabolism of the potentially excitotoxic neurotransmitter glutamate. A number of metabolites modify the activity of KGDHC, including inactivation by 4-hydroxynonenal and other reactive oxygen species (ROS). In human brain, the activity of KGDHC is lower than that of any other enzyme of energy metabolism, including phosphofructokinase, aconitase, and the electron transport complexes. Deficiencies of KGDHC are likely to impair brain energy metabolism and therefore brain function, and lead to manifestations of brain disease. In general, the clinical manifestations of KGDHC deficiency relate to the severity of the deficiency. Several such disorders have been recognized: infantile lactic acidosis, psychomotor retardation in childhood, intermittent neuropsychiatric disease with ataxia and other motor manifestations, Friedreich's and other spinocerebellar ataxias, Parkinson's disease, and Alzheimer's disease (AD). A KGDHC gene has been associated with the first two and last two of these disorders. KGDHC is not uniformly distributed in human brain, and the neurons that appear selectively vulnerable in human temporal cortex in AD are enriched in KGDHC. We hypothesize that variations in KGDHC that are not deleterious during reproductive life become deleterious with aging, perhaps by predisposing this mitochondrial metabolon to oxidative damage.

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Section: Enzymology Of Kgdhc and Its Componentsmentioning

confidence: 99%

The α‐Ketoglutarate Dehydrogenase Complex

Sheu

Blass

1999

Annals of the New York Academy of Sciences

102

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“…3 The unique structure of the G4-DNA consists of stacked G quartets, where each G quartet is a planar aggregate of four hydrogen-bonded G nucleotides arranged in a squarelike configuration. 3 The G4-DNA can be formed spontaneously in many G-rich sequences, including telomeres, ribosomal DNA, minisatellites, and immunoglobulin heavy-chain switch regions, 4,5 while the long uniform samples can be synthesized from poly͑G͒-poly͑C͒ molecules ͑C: cytosine͒. 6 The G4-DNA is of particular importance in the telomeric regions of all eukaryotic chromosomes as a target for anticancer agent 7,8 and is argued to play a regulatory role in gene transcription based on the genome-wide analysis.…”

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confidence: 99%

Effects of contact and efficient charge transport in G4-DNA molecules

Guo

Xiong

2009

Phys. Rev. B

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We report a theoretical study highlighting the fundamental effects of contact between molecule and electrodes and of the off-diagonal disorder on the transport properties of guanine-quadruplex DNA ͑G4-DNA͒ molecules. On the basis of the effective tight-binding model which simulates charge transport through G4-DNA, the transmission coefficient and localization length are numerically calculated by using the transfermatrix method. In contrast to the physical intuition that a strong coupling at the molecule-metal interface will lead to a large conductance, we find that the averaged transmission coefficient is decreased by increasing the coupling when the coupling strength surpasses a critical value and the optimal configuration of contact for efficient charge transport through G4-DNA is obtained. In addition, the localization length of G4-DNA, especially at band centers, is much larger than that of poly͑G͒-poly͑cytosine͒ molecules, suggesting that G4-DNA is potentially better as a conducting molecular wire than double-stranded DNA molecules. Several effectively delocalized states can be found in realistic G4-DNA molecules at low temperatures. These results may provide perspectives for experimental work aimed at controlling charge transport through DNA-based nanodevices.

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“…31 Another dehydrogenase, isolated from Tetrahymena thermophile (TPG2) binds to guanine-rich ssG4 structures in the bacterial DNA. 74 To explore DNA interactions with DLDH under cell-free conditions, we have analyzed the formation of a complex between the protein and phage lambda dsDNA (λ) as a model. Two tools were used in these analyses: gel electrophoretic band-shift assays and analytical ultracentrifugation.…”

Section: Dna-binding Properties Of Dldhmentioning

confidence: 99%

The moonlighting activities of dihydrolipoamide dehydrogenase: Biotechnological and biomedical applications

Fleminger

Dayan

2021

J of Molecular Recognition

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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.

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A Tetrahymena thermophila G4-DNA Binding Protein with Dihydrolipoamide Dehydrogenase Activity

Cited by 20 publications

References 30 publications

The α‐Ketoglutarate Dehydrogenase Complex

The α‐Ketoglutarate Dehydrogenase Complex

Effects of contact and efficient charge transport in G4-DNA molecules

The moonlighting activities of dihydrolipoamide dehydrogenase: Biotechnological and biomedical applications

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