Structure of monensic acid, a new biologically active compound

A, Agtarap; Chamberlin, James W.; Pinkerton, Mary; Steinrauf, L. K.

doi:10.1021/ja00998a062

Cited by 299 publications

(125 citation statements)

References 0 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Monensin is a well-known polyether antibiotic whose structure has been described (30) and which was isolated from Streptomyces cinnamonensis (31). It specifically exchanges Na ϩ for H ϩ , resulting in an elevated cytosolic Ca 2ϩ concentration and pH (32).…”

mentioning

confidence: 99%

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A

Fénéant

Potel

François³

et al. 2015

J Virol

View full text Add to dashboard Cite

In our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular pH, on the hepatitis C virus (HCV) life cycle. We showed that monensin inhibits HCV entry in a pangenotypic and dose-dependent manner. Monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. Interestingly, we demonstrated that HCV cell-to-cell transmission is dependent on the vesicular pH. Using the selective pressure of monensin, we selected a monensin-resistant virus which has evolved to use a new entry route that is partially pH and clathrin independent. Characterization of this mutant led to the identification of two mutations in envelope proteins, the Y297H mutation in E1 and the I399T mutation in hypervariable region 1 (HVR1) of E2, which confer resistance to monensin and thus allow HCV to use a pH-independent entry route. Interestingly, the I399T mutation introduces an N-glycosylation site within HVR1 and increases the density of virions and their sensitivity to neutralization with anti-apolipoprotein E (anti-ApoE) antibodies, suggesting that this mutation likely induces conformational changes in HVR1 that in turn modulate the association with ApoE. Strikingly, the I399T mutation dramatically reduces HCV cell-to-cell spread. In summary, we identified a mutation in HVR1 that overcomes the vesicular pH dependence, modifies the biophysical properties of particles, and drastically reduces cellto-cell transmission, indicating that the regulation by HVR1 of particle association with ApoE might control the pH dependence of cell-free and cell-to-cell transmission. Thus, HVR1 and ApoE are critical regulators of HCV propagation. IMPORTANCEAlthough several cell surface proteins have been identified as entry factors for hepatitis C virus (HCV), the precise mechanisms regulating its transmission to hepatic cells are still unclear. In our study, we used monensin A, an ionophore that is known to raise the intracellular pH, and demonstrated that cell-free and cell-to-cell transmission pathways are both pH-dependent processes. We generated monensin-resistant viruses that displayed different entry routes and biophysical properties. Thanks to these mutants, we highlighted the importance of hypervariable region 1 (HVR1) of the E2 envelope protein for the association of particles with apolipoprotein E, which in turn might control the pH dependency of cell-free and cell-to-cell transmission. H epatitis C virus (HCV) infection is a global public health problem affecting over 130 million individuals worldwide.Chronic HCV infection can result in liver cirrhosis and hepatocellular carcinoma (1). While previous interferon (IFN)-based therapies have been limited by drug resistance and marked toxicity (2), the recently clinically licensed direct-acting antivirals are expected to cure the large majority of infected patients without major adverse effects (3). Nevertheless, several challenges remain: high costs limit access to therapy ...

show abstract

mentioning

confidence: 99%

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A

Fénéant

Potel

François³

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…Abbreviations used in this paper: DCCD, NN'-dicyclohexylcarbodiimide; pH,, intracellular pH. (8). Little is known about the structure of Na+/H+ or K+/H+ antiporters from higher organisms, but two lines of evidence suggest that they are much more complex.…”

mentioning

confidence: 99%

Proton transport and cell function.

Ives¹,

Rector²

1984

J. Clin. Invest.

View full text Add to dashboard Cite

T he past five years have witnessed an explosion of information on the many and varied roles of H+ transport in cell function. H+ transport is involved in three broad areas of cell function: (a) maintenance and alteration of intracellular pH for initiation of specific cellular events, (b) generation of pH gradients in localized regions of the cell, including gradients involved in energy transduction, and (c) transepithelial ion transport. These processes each involve one or more of several H+ translocating mechanisms. The first section of this review will discuss these H+ translocating mechanisms and the second part will deal with the cellular functions controlled by H+ transport. Mechanisms of H+/OH-TransportPrimary active H+ transport Primary active H' transport mechanisms consume energy directly for the translocation of HW. This energy can be derived from redox reactions, light, or ATP. Since most of the primary active H+ translocating processes are electrogenic, their action will produce only a membrane potential difference unless there is some provision in the membrane for counter ion movement. This is usually accomplished by a simple conductive pathway through which Cl-can move in the same direction as, or cations (e.g., K+ or Na+) can move in the opposite direction to H+ transport. As will be seen below, some ofthe active H' transport mechanisms do generate primarily a membrane potential difference, while others move significant amounts of acid across membranes. To date, there are no known primary active OHor HCO-transport mechanisms.H+ translocation by the electron transport chain. In the mitochondrion, three electron transport complexes (reduced nic-

show abstract

“…Monensin, a monovalent cationic ionophore with high specificity for the sodium ion (2), inhibits the secretion and intracellular transport of several glycoproteins (10,11,23,31,33), and also alters sugar modification in the cell (14). Although t-H. Fukao, et al…”

mentioning

confidence: 99%

Effect of monensin on secretion of t-PA from melanoma (Bowes).

Fukao

Ueshima

Sakai

et al. 1989

Cell Struct. Funct.

View full text Add to dashboard Cite

ABSTRACT.The secretion of tissue-type plasminogen activator (t-PA) from melanoma cells (Bowes) was investigated with or without monensin treatment. Monensin inhibited secretion of t-PA from the cells to the medium in a dose-and time-dependent manner. The inhibition was accompanied by an intracellular accumulation of t-PA. Electrophoretic enzymography of the cell homogenate showed the main lytic zone at 72 kDa, which reacted with the IgG of anti-t-PA.Analysis of the cell organelles using ultracentrifugation with a discontinuous sucrose density gradient revealed that the activity and the antigen of t-PA were observed near the discontinuous phase of the sucrose gradient.Analysis of 3H-mannose-and 35S-methionine-labeled t-PA in the cell organelles revealed that the radioactivity of each was increased by monensin treatment, and that such treatment increased the ratio of 3H-mannose-related glycoprotein to 35S-methionine-related protein.The sugar chain of intracellular t-PA was analyzed with endoglycosidase H and N-glycanase, which reduced the molecular weight of t-PA by 4.5-10 kDa, indicating the intracellular presence of a high-mannose type sugar chain and a complex-type sugar chain of t-PA. t-PA secreted from the monensin-treated cells possesses a high-mannose type sugar chain only. Therefore, monensin alters the secretion of t-PA by abnormal glycosylation.

show abstract

Structure of monensic acid, a new biologically active compound

Cited by 299 publications

References 0 publications

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A

Proton transport and cell function.

Effect of monensin on secretion of t-PA from melanoma (Bowes).

Contact Info

Product

Resources

About