Inhibition of the High Affinity Myo-Inositol Transport System A Common Mechanism of Action of Antibipolar Drugs?

The napEDABC genes of Bradyrhizobium japonicum encode the periplasmic nitrate reductase, an Mo-containing enzyme which catalyses the reduction of nitrate to nitrite when oxygen concentrations are limiting. In this bacterium, another set of genes, modABC, code for a high affinity ABC-type Mo transport system. A B. japonicum modA mutant has been obtained that is not capable of growing anaerobically with nitrate and lacks nitrate reductase activity. Under nitrate respiring conditions, when Mo concentrations are limiting, the B. japonicum modA mutant lacked both the 90 kDa protein corresponding to the NapA component of the periplasmic nitrate reductase, and the membrane-bound 25 kDa c-type cytochrome NapC. Regulatory studies using a napE–lacZ fusion indicated that napE expression was highly reduced in the modA mutant background when the cells were incubated anaerobically with nitrate under Mo-deficient conditions.

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THERAPIE EINES METASTASIERENDEN INSELZELLTUMORS MIT STREPTOZOTOCIN

Acta Endocrinologica ◽

10.1530/acta.0.0670405 ◽

1971 ◽

Vol 67 (2) ◽

pp. 405-416 ◽

Cited By ~ 8

Author(s):

E. Nieschlag ◽

H. Wombacher ◽

F. J. Kroeger ◽

L.V. Habighorst

Keyword(s):

Liver Metastases ◽

Blood Sugar ◽

Mechanism Of Action ◽

Islet Cell ◽

Plasma Insulin ◽

Severe Hypoglycaemia ◽

Islet Cells ◽

Intravenous Injections ◽

High Affinity ◽

Methyl Nitrosourea

A patient with a metastazing functional islet cell tumour suffering from severe hypoglycaemia was treated with streptozotocin. Four intravenous injections of 1.5 g streptozotocin each were administered in 4 to 6 days intervals. After the 4th injection there were no further episodes of hypoglycaemia, parenteral glucose administration could be stopped and blood sugar and plasma insulin, showing concentrations of up to 405 μU/ml before treatment, reached normal levels. The tumours in the pancreas disappeared and the liver metastases decreased in size and number as judged by arteriography. A hypothesis for the mechanism of action of streptozotocin is proposed. The glucose moiety is considered to facilitate a high affinity to the islet cells whereas the N-methyl-nitrosourea residue serves the active antitumour part of the molecule.

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Faculty Opinions recommendation of A common mechanism of action for three mood-stabilizing drugs.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006228.86006 ◽

2002 ◽

Author(s):

Sally Temple

Keyword(s):

Mechanism Of Action ◽

Common Mechanism

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Faculty Opinions recommendation of A common mechanism of action for three mood-stabilizing drugs.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006228.81805 ◽

2002 ◽

Author(s):

Liang Tong

Keyword(s):

Mechanism Of Action ◽

Common Mechanism

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Faculty Opinions recommendation of Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736585207.793572723 ◽

2020 ◽

Author(s):

Gregg B Fields

Keyword(s):

Clinical Trials ◽

Mechanism Of Action ◽

Common Mechanism ◽

Cancer Drugs

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The interaction of divalent copper and the microsomal electron transport system. A re-examination of the effects of copper chelates on the function of cytochrome P-450.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)86393-7 ◽

1979 ◽

Vol 254 (23) ◽

pp. 11839-11846

Author(s):

J. Werringloer ◽

S. Kawano ◽

N. Chacos ◽

R.W. Estabrook

Keyword(s):

Electron Transport ◽

Transport System ◽

Electron Transport System ◽

Divalent Copper ◽

System A ◽

Copper Chelates ◽

Cytochrome P 450

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Bacteriophage-derived CHAP domain protein, P128, kills Staphylococcus cells by cleaving interpeptide cross-bridge of peptidoglycan

Microbiology ◽

10.1099/mic.0.079111-0 ◽

2014 ◽

Vol 160 (10) ◽

pp. 2157-2169 ◽

Cited By ~ 13

Author(s):

Sudarson Sundarrajan ◽

Junjappa Raghupatil ◽

Aradhana Vipra ◽

Nagalakshmi Narasimhaswamy ◽

Sanjeev Saravanan ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Mechanism Of Action ◽

Catalytic Domain ◽

Antibiotic Sensitivity ◽

High Sensitivity ◽

Common Mechanism ◽

Cross Bridge ◽

Sensitivity Pattern

P128 is an anti-staphylococcal protein consisting of the Staphylococcus aureus phage-K-derived tail-associated muralytic enzyme (TAME) catalytic domain (Lys16) fused with the cell-wall-binding SH3b domain of lysostaphin. In order to understand the mechanism of action and emergence of resistance to P128, we isolated mutants of Staphylococcus spp., including meticillin-resistant Staphylococcus aureus (MRSA), resistant to P128. In addition to P128, the mutants also showed resistance to Lys16, the catalytic domain of P128. The mutants showed loss of fitness as shown by reduced rate of growth in vitro. One of the mutants tested was found to show reduced virulence in animal models of S. aureus septicaemia suggesting loss of fitness in vivo as well. Analysis of the antibiotic sensitivity pattern showed that the mutants derived from MRSA strains had become sensitive to meticillin and other β-lactams. Interestingly, the mutant cells were resistant to the lytic action of phage K, although the phage was able to adsorb to these cells. Sequencing of the femA gene of three P128-resistant mutants showed either a truncation or deletion in femA, suggesting that improper cross-bridge formation in S. aureus could be causing resistance to P128. Using glutathione S-transferase (GST) fusion peptides as substrates it was found that both P128 and Lys16 were capable of cleaving a pentaglycine sequence, suggesting that P128 might be killing S. aureus by cleaving the pentaglycine cross-bridge of peptidoglycan. Moreover, peptides corresponding to the reported cross-bridge of Staphylococcus haemolyticus (GGSGG, AGSGG), which were not cleaved by lysostaphin, were cleaved efficiently by P128. This was also reflected in high sensitivity of S. haemolyticus to P128. This showed that in spite of sharing a common mechanism of action with lysostaphin, P128 has unique properties, which allow it to act on certain lysostaphin-resistant Staphylococcus strains.

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