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1.
Equilibrium properties of E. coli lactose permease symport-A random-walk model approach.
Sun, H
PloS one. 2022;(2):e0263286
Abstract
The symport of lactose and H+ is an important physiological process in E. coli, for it is closely related to cellular energy supply. In this paper, we review, extend and analyse a newly proposed cotransport model that takes the "leakage" phenomenon (uncoupled particle translocation) into account and also satisfies the static head equilibrium condition. Then, we use the model to study the equilibrium properties, including equilibrium solution and the time required to reach equilibrium, of the symport process of E. coli LacY protein, when varying the parameters of the initial state of cotransport system. It can be found that in our extended model, H+ and lactose will reach their equilibrium state separately, and when "leakage" exists, it linearly affects the equilibrium solution, which is a useful property that the original model does not have. We later investigated the effect of the volume of periplasm and cytoplasm on the equilibrium properties. For a certain E. coli cell, as it continues to lose water and contract, the time for cytoplasm pH to be stabilized by symport increases monotonically when the cell survives. Finally, we reproduce the experimental data from a literature to verify the validity of the extension in this symport process. The above phenomena and other findings in this paper may help us to not only further validate or improve the model, but also deepen our understanding of the cotransport process of E. coli LacY protein.
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2.
Outstanding Questions on the Beneficial Role of Silicon in Crop Plants.
Shivaraj, SM, Mandlik, R, Bhat, JA, Raturi, G, Elbaum, R, Alexander, L, Tripathi, DK, Deshmukh, R, Sonah, H
Plant & cell physiology. 2022;(1):4-18
Abstract
Silicon (Si) is widely accepted as a beneficial element for plants. Despite the substantial progress made in understanding Si transport mechanisms and modes of action in plants, several questions remain unanswered. In this review, we discuss such outstanding questions and issues commonly encountered by biologists studying the role of Si in plants in relation to Si bioavailability. In recent years, advances in our understanding of the role of Si-solubilizing bacteria and the efficacy of Si nanoparticles have been made. However, there are many unknown aspects associated with structural and functional features of Si transporters, Si loading into the xylem, and the role of specialized cells like silica cells and compounds preventing Si polymerization in plant tissues. In addition, despite several 1,000 reports showing the positive effects of Si in high as well as low Si-accumulating plant species, the exact roles of Si at the molecular level are yet to be understood. Some evidence suggests that Si regulates hormonal pathways and nutrient uptake, thereby explaining various observed benefits of Si uptake. However, how Si modulates hormonal pathways or improves nutrient uptake remains to be explained. Finally, we summarize the knowledge gaps that will provide a roadmap for further research on plant silicon biology, leading to an exploration of the benefits of Si uptake to enhance crop production.
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3.
Pharmacogenomics with red cells: a model to study protein variants of drug transporter genes.
Flegel, WA, Srivastava, K, Sissung, TM, Goldspiel, BR, Figg, WD
Vox sanguinis. 2021;(2):141-154
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Abstract
The PharmacoScan pharmacogenomics platform screens for variation in genes that affect drug absorption, distribution, metabolism, elimination, immune adverse reactions and targets. Among the 1,191 genes tested on the platform, 12 genes are expressed in the red cell membrane: ABCC1, ABCC4, ABCC5, ABCG2, CFTR, SLC16A1, SLC19A1, SLC29A1, ATP7A, CYP4F3, EPHX1 and FLOT1. These genes represent 5 ATP-binding cassette proteins, 3 solute carrier proteins, 1 ATP transport protein and 3 genes associated with drug metabolism and adverse drug reactions. Only ABCG2 and SLC29A1 encode blood group systems, JR and AUG, respectively. We propose red cells as an ex vivo model system to study the effect of heritable variants in genes encoding the transport proteins on the pharmacokinetics of drugs. Altered pharmacodynamics in red cells could also cause adverse reactions, such as haemolysis, hitherto unexplained by other mechanisms.
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4.
The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes.
Kell, DB
Molecules (Basel, Switzerland). 2021;(18)
Abstract
Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport "phospholipid bilayer transport is negligible".
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5.
Cellular export of sugars and amino acids: role in feeding other cells and organisms.
Kim, JY, Loo, EP, Pang, TY, Lercher, M, Frommer, WB, Wudick, MM
Plant physiology. 2021;(4):1893-1914
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Abstract
Sucrose, hexoses, and raffinose play key roles in the plant metabolism. Sucrose and raffinose, produced by photosynthesis, are translocated from leaves to flowers, developing seeds and roots. Translocation occurs in the sieve elements or sieve tubes of angiosperms. But how is sucrose loaded into and unloaded from the sieve elements? There seem to be two principal routes: one through plasmodesmata and one via the apoplasm. The best-studied transporters are the H+/SUCROSE TRANSPORTERs (SUTs) in the sieve element-companion cell complex. Sucrose is delivered to SUTs by SWEET sugar uniporters that release these key metabolites into the apoplasmic space. The H+/amino acid permeases and the UmamiT amino acid transporters are hypothesized to play analogous roles as the SUT-SWEET pair to transport amino acids. SWEETs and UmamiTs also act in many other important processes-for example, seed filling, nectar secretion, and pollen nutrition. We present information on cell type-specific enrichment of SWEET and UmamiT family members and propose several members to play redundant roles in the efflux of sucrose and amino acids across different cell types in the leaf. Pathogens hijack SWEETs and thus represent a major susceptibility of the plant. Here, we provide an update on the status of research on intercellular and long-distance translocation of key metabolites such as sucrose and amino acids, communication of the plants with the root microbiota via root exudates, discuss the existence of transporters for other important metabolites and provide potential perspectives that may direct future research activities.
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6.
A guide to plasma membrane solute carrier proteins.
Pizzagalli, MD, Bensimon, A, Superti-Furga, G
The FEBS journal. 2021;(9):2784-2835
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Abstract
This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.
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The plant axis as the command centre for (re)distribution of sucrose and amino acids.
van Bel, AJE
Journal of plant physiology. 2021;:153488
Abstract
Along with the increase in size required for optimal colonization of terrestrial niches, channels for bidirectional bulk transport of materials in land plants evolved during a period of about 100 million years. These transport systems are essentially still in operation - though perfected over the following 400 million years - and make use of hydrostatic differentials. Substances are accumulated or released at the loading and unloading ends, respectively, of the transport channels. The intermediate stretch between the channel termini is bifunctional and executes orchestrated release and retrieval of solutes. Analyses of anatomical and physiological data demonstrate that the release/retrieval zone extends deeper into sources and sinks than is commonly thought and covers usually much more than 99% of the translocation stretch. This review sketches the significance of events in the intermediate stretch for distribution of organic materials over the plant body. Net leakage from the channels does not only serve maintenance and growth of tissues along the pathway, but also diurnal, short-term or seasonal storage of reserve materials, and balanced distribution of organic C- and N-compounds over axial and terminal sinks. Release and retrieval are controlled by plasma-membrane transporters at the vessel/parenchyma interface in the contact pits along xylem vessels and by plasma-membrane transporters at the interface between companion cells and phloem parenchyma along sieve tubes. The xylem-to-phloem pathway vice versa is a bifacial, radially oriented system comprising a symplasmic pathway, of which entrance and exit are controlled at specific membrane checkpoints, and a parallel apoplasmic pathway. A broad range of specific sucrose and amino-acid transporters are deployed at the checkpoint plasma membranes. SUCs, SUTs, STPs, SWEETs, and AAPs, LTHs, CATs are localized to the plasma membranes in question, both in monocots and eudicots. Presence of Umamits in monocots is uncertain. There is some evidence for endo- and exocytosis at the vessel/parenchyma interface supplementary to the transporter-mediated uptake and release. Actions of transporters at the checkpoints are equally decisive for storage and distribution of amino acids and sucrose in monocots and eudicots, but storage and distribution patterns may differ between both taxa. While the majority of reserves is sequestered in vascular parenchyma cells in dicots, lack of space in monocot vasculature urges "outsourcing" of storage in ground parenchyma around the translocation path. In perennial dicots, specialized radial pathways (rays) include the sites for seasonal alternation of storage and mobilization. In dicots, apoplasmic phloem loading and a correlated low rate of release along the path would favour supply with photoassimilates of terminal sinks, while symplasmic phloem loading and a correlated higher rate of release along the path favours supply of axial sinks and transfer to the xylem. The balance between the resource acquisition by terminal and axial sinks is an important determinant of relative growth rate and, hence, for the fitness of plants in various habitats. Body enlargement as the evolutionary drive for emergence of vascular systems and mass transport propelled by hydrostatic differentials.
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Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease.
Dietl, P, Frick, M
Cells. 2021;(1)
Abstract
The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.
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Novel mutations associated with carnitine-acylcarnitine translocase and carnitine palmitoyl transferase 2 deficiencies in Malaysia.
Habib, A, Azize, NAA, Rahman, SA, Yakob, Y, Suberamaniam, V, Nazri, MIBA, Abdullah Sani, H, Ch'ng, GS, Yin, LH, Olpin, S, et al
Clinical biochemistry. 2021;:48-53
Abstract
OBJECTIVE Carnitine-acylcarnitine Translocase (CACT) deficiency (OMIM 212138) and carnitine palmitoyl transferase 2 (CPT2) deficiency (OMIM 60065050) are rare inherited disorders of mitochondrial long chain fatty acid oxidation. The aim of our study is to review the clinical, biochemical and molecular characteristics in children diagnosed with CACT and CPT2 deficiencies in Malaysia. DESIGN AND METHODS This is a retrospective study. We reviewed medical records of six patients diagnosed with CACT and CPT2 deficiencies. They were identified from a selective high-risk screening of 50,579 patients from January 2010 until Jun 2020. RESULTS All six patients had either elevation of the long chain acylcarnitines and/or an elevated (C16 + C18:1)/C2 acylcarnitine ratio. SLC25A20 gene sequencing of patient 1 and 6 showed a homozygous splice site mutation at c.199-10 T > G in intron 2. Two novel mutations at c.109C > T p. (Arg37*) in exon 2 and at c.706C > T p. (Arg236*) in exon 7 of SLC25A20 gene were found in patient 2. Patient 3 and 4 (siblings) exhibited a compound heterozygous mutation at c.638A > G p. (Asp213Gly) and novel mutation c.1073 T > G p. (Leu358Arg) in exon 4 of CPT2 gene. A significant combined prevalence at 0.01% of CACT and CPT2 deficiencies was found in the symptomatic Malaysian patients. CONCLUSIONS The use of the (C16 + C18:1)/C2 acylcarnitine ratio in dried blood spot in our experience improves the diagnostic specificity for CACT/CPT2 deficiencies over long chain acylcarnitine (C16 and C18:1) alone. DNA sequencing for both genes aids in confirming the diagnosis.
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10.
Spatiotemporal determination of metabolite activities in the corneal epithelium on a chip.
Abdalkader, R, Chaleckis, R, Wheelock, CE, Kamei, KI
Experimental eye research. 2021;:108646
Abstract
The corneal epithelial barrier maintains the metabolic activities of the ocular surface by regulating membrane transporters and metabolic enzymes responsible for the homeostasis of the eye as well as the pharmacokinetic behavior of drugs. Despite its importance, no established biomimetic in vitro methods are available to perform the spatiotemporal investigation of metabolism and determine the transportation of endogenous and exogenous molecules across the corneal epithelium barrier. This study introduces multiple corneal epitheliums on a chip namely, Corneal Epithelium on a Chip (CEpOC), which enables the spatiotemporal collection as well as analysis of micro-scaled extracellular metabolites from both the apical and basolateral sides of the barriers. Longitudinal samples collected during 48 h period were analyzed using untargeted liquid chromatography-mass spectrometry metabolomics method, and 104 metabolites were annotated. We observed the spatiotemporal secretion of biologically relevant metabolites (i.e., antioxidant, glutathione and uric acid) as well as the depletion of essential nutrients such as amino acids and vitamins mimicking the in vivo molecules trafficking across the human corneal epithelium. Through the shifts of extracellular metabolites and quantitative analysis of mRNA associated with transporters, we were able to investigate the secretion and transportation activities across the polarized barrier in a correlation with the expression of corneal transporters. Thus, CEpOC can provide a non-invasive, simple, yet effectively informative method to determine pharmacokinetics and pharmacodynamics as well as to discover novel biomarkers for drug toxicological and safety tests as advanced experimental model of the human corneal epithelium.