The 2-Oxoacid Dehydrogenase Complexes in Mitochondria Can Produce Superoxide/Hydrogen Peroxide at Much Higher Rates than Complex I

The α-ketoglutarate dehydrogenase complex in neurodegeneration

The 2-oxoglutarate dehydrogenase complex constitutes a mitochondrially localized tricarboxylic acid cycle multienzyme system responsible for the conversion of 2-oxoglutarate to succinyl-coenzyme A concomitant with NAD+ reduction. Although regulatory mechanisms of plant enzyme complexes have been characterized in vitro, little is known concerning their role in plant metabolism in situ. This issue has recently been addressed at the cellular level in nonplant systems via the use of specific phosphonate inhibitors of the enzyme. Here, we describe the application of these inhibitors for the functional analysis of the potato (Solanum tuberosum) tuber 2-oxoglutarate dehydrogenase complex. In vitro experiments revealed that succinyl phosphonate (SP) and a carboxy ethyl ester of SP are slow-binding inhibitors of the 2-oxoglutarate dehydrogenase complex, displaying greater inhibitory effects than a diethyl ester of SP, a phosphono ethyl ester of SP, or a triethyl ester of SP. Incubation of potato tuber slices with the inhibitors revealed that they were adequately taken up by the tissue and produced the anticipated effects on the in situ enzyme activity. In order to assess the metabolic consequences of the 2-oxoglutarate dehydrogenase complex inhibition, we evaluated the levels of a broad range of primary metabolites using an established gas chromatography-mass spectrometry method. We additionally analyzed the rate of respiration in both tuber discs and isolated mitochondria. Finally, we evaluated the metabolic fate of radiolabeled acetate, 2-oxoglutarate or glucose, and 13C-labeled pyruvate and glutamate following incubation of tuber discs in the presence or absence of either SP or the carboxy ethyl ester of SP. The data obtained are discussed in the context of the roles of the 2-oxoglutarate dehydrogenase complex in respiration and carbon-nitrogen interactions.

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Inhibition of 2-Oxoglutarate Dehydrogenase in Potato Tuber Suggests the Enzyme Is Limiting for Respiration and Confirms Its Importance in Nitrogen Assimilation

Mechanism-based inhibitors and both forward and reverse genetics have proved to be essential tools in revealing roles for specific enzymatic processes in cellular function. Here, we review experimental studies aimed at assessing the impact of OG (2-oxoglutarate) oxidative decarboxylation on basic cellular activities in a number of biological systems. After summarizing the catalytic and regulatory properties of the OGDHC (OG dehydrogenase complex), we describe the evidence that has been accrued on its cellular role. We demonstrate an essential role of this enzyme in metabolic control in a wide range of organisms. Targeting this enzyme in different cells and tissues, mainly by its specific inhibitors, effects changes in a number of basic functions, such as mitochondrial potential, tissue respiration, ROS (reactive oxygen species) production, nitrogen metabolism, glutamate signalling and survival, supporting the notion that the evolutionary conserved reaction of OG degradation is required for metabolic adaptation. In particular, regulation of OGDHC under stress conditions may be essential to overcome glutamate excitotoxicity in neurons or affect the wound response in plants. Thus, apart from its role in producing energy, the flux through OGDHC significantly affects nitrogen assimilation and amino acid metabolism, whereas the side reactions of OGDHC, such as ROS production and the carboligase reaction, have biological functions in signalling and glyoxylate utilization. Our current view on the role of OGDHC reaction in various processes within complex biological systems allows us a far greater fundamental understanding of metabolic regulation and also opens up new opportunities for us to address both biotechnological and medical challenges.

Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation.

The phosphonic acid functional group, which is characterized by a phosphorus atom bonded to three oxygen atoms (two hydroxy groups and one P=O double bond) and one carbon atom, is employed for many applications due to its structural analogy with the phosphate moiety or to its coordination or supramolecular properties. Phosphonic acids were used for their bioactive properties (drug, pro-drug), for bone targeting, for the design of supramolecular or hybrid materials, for the functionalization of surfaces, for analytical purposes, for medical imaging or as phosphoantigen. These applications are covering a large panel of research fields including chemistry, biology and physics thus making the synthesis of phosphonic acids a determinant question for numerous research projects. This review gives, first, an overview of the different fields of application of phosphonic acids that are illustrated with studies mainly selected over the last 20 years. Further, this review reports the different methods that can be used for the synthesis of phosphonic acids from dialkyl or diaryl phosphonate, from dichlorophosphine or dichlorophosphine oxide, from phosphonodiamide, or by oxidation of phosphinic acid. Direct methods that make use of phosphorous acid (H3PO3) and that produce a phosphonic acid functional group simultaneously to the formation of the P–C bond, are also surveyed. Among all these methods, the dealkylation of dialkyl phosphonates under either acidic conditions (HCl) or using the McKenna procedure (a two-step reaction that makes use of bromotrimethylsilane followed by methanolysis) constitute the best methods to prepare phosphonic acids.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-13-219.pdf

Phosphonic acid: Preparation and applications

Inhibition of pigeon breast muscle α-ketoglutarate dehydrogenase by phosphonate analogues of α-ketoglutarate

We consider a classical gas of particles in ℝ
 d
 interacting via a pair potential. We prove that in a given region of the (β, μ) plane, where β is the inverse temperature, and μ is the chemical potential, either the Gibbs state is unique or it does not exist. Our method uses a version of the well-known Dobrushin uniqueness theorem adapted for lattice systems with a noncompact spin space and proved by Dobrushin and Pechersky. The advantage of this version is that using it one needs to check Dobrushin's contraction condition not for all boundary configurations, but only for those that have spin values in some compact subset of the spin space.

Uniqueness of Gibbs State for Nonideal Gas in ℝ d : The Case of Pair Potentials

Phosphinic analogs of the key compounds of the metabolism of methionine were synthesized. The compounds obtained were selectively oxidized either at the phosphinic group or at the sulfur-containing fragment.

Synthesis of phosphinic analogs of sulfur-containing amino acids

The reaction of ketoximes with hypophosphorous acid resulted in previously unknown α-substituted-α-aminophosphinic acids, which were oxidized into the corresponding α-substituted-α-aminophosphonic acids

Synthesis of (α-substituted α-aminophosphinic and α-aminophosphonic acids

1.

A new method has been proposed for the synthesis of α-amino- and α-alkylaminophosphonic acids.




2.

N-formyl, N-trifluoroacetyl, and N-carbobenzoxy derivatives of α-aminophosphonic acids were synthesized.




3.

Methods were developed for obtaining monoesters of α-aminophosphonic acids.




4.

Formation of pyridoxamine from pyridoxal and α-aminoisobutylphosphonic acid was not found under conditions for nonenzymatic transamination.

Yu. N. Zhukov

Papers

Inhibition of pigeon breast muscle α-ketoglutarate dehydrogenase by phosphonate analogues of α-ketoglutarate

Uniqueness of Gibbs State for Nonideal Gas in ℝ d : The Case of Pair Potentials

Synthesis of phosphinic analogs of sulfur-containing amino acids

Synthesis of (α-substituted α-aminophosphinic and α-aminophosphonic acids

Organophosphorus analogs of biologically active compounds