scholarly journals Computational Model for Membrane Transporters. Potential Implications for Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
María Florencia Carusela ◽  
J. Miguel Rubi
Keyword(s):  
Computational Model ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Transport Proteins ◽  
Membrane Transporters ◽  
Electrochemical Gradient ◽  
Drug Molecules ◽  
Membrane Transport Proteins ◽  
Hydrolysis Of ◽  
Structure And Activity

To explain the increased transport of nutrients and metabolites and to control the movement of drug molecules through the transporters to the cancer cells, it is important to understand the exact mechanism of their structure and activity, as well as their biological and physical characteristics. We propose a computational model that reproduces the functionality of membrane transporters by quantifying the flow of substrates through the cell membrane. The model identifies the force induced by conformational changes of the transporter due to hydrolysis of ATP, in ABC transporters, or by an electrochemical gradient of ions, in secondary transporters. The transport rate is computed by averaging the velocity generated by the force along the paths followed by the substrates. The results obtained are in accordance with the experiments. The model provides an overall framework for analyzing the membrane transport proteins that regulate the flows of ions, nutrients and other molecules across the cell membranes, and their activities.

scholarly journals Amphiphilic drug interactions with model cellular membranes are influenced by lipid chain-melting temperature

2014 ◽  
Vol 11 (94) ◽  
pp. 20131062 ◽  
Author(s):  
Duncan Casey ◽  
Kalypso Charalambous ◽  
Antony Gee ◽  
Robert V. Law ◽  
Oscar Ces
Keyword(s):  
Drug Interactions ◽  
Melting Temperature ◽  
Small Molecule ◽  
Aqueous Solubility ◽  
Transport Proteins ◽  
Biologically Relevant ◽  
Drug Molecules ◽  
Amphiphilic Drug ◽  
Lipid Chain ◽  
Hydrolysis Of

Small-molecule amphiphilic species such as many drug molecules frequently exhibit low-to-negligible aqueous solubility, and generally have no identified transport proteins assisting their distribution, yet are able to rapidly penetrate significant distances into patient tissue and even cross the blood–brain barrier. Previous work has identified a mechanism of translocation driven by acid-catalysed lipid hydrolysis of biological membranes, a process which is catalysed by the presence of cationic amphiphilic drug molecules. In this study, the interactions of raclopride, a model amphiphilic drug, were investigated with mixtures of biologically relevant lipids across a range of compositions, revealing the influence of the chain-melting temperature of the lipids upon the rate of acyl hydrolysis.

scholarly journals PMRT1, a Plasmodium specific parasite plasma membrane transporter is essential for asexual and sexual blood stage development

2021 ◽  
Author(s):  
Jan Stephan Wichers ◽  
Paolo Mesén-Ramírez ◽  
Jing Yu-Strzelczyk ◽  
Gwendolin Fuchs ◽  
Jan Stäcker ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Transport ◽  
Transport Proteins ◽  
Membrane Transporters ◽  
Blood Stage ◽  
Cell Physiology ◽  
Membrane Transporter ◽  
Membrane Hyperpolarization ◽  
Membrane Transport Proteins ◽  
Plasma Membrane Transporter

Membrane transport proteins perform crucial roles in cell physiology. The obligate intracellular parasite Plasmodium falciparum, an agent of human malaria, relies on membrane transport proteins for the uptake of nutrients from the host, disposal of metabolic waste, exchange of metabolites between organelles and generation and maintenance of transmembrane electrochemical gradients for its growth and replication within human erythrocytes. Despite their importance for Plasmodium cellular physiology, the functional roles of a number of membrane transport proteins remain unclear, which is particularly true for orphan membrane transporters that have no or limited sequence homology to transporter proteins in other evolutionary lineages. Therefore, in the current study, we applied endogenous tagging, targeted gene disruption, conditional knockdown and knockout approaches to investigate the subcellular localization and essentiality of six membrane transporters during intraerythrocytic development of P. falciparum parasites. They are localized at different subcellular structures – the food vacuole, the apicoplast, and the parasite plasma membrane – and showed essentiality of four out of the six membrane transporters during asexual development. Additionally, the plasma membrane resident transporter 1 (PMRT1, PF3D7_1135300), a unique Plasmodium-specific plasma membrane transporter, was shown to be essential for gametocytogenesis. Heterologous expression of wild-type and mutation constructs in Xenopus laevis oocytes indicated ion transport upon membrane hyperpolarization and a functional role of negatively charged amino acids protruding into the parasitophorous vacuole lumen. Overall, we reveal the importance of four orphan transporters to blood stage P. falciparum development and provide the first functional characterization of PfPMRT1, an essential parasite membrane transporter.

When two turn into one: evolution of membrane transporters from half modules

2014 ◽  
Vol 395 (12) ◽  
pp. 1379-1388 ◽  
Author(s):  
Rebecca Keller ◽  
Christine Ziegler ◽  
Dirk Schneider
Keyword(s):  
Gene Fusion ◽  
Structural Data ◽  
Building Blocks ◽  
Transport Proteins ◽  
Membrane Transporters ◽  
Atomic Structures ◽  
Membrane Transport Proteins ◽  
Fold Family ◽  
Secondary Transporter ◽  
Genes Encoding

Abstract The recently increasing number of atomic structures for active transporters has not only revealed strong conservation in the architecture of sequence-unrelated transporter families, but also identified a unifying element called the ‘inverted repeat topology,’ which is found in nearly all transporter folds to date. Indeed, most membrane transporters consist of two or more domains with similar structure, so-called repeats. It is tempting to speculate that transporters have evolved by duplication of one repeat followed by gene fusion and modification events. An intriguing question is, whether recent genes encoding such a ‘half-transporter’ still exist as independent folding units. Although it seems likely that the evolution of membrane transport proteins, which harbor internal repeats, is linked to these minimal structural building blocks, their identification in the absence of structural data represents a major challenge, as sequence homology is not an issue. In this review we discuss two protein families, the DedA family and the SWEET family, being potential half-transporters and putative ancestors for two of the most abundant secondary transporter families, the MFS family and the LeuT-fold family.

scholarly journals A Proposed Time-Resolved X-Ray Scattering Approach to Track Local and Global Conformational Changes in Membrane Transport Proteins

Structure ◽  
2008 ◽  
Vol 16 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Magnus Andersson ◽  
Jonathan Vincent ◽  
David van der Spoel ◽  
Jan Davidsson ◽  
Richard Neutze
Keyword(s):  
Membrane Transport ◽  
Conformational Changes ◽  
Transport Proteins ◽  
Time Resolved ◽  
X Ray ◽  
X Ray Scattering ◽  
Membrane Transport Proteins ◽  
Ray Scattering

scholarly journals EPR Spectroscopy of MolB2C2-A Reveals Mechanism of Transport for a Bacterial Type II Molybdate Importer

2013 ◽  
Vol 288 (29) ◽  
pp. 21228-21235 ◽  
Author(s):  
Austin J. Rice ◽  
Frances J. D. Alvarez ◽  
Kathryn M. Schultz ◽  
Candice S. Klug ◽  
Amy L. Davidson ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Abc Transporters ◽  
Epr Spectroscopy ◽  
Vitamin B ◽  
Type I ◽  
Type Ii ◽  
Bacterial Type ◽  
Uptake Of Nutrients ◽  
Structure And Activity ◽  
Alternating Access

In bacteria, ATP-binding cassette (ABC) transporters are vital for the uptake of nutrients and cofactors. Based on differences in structure and activity, ABC importers are divided into two types. Type I transporters have been well studied and employ a tightly regulated alternating access mechanism. Less is known about Type II importers, but much of what we do know has been observed in studies of the vitamin B12 importer BtuC2D2. MolB2C2 (formally known as HI1470/71) is also a Type II importer, but its substrate, molybdate, is ∼10-fold smaller than vitamin B12. To understand mechanistic differences among Type II importers, we focused our studies on MolBC, for which alternative conformations may be required to transport its relatively small substrate. To investigate the mechanism of MolBC, we employed disulfide cross-linking and EPR spectroscopy. From these studies, we found that nucleotide binding is coupled to a conformational shift at the periplasmic gate. Unlike the larger conformational changes in BtuCD-F, this shift in MolBC-A is akin to unlocking a swinging door: allowing just enough space for molybdate to slip into the cell. The lower cytoplasmic gate, identified in BtuCD-F as “gate I,” remains open throughout the MolBC-A mechanism, and cytoplasmic gate II closes in the presence of nucleotide. Combining our results, we propose a peristaltic mechanism for MolBC-A, which gives new insight in the transport of small substrates by a Type II importer.

Structure and Activity of Pentacyclic Triterpenes Codrugs. A Review

2021 ◽  
Vol 21 ◽  
Author(s):  
Justyna Żwawiak ◽  
Anna Pawełczyk ◽  
Dorota Olender ◽  
Lucjusz Zaprutko
Keyword(s):  
Biological Activities ◽  
Anticancer Activities ◽  
Drug Molecule ◽  
Pentacyclic Triterpene ◽  
Formation Pathway ◽  
Chemical Systems ◽  
Drug Molecules ◽  
Wide Range ◽  
Anti Hiv ◽  
Structure And Activity

: Triterpenes are a wide and important group of compounds that have several promising pharmacological properties, such as hepatoprotective, anti-inflammatory, anti-HIV, antioxidant, or anticancer activities. Such potent substances can be successfully incorporated in more complex chemical systems e.g. codrugs or pro-drugs that have better pharmacological profile. The codrug is connected with a drug formation pathway to chemically cohere at least two drug molecules to improve positive therapeutic efficiency or decrease side effects. The codrug can be cleaved in the organism to generate effective compounds previously used as substrates. This article presents an overview of codrugs that consist of pentacyclic triterpene moiety that is chosen as a basic codrug moiety due to their wide range of vital activities and another drug molecule fragment. It was found that triterpenoid codrugs are characterized by a wide range of biological activities. However, most of them have anticancer potency.

Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications

2015 ◽  
Vol 43 (5) ◽  
pp. 1023-1032 ◽  
Author(s):  
Thomas Stockner ◽  
Anna Mullen ◽  
Fraser MacMillan
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Epr Spectroscopy ◽  
Structural Information ◽  
Dynamic Properties ◽  
Molecular System ◽  
Synergistic Effects ◽  
Md Simulations ◽  
Substrate Spectrum

ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented.

Development of a multiplex UPLC-MRM MS method for quantification of human membrane transport proteins OATP1B1, OATP1B3 and OATP2B1 in in vitro systems and tissues

2012 ◽  
Vol 717 ◽  
pp. 67-76 ◽  
Author(s):  
Chengjie Ji ◽  
William R. Tschantz ◽  
Nathan D. Pfeifer ◽  
Mohammed Ullah ◽  
Nalini Sadagopan
Keyword(s):  
Membrane Transport ◽  
Transport Proteins ◽  
Membrane Transport Proteins ◽  
In Vitro Systems
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