Inhibition of pigeon breast muscle α&amp;#x2010;ketoglutarate dehydrogenase by phosphonate analogues of α&amp;#x2010;ketoglutarate

Bunik, Victoria I.; Biryukov, A.I.; Zhukov, Yu. N.

doi:10.1016/0014-5793(92)80518-l

Cited by 25 publications

(15 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously demonstrated that the phosphonate analogs succinylphosphonate (SP) and carboxy ethyl ester of SP (CESP) inhibited the 2-OGDHC activity markedly in a concentration-dependent manner, whereas the phosphono ethyl ester of SP (PESP) and triethyl ester of SP (TESP) gave less efficient inhibition in plant tissues (Araújo et al, 2008) which is a common feature of the inhibition, observed also in animal tissues (Bunik et al, 1992, 2005, 2009a). On the basis of these experiments we decided to concentrate our studies in illuminated leaf using the former two analogs.…”

Section: Resultsmentioning

confidence: 99%

“…Having the phosphonate residue instead of the leaving carboxyl group of 2OG, these synthetic inhibitors target the starting and rate-limiting E1o component of 2-oxoglutarate dehydrogenase complex in a highly specific manner, imitating the transition state of the E1o-catalyzed step (Bunik et al, 1992, 2005). Hence, application of such phosphonate analogs of 2OG mimics the state following a decrease in 2-OGDHC activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphonate Analogs of 2-Oxoglutarate Perturb Metabolism and Gene Expression in Illuminated Arabidopsis Leaves

Araújo¹,

Tohge²,

Nunes‐Nesi³

et al. 2012

Front. Plant Sci.

View full text Add to dashboard Cite

Although the role of the 2-oxoglutarate dehydrogenase complex (2-OGDHC) has previously been demonstrated in plant heterotrophic tissues its role in photosynthetically active tissues remains poorly understood. By using a combination of metabolite and transcript profiles we here investigated the function of 2-OGDHC in leaves of Arabidopsis thaliana via use of specific phosphonate inhibitors of the enzyme. Incubation of leaf disks with the inhibitors revealed that they produced the anticipated effects on the in situ enzyme activity. In vitro experiments revealed that succinyl phosphonate (SP) and a carboxy ethyl ester of SP are slow-binding inhibitors of the 2-OGDHC. Our results indicate that the reduced respiration rates are associated with changes in the regulation of metabolic and signaling pathways leading to an imbalance in carbon-nitrogen metabolism and cell homeostasis. The inducible alteration of primary metabolism was associated with altered expression of genes belonging to networks of amino acids, plant respiration, and sugar metabolism. In addition, by using isothermal titration calorimetry we excluded the possibility that the changes in gene expression resulted from an effect on 2-oxoglutarate (2OG) binding to the carbon/ATP sensing protein PII. We also demonstrated that the 2OG degradation by the 2-oxoglutarate dehydrogenase strongly influences the distribution of intermediates of the tricarboxylic acid (TCA) cycle and the GABA shunt. Our results indicate that the TCA cycle activity is clearly working in a non-cyclic manner upon 2-OGDHC inhibition during the light period.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphonate Analogs of 2-Oxoglutarate Perturb Metabolism and Gene Expression in Illuminated Arabidopsis Leaves

Araújo¹,

Tohge²,

Nunes‐Nesi³

et al. 2012

Front. Plant Sci.

View full text Add to dashboard Cite

show abstract

“…As a result, molecular basis of the selective regulation of the OGDH or OADH isoenzymes by the synthetic phosphonate inhibitors is revealed, providing new knowledge on the directed regulation of the target enzymes in cells and organisms. While SP, whose inhibition of OGDH was first published about three decades ago (Bunik et al, 1992), is by now wellrecognized as a specific and efficient inhibitor of OGDH in vivo, our development of a similar inhibitor of OADH opens new ways to study the poorly understood biological role of this isoenzyme. Moreover, pharmacological tools to specifically affect the OADH function may be of therapeutic significance, as regulation of the DHTKD1 expression is observed in a number of pathological conditions, including diabetes, obesity and malignant transformation.…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of 2-Oxoglutarate and 2-Oxoadipate Dehydrogenases by the Phosphonate Analogs of Their 2-Oxo Acid Substrates

et al. 2021

View full text Add to dashboard Cite

Phosphonate analogs of pyruvate and 2-oxoglutarate are established specific inhibitors of cognate 2-oxo acid dehydrogenases. The present work develops application of this class of compounds to specific in vivo inhibition of 2-oxoglutarate dehydrogenase (OGDH) and its isoenzyme, 2-oxoadipate dehydrogenase (OADH). The isoenzymes-enriched preparations from the rat tissues with different expression of OADH and OGDH are used to characterize their interaction with 2-oxoglutarate (OG), 2-oxoadipate (OA) and the phosphonate analogs. Despite a 100-fold difference in the isoenzymes ratio in the heart and liver, similar Michaelis saturations by OG are inherent in the enzyme preparations from these tissues (KmOG = 0.45 ± 0.06 and 0.27 ± 0.026 mM, respectively), indicating no significant contribution of OADH to the OGDH reaction, or similar affinities of the isoenzymes to OG. However, the preparations differ in the catalysis of OADH reaction. The heart preparation, where OADH/OGDH ratio is ≈ 0.01, possesses low-affinity sites to OA (KmOA = 0.55 ± 0.07 mM). The liver preparation, where OADH/OGDH ratio is ≈ 1.6, demonstrates a biphasic saturation with OA: the low-affinity sites (Km,2OA = 0.45 ± 0.12 mM) are similar to those of the heart preparation; the high-affinity sites (Km,1OA = 0.008 ± 0.001 mM), revealed in the liver preparation only, are attributed to OADH. Phosphonate analogs of C5-C7 dicarboxylic 2-oxo acids inhibit OGDH and OADH competitively to 2-oxo substrates in all sites. The high-affinity sites for OA are affected the least by the C5 analog (succinyl phosphonate) and the most by the C7 one (adipoyl phosphonate). The opposite reactivity is inherent in both the low-affinity OA-binding sites and OG-binding sites. The C6 analog (glutaryl phosphonate) does not exhibit a significant preference to either OADH or OGDH. Structural analysis of the phosphonates binding to OADH and OGDH reveals the substitution of a tyrosine residue in OGDH for a serine residue in OADH among structural determinants of the preferential binding of the bulkier ligands to OADH. The consistent kinetic and structural results expose adipoyl phosphonate as a valuable pharmacological tool for specific in vivo inhibition of the DHTKD1-encoded OADH, a new member of mammalian family of 2-oxo acid dehydrogenases, up-regulated in some cancers and associated with diabetes and obesity.

show abstract

“…The lack of specific knowledge on the role of OGDH in cancer metabolism and the recent development of the OGDH inhibitors selectively targeting the enzyme in vivo [ 20 - 22 ], prompted us to study the role of OGDH in cancer cell viability using the phosphonate analog of 2-oxoglutarate, succinyl phosphonate (SP). Binding to the enzyme as a tight transition-state analog [ 35 , 36 ], SP inhibits OGDH, the first rate-limiting component of the mitochondrial multi-enzyme complex of oxidative decarboxylation of 2-oxoglutarate, in a highly selective and efficient manner. This was demonstrated using different approaches in a number of in vivo and cellular ( in situ ) systems [ 20 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner

et al. 2016

View full text Add to dashboard Cite

2-Oxoglutarate dehydrogenase (OGDH) of the tricarboxylic acid (TCA) cycle is often implied to be inactive in cancer, but this was not experimentally tested. We addressed the question through specific inhibition of OGDH by succinyl phosphonate (SP). SP action on different cancer cells was investigated using indicators of cellular viability and reactive oxygen species (ROS), metabolic profiling and transcriptomics. Relative sensitivity of various cancer cells to SP changed with increasing SP exposure and could differ in the ATP- and NAD(P)H-based assays. Glioblastoma responses to SP revealed metabolic sub-types increasing or decreasing cellular ATP/NAD(P)H ratio under OGDH inhibition. Cancer cell homeostasis was perturbed also when viability indicators were SP-resistant, e.g. in U87 and N2A cells. The transcriptomics database analysis showed that the SP-sensitive cells, such as A549 and T98G, exhibit the lowest expression of OGDH compared to other TCA cycle enzymes, associated with higher expression of affiliated pathways utilizing 2-oxoglutarate. Metabolic profiling confirmed the dependence of cellular SP reactivity on cell-specific expression of the pathways. Thus, oxidative decarboxylation of 2-oxoglutarate is significant for the interdependent homeostasis of NAD(P)H, ATP, ROS and key metabolites in various cancer cells. Assessment of cell-specific responses to OGDH inhibition is of diagnostic value for anticancer strategies.

show abstract

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

Cited by 25 publications

References 9 publications

Phosphonate Analogs of 2-Oxoglutarate Perturb Metabolism and Gene Expression in Illuminated Arabidopsis Leaves

Phosphonate Analogs of 2-Oxoglutarate Perturb Metabolism and Gene Expression in Illuminated Arabidopsis Leaves

Selective Inhibition of 2-Oxoglutarate and 2-Oxoadipate Dehydrogenases by the Phosphonate Analogs of Their 2-Oxo Acid Substrates

Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner

Contact Info

Product

Resources

About