Solvent-assisted slow conversion of a dithiazole derivative produces a competitive inhibitor of peptide deformylase.

Biochimica Et Biophysica Acta
Alexander K BergD K Srivastava

Abstract

Due to its potential as an antibiotic target, E. coli peptide deformylase (PDF(Ec)) serves as a model enzyme system for inhibitor design. While investigating the structural-functional and inhibitory features of this enzyme, we unexpectedly discovered that 2-amino-5-mercapto-1,3,4-thiadiazole (AMT) served as a slow-binding inhibitor of PDF(Ec) when the above compound was dissolved only in dimethylformamide (DMF), but not in any other solvent, and allowed to age. The time dependent inhibitory potency of the DMF-dissolved AMT was correlated with the broadening of the inhibitor's 295 nm spectral band toward the visible region, concomitant with the increase in the mass of the parent compound by about 2-fold. These data led to the suggestion that DMF facilitated the slow dimerization of AMT (via the formation of a disulfide bond), and that the dimeric form of AMT served as an inhibitor for PDF(Ec). The latter is not caused by the simple oxidation of sulfhydryl groups by oxidizing agents such as H(2)O(2). Newly synthesized dimeric/dithiolated form of AMT ("bis-AMT") exhibited similar spectral and inhibitory features as given by the parent compound when incubated with DMF. The computer graphic modeling data revealed that bis-AMT could ...Continue Reading

References

Jan 1, 1975·Journal of the Chemical Society. Perkin Transactions 1·B J BroughtonD E Wright
May 14, 1968·Journal of Molecular Biology·J M Adams
Nov 14, 1996·Biochimica Et Biophysica Acta·M J SculleyW W Cleland
Jul 15, 1997·Analytical Biochemistry·Y Wei, D Pei
Jul 17, 1998·Journal of Molecular Biology·S RagusaT Meinnel
Dec 10, 1998·Nature Structural Biology·A BeckerA F Wagner
Feb 13, 2001·Antimicrobial Agents and Chemotherapy·J M ClementsM G Hunter
Apr 24, 2001·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·F MusianiS Ciurli
Dec 31, 2002·The EMBO Journal·Carmela GiglioneThierry Meinnel
Mar 11, 2003·Proteomics·Julia Elisabeth BandowMichael Hecker
Jun 1, 1964·Journal of Molecular Biology·K MARCKER, F SANGER
Oct 9, 2003·The Journal of Biological Chemistry·Alexandre SereroThierry Meinnel
Nov 26, 2003·Biochemical and Biophysical Research Communications·Mona D LeeDavid A Scheinberg
Jun 16, 2004·Cellular and Molecular Life Sciences : CMLS·C GiglioneT Meinnel
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Aug 3, 2004·Nature Reviews. Drug Discovery·Ismail Kola, John Landis
Jan 5, 2005·Biochemistry·Glenn S Van AllerZhihong Lai
Jul 5, 2005·Expert Opinion on Therapeutic Targets·C Giglione, T Meinnel
Jul 19, 2005·Current Medicinal Chemistry·R JainZ Yuan
Nov 18, 2005·Biochemical Pharmacology·Zhengyu Yuan, Richard J White
Apr 28, 2006·Antimicrobial Agents and Chemotherapy·Wen WangZhengyu Yuan
Jan 5, 2007·Journal of Medicinal Chemistry·Adrien BoularotThierry Meinnel
Feb 3, 2007·Journal of Computational Chemistry·Ruth HueyDavid S Goodsell
Mar 24, 2007·Inorganic Chemistry·Aramice Y S MalkhasianFerman A Chavez
Nov 29, 2007·Protein Science : a Publication of the Protein Society·Alexander K BergD K Srivastava
Dec 21, 2007·Bioorganic & Medicinal Chemistry Letters·Gang ShenDehua Pei
Apr 1, 1948·Journal of the American Chemical Society·R A MATHES, A J BEBER

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.