Fungicidal Activity of Phosphinic Analogues of Amino Acids Involved in Methionine Metabolism

Zhukov, Yu. N.; Vavilova, N. A.; Osipova, T. I.; Voinova, T. M.; Khurs, Elena N.; Dzhavakhia, V. G.; Khomutov, R. M.

doi:10.1023/b:dobi.0000039465.65071.6e

Doklady Biochemistry and Biophysics

2004

DOI: 10.1023/b:dobi.0000039465.65071.6e

|View full text |Cite

Fungicidal Activity of Phosphinic Analogues of Amino Acids Involved in Methionine Metabolism

Yu. N. Zhukov

N. A. Vavilova

T. I. Osipova

et al.

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Citation Types

Supporting

Mentioning

Contrasting

Year Published

2005

Publication Types

Select...

Article1

Relationship

Self Cite0

Independent1

Authors

Journals

Cited by 1 publication

(1 citation statement)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Limited pathways for biodegradation of the C−P bond () ensure that phosphonates, upon entering cells, will not be quickly metabolized to ineffective species. Indeed, several phosphonate analogues of α-keto and α-amino acids have been successfully used to target specific pathways in intact cells and organisms ( , ). These considerations suggest that the phosphonate analogues of KG will specifically target cellular KGDHC.…”

mentioning

confidence: 99%

Phosphonate Analogues of α-Ketoglutarate Inhibit the Activity of the α-Ketoglutarate Dehydrogenase Complex Isolated from Brain and in Cultured Cells

et al. 2005

View full text Add to dashboard Cite

The alpha-ketoglutarate dehydrogenase complex (KGDHC), a control point of the tricarboxylic acid cycle, is partially inactivated in brain in many neurodegenerative diseases. Potent and specific KGDHC inhibitors are needed to probe how the reduced KGDHC activity alters brain function. Previous studies showed that succinyl phosphonate (SP) effectively inhibits muscle and Escherichia coli KGDHC [Biryukov, A. I., Bunik, V. I., Zhukov, Yu. N., Khurs, E. N., and Khomutov, R. M. (1996) FEBS Lett. 382, 167-170]. To identify the phosphonates with the highest affinity toward brain KGDHC and with the greatest effect in living cells, we investigated the ability of SP and several of its ethyl esters to inhibit brain KGDHC, other alpha-keto acid-dependent enzymes, and KGDHC in intact cells. At a concentration of 0.01 mM, SP and its phosphonoethyl (PESP) and carboxyethyl (CESP) esters completely inhibited isolated brain KGDHC even in the presence of a 200-fold higher concentration of its substrate [alpha-ketoglutarate (KG)], while the diethyl (DESP) and triethyl (TESP) esters were ineffective. In cultured human fibroblasts, 0.01 mM SP, PESP, or CESP produced 70% inhibition of KGDHC. DESP and TESP were also inhibitory in the cell system, but only after preincubation, suggesting the release of their charged groups by cellular esterases. Thus, SP and its monoethyl esters target cellular KGDHC directly, while the di- and triethyl esters are activated in intact cells. When tested on other enzymes that bind KG or related alpha-keto acids, SP had minimal effects and its two esters (CESP and TESP) were ineffective even at a concentration (0.1 mM) 1 order of magnitude higher than that which inhibited cellular KGDHC activity. The high specificity in targeting KGDHC, penetration into cells, and minimal transformation by cellular enzymes indicate that SP and its esters should be useful in studying the effects of reduced KGDHC activity on neuronal and brain function.

show abstract

mentioning

confidence: 99%

Phosphonate Analogues of α-Ketoglutarate Inhibit the Activity of the α-Ketoglutarate Dehydrogenase Complex Isolated from Brain and in Cultured Cells

et al. 2005

View full text Add to dashboard Cite

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

hi@scite.ai

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

Fungicidal Activity of Phosphinic Analogues of Amino Acids Involved in Methionine Metabolism

Cited by 1 publication

References 2 publications

Phosphonate Analogues of α-Ketoglutarate Inhibit the Activity of the α-Ketoglutarate Dehydrogenase Complex Isolated from Brain and in Cultured Cells

Phosphonate Analogues of α-Ketoglutarate Inhibit the Activity of the α-Ketoglutarate Dehydrogenase Complex Isolated from Brain and in Cultured Cells

Contact Info

Product

Resources

About