1.
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.
2.
Self-immunity to antibacterial peptides by ABC transporters.
Smits, SHJ, Schmitt, L, Beis, K
FEBS letters. 2020;(23):3920-3942
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Abstract
Bacteria produce under certain stress conditions bacteriocins and microcins that display antibacterial activity against closely related species for survival. Bacteriocins and microcins exert their antibacterial activity by either disrupting the membrane or inhibiting essential intracellular processes of the bacterial target. To this end, they can lyse bacterial membranes and cause subsequent loss of their integrity or nutrients, or hijack membrane receptors for internalisation. Both bacteriocins and microcins are ribosomally synthesised and several are posttranslationally modified, whereas others are not. Such peptides are also toxic to the producer bacteria, which utilise immunity proteins or/and dedicated ATP-binding cassette (ABC) transporters to achieve self-immunity and peptide export. In this review, we discuss the structure and mechanism of self-protection that is conferred by these ABC transporters.
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Importance of TAP-independent processing pathways.
Oliveira, CC, van Hall, T
Molecular immunology. 2013;(2):113-6
Abstract
The majority of peptides presented in MHC class I at the cell surface originate from the conventional antigen processing pathway, involving the proteasome and TAP peptide transporter. Alternative pathways, however, certainly contribute to the diversity of the total peptide repertoire. The importance of such TAP-independent processing pathways is nicely illustrated by the finding that individuals with an inherited deficiency in this peptide transporter still sufficiently mount T cell responses against viruses. Although defects in TAP do result in strongly decreased surface display of MHC class I molecules, the residual levels are capable to educate and elicit T cell immunity. In our work, we have shown that a broad repertoire of peptides is presented on processing-deficient cells. The characterization of these peptides, which we called TEIPP - "T-cell epitopes associated with impaired peptide processing", showed that they derive from housekeeping proteins, are diverse in length and amino-acid composition, and are not presented on normal cells. So, TAP-deficiency promotes the emergence of neo-antigens. These TAP-independent peptides might be processed via the two already known pathways, signal sequence liberation or furin-mediated cleavage in the Golgi, or via yet other routes. Our study on TEIPP antigens reveals that there is a world to be discovered in the alternative antigen processing field. Autophagy, vesicular routing, membrane-associated proteolysis, invariant chain involvement and recycling of MHC class I molecules all might come to the stage in this interesting research area.
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Multiple drug resistance associated with function of ABC-transporters in diabetes mellitus: molecular mechanism and clinical relevance.
Koehn, J, Fountoulakis, M, Krapfenbauer, K
Infectious disorders drug targets. 2008;(2):109-18
Abstract
ATP-binding cassette (ABC) transporters are involved in a variety of physiological processes such as lipid metabolism, ion homeostasis and immune functions. A large number of these proteins have been causatively linked to rare and common human genetic diseases including familial high-density lipoprotein deficiency, retinopathies, cystic fibrosis, diabetes and cardiomyopathies. Furthermore, genetic variations in ABC transporter genes and deregulated expression patterns significantly contribute to drug resistance in human cancer and pancreatic beta cells and alter the pharmacokinetic properties of a variety of drugs. Up-to-date 15 ABC transporters have been identified in human pancreatic beta cells, however only a few of them are identified to date as proteins/genes associated with multidrug resistance (MDR) in diabetes mellitus. Prominent members include the multidrug resistance protein 1 (MRP1/ABCC1), sulfonylurea receptor 1 (SUR1/ABCC8), the multi drug transporter TAP2 and member of the ATP-binding cassette transporter subfamily A (ABCA1). ABCC8 is a subunit of the pancreatic beta-cell K(ATP) channel and plays a key role in the regulation of glucose-induced insulin secretion. Although the physiological role of these transporters to MDR is not yet fully understood, they play an important role in the blood-membrane barrier in pancreatic beta cells. The aim of this article is to provide an overview and to present few examples of drug treatment in MDR in diabetes mellitus associated with function of ABC-transporters.