Receptor site and stereospecifity of dihydrolipoamide dehydrogenase for R- and S-lipoamide: a molecular modeling study

Raddatz, Günter; Bisswanger, Hans

doi:10.1016/s0168-1656(97)00135-1

Cited by 23 publications

(15 citation statements)

References 34 publications

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“…These compounds are cyclic disulfides and the corresponding reduced dithiol forms of the lipoyl moiety are used by several mitochondrial metabolic enzymes, including dihydrolipoyl transacetylase feeding into the TCA cycle and dihydrolipoamide succinyltransferase in the TCA cycle. The R-(+) isomer is reduced from the cyclic disulphide to the dithol state in cells by dihydrolipoamide dehydrogenase 38 , however its natural substrate is the lipoyl moiety rather than free lipoic acid. We determined whether 10 μM R-(+), S-(−) or racemic (±, a mix of both stereoisomers) lipoic acid also reduced stress granule formation in HeLa cells.…”

Section: Lipoamide Action In Cells Is Non-enzymatic and Non-antioxidantmentioning

confidence: 99%

Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models

Wheeler

Lee

Poser

et al. 2019

Preprint

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with few avenues for treatment.Many proteins implicated in ALS associate with stress granules, which are examples of liquid-like compartments formed by phase separation. Aberrant phase transition of stress granules has been implicated in disease, suggesting that modulation of phase transitions could be a possible therapeutic route. Here, we combine cell-based and protein-based screens to show that lipoamide, and its related compound lipoic acid, reduce the propensity of stress granule proteins to aggregate in vitro. More significantly, they also prevented aggregation of proteins over the life time of Caenorhabditis elegans. Observations that they prevent dieback of ALS patient-derived (FUS mutant) motor neuron axons in culture and recover motor defects in Drosophila melanogaster expressing FUS mutants suggest plausibility as effective therapeutics. Our results suggest that altering phase behaviour of stress granule proteins in the cytoplasm could be a novel route to treat ALS.

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Section: Lipoamide Action In Cells Is Non-enzymatic and Non-antioxidantmentioning

confidence: 99%

Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models

Wheeler

Lee

Poser

et al. 2019

Preprint

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“…28 The R‐enantiomer is >25‐fold more active as a substrate than the S‐enantiomer. 34 The amount of E3 found in mitochondria typically exceeds the amount required for the activity of the intramitochondrial complexes of which it is known to be a part (namely, KGDHC, PDHC, BCDHC). This finding has led to speculation that E3 may also have other roles in the transfer of electrons among substrates within mitochondria 28 including ascorbic acid 35 and ubiquinone.…”

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

104

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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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“…α-lipoic acid (ALA) is an organosulfur compound with antioxidant, anti-inflammatory, antifibrotic properties, and has been used successfully in a wide range of nonocular pathologies 6. It is a key contributor to hepatoprotection by improving liver circulation 7,8.…”

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confidence: 99%

Reduction of Conjunctival Fibrosis After Trabeculectomy Using Topical α-Lipoic Acid in Rabbit Eyes

Ekinci

Çağatay

Ceylan

et al. 2014

Journal of Glaucoma

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Purpose:To evaluate the efficacy of α-lipoic acid (ALA) in reducing scarring after trabeculectomy.Materials and Methods:Eighteen adult New Zealand white rabbits underwent trabeculectomy. During trabeculectomy, thin sponges were placed between the sclera and Tenon’s capsule for 3 minutes, saline solution, mitomycin-C (MMC) and ALA was applied to the control group (CG) (n=6 eyes), MMC group (MMCG) (n=6 eyes), and ALA group (ALAG) (n=6 eyes), respectively. After surgery, topical saline and ALA was applied for 28 days to the control and ALAGs, respectively. Filtrating bleb patency was evaluated by using 0.1% trepan blue. Hematoxylin and eosin and Masson trichrome staining for toxicity, total cellularity, and collagen organization; α-smooth muscle actin immunohistochemistry staining performed for myofibroblast phenotype identification.Results:Clinical evaluation showed that all 6 blebs (100%) of the CG had failed, whereas there were only 2 failures (33%) in the ALAG and no failures in the MMCG on day 28. Histologic evaluation showed significantly lower inflammatory cell infiltration in the ALAGs and CGs than the MMCG. Toxicity change was more significant in the MMCG than the control and ALAGs. Collagen was better organized in the ALAG than control and MMCGs. In immunohistochemistry evaluation, ALA significantly reduced the population of cells expressing α-smooth muscle action.Conclusions:ΑLA prevents and/or reduces fibrosis by inhibition of inflammation pathways, revascularization, and accumulation of extracellular matrix. It can be used as an agent for delaying tissue regeneration and for providing a more functional-permanent fistula.

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Receptor site and stereospecifity of dihydrolipoamide dehydrogenase for R- and S-lipoamide: a molecular modeling study

Cited by 23 publications

References 34 publications

Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models

Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models

The α‐Ketoglutarate Dehydrogenase Complex

Reduction of Conjunctival Fibrosis After Trabeculectomy Using Topical α-Lipoic Acid in Rabbit Eyes

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