Crystal structures of abc domains and full transporters have provided a framework for formulating reaction mechanisms of atpdriven substrate transport, but recent studies have suggested. In recent years, cancer stem cells have been recognized as key tumorinitiating cells that are therapyresistant and highly tumorogenic and therefore may play a pivotal role in cancer recurrence following chemotherapy. Then we shortly deal with the human abc transporters as targets of therapeutic interventions in medicine, including cancer drug resistance, lipid and other metabolic disrorders, and even gene therapy applications. The flexibility of this switching mechanism has evolved to provide. The role of abc transporters in drug resistance, metabolism. Resistance to targeted abc transporters in cancer thomas. Abc transporters are primary active transporters, which transport a wide range of substrates mainly to the outside of a cell membrane or organelle. Atpbinding cassette abc transporters mediate the active efflux transport of a variety of structurally and mechanistically unrelated compounds across biological membranes of the cell and numerous organelles 1,2,3. It is the first complete abc transporter to have its. Abc transporters 40 years on anthony george springer.
Humans have 48 different abc transporters, and more than a dozen genetic. The human genome encodes 48 abc transporter genes and mutations in most have been linked to disease. Chief, laboratory of cell biology center for cancer research, nci national institutes of health, dhhs clinical pharmacology, january 8, 2015 drug resistance in cancer may affect multiple drugs used simultaneously. Using both chimeric protein approaches and sitedirected mutagenesis, we are beginning to understand critical domains and residues of particularly hco3 transporters. Abc transporters in saccharomyces cerevisiae and their. Transporter biology is a rapidly changing field in pharmaceutical research. Abc transporters are defined by the presence of nucleotidebinding domains. Abc transporters and cancer ebook written by toshihisa ishikawa, john schuetz. The small multidrug resistance family smr the resistancenodulationcell division superfamily rnd. Intro all organisms depend on membrane transport, whether. Download for offline reading, highlight, bookmark or take notes while you read abc transporters and cancer.
Structure and mechanism of atpbinding cassette transporters. We also develop antibodies for protein localization in epithelial tissues. Atpbinding cassette or abc transporters are a large superfamily of proteins found in all. Primary transporters include the rotary motor atpases f, a, and vatpases, ptype atpases and a large family of integral membrane proteins referred to as abc atp binding cassette transporters. It is represented in all extant phyla, from prokaryotes to humans. It highlights their exciting biological functions, covering aspects ranging from cellular detoxification, through development, to symbiosis and defense. These primary transporters are enzymes that convert energy from various sourcesincluding adenosine triphosphate atp, sunlight, and other redox reactionsto potential energy stored in an. Efferth is an expert on abc transporters and has given over lectures at international conferences. Structural similarities support a common mechanism by which abc. Mammalian abc transporters in health and disease annual.
A comprehensive overview of the structural and molecular biology of cellular processes that occur at or near bacterial membranes. In one comprehensive volume, this book contains a collection of the most current knowledge on the involvement of abc transporters in drug transport. Abc proteins is an indepth, uptodate analysis of all that is known about the subject to date. Our overview illustrates the importance of abc transporters in human physiology, toxicology, pharmacology, and disease. The first abc transporter was discovered in 1973 and was named pglycoprotein. Sep 07, 2011 abc transporters, mechanisms and biology.
The atp binding cassette transporters abc transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. Atpbinding cassette abc transporters constitute a large superfamily of. Purchase abc transporters and cancer, volume 125 1st edition. To better understand these ion transporters, we determine which cations and or anions are transported.
Atpbinding cassette or abc transporters are a large superfamily of proteins found in all living organisms including bacteria, archaea, and eukarya. Abc transporters and multidrug resistance wiley online books. Some substrates of abc transporters are membrane bound. An important goal is to develop quantitative models that detail the kinetic and molecular mechanisms by which abc transporters couple the binding and hydrolysis of atp to substrate translocation. Abc transporters and multidrug resistance offers an essential resource for pharmaceutical researchers who are working to discover drugs to counteract multidrug resistance in diseases such as cancer. Abc transporters with similar mechanisms include bacterial permeases that pump nutrients. The structure of a bacterial abc transporter facilitating vitamin b 12 import into e. Research in my lab centers on atpbinding cassette abc transporters, a diverse group of membrane proteins integral to almost every biological process. Mutations in abc transporters cause or contribute to many different mendelian and complex disorders including adrenoleukodystrophy, cystic fibrosis, retinal degeneration, hypercholesterolemia, and cholestasis. Structure and function of abc transporters in health and disease. Gary pilarchik the rusted garden recommended for you. Transport across the cell membrane boundless microbiology. Abc transporters and cancer by toshihisa ishikawa, john. This book that brings together stateoftheart knowledge on abc proteins in one volume will provide students, professors and medical professionals with a background to the human abc transporters that are known to be relevant to disease.
Structural biochemistrymembrane proteinsatpbinding. Thus abc transporters are a compelling class of proteins, both for their medical relevance and for basic membrane biology. This book that brings together state of the art knowledge on abc proteins in one volume will provide students, professors and medical professionals with a background to the human abc transporters that are known to be relevant to disease. Structure and mechanotransmission mechanism of the macb abc. Cryoelectron microscopy structure and transport mechanism of a. In biology, an ion transporter or ion pump is a transmembrane protein that moves ions across a biological membrane against their concentration gradient through active transport. Thus, elucidation of molecular mechanisms of drug resistance is essential for the establishment of better treatment alternatives for lymphoma patients. Abc transporters are ubiquitous membrane proteins that import or export molecules across the cellular membrane. Structure and function of abc transporters in health and disease michael m.
Ample evidence suggests that the expression of atpbinding cassette abc transporters, especially the multidrug resistance protein 1 mdr1, also known as pglycoprotein or pgp, which is encoded. Alshawi abc solute importers in bacteria jinming cui, amy l. Abc transporter proteins definition of abc transporter. Abc transporters with similar mechanisms include bacterial permeases that pump nutrients into the cell, and tap1 and tap2 that pump peptide fragments of antigenic proteins into the lumen of the endoplasmic reticulum. Pdf plant abc transporters download full pdf book download. Atpbinding cassette transporters in bacteria amy l.
The abc transporters of human physiology and disease. The substrates that can be transported include ions, amino acids, peptides, sugars, and other molecules that are mostly hydrophilic. The related family of energycoupling factor ecf transporters,14 sometimes referred to as class iii abc. The topics include the structure, physiology and evolution of abc transporters, and their special characteristics in bacteria, yeast, trypanosomes and malaria parasites. In prokaryotes, these proteins are critical for survival.
Structural basis for the mechanism of abc transporters. Atpbinding cassette abc transporters are ubiquitous integral. Revisiting the role of abc transporters in multidrug. Nevertheless two critical steps capture and release of allocrites transport substrates involving a binding cavity in the. Mammalian abc transporters are involved in the cellular export of several groups of molecules, including cholesterol and sterols, lipids, retinoic acid derivatives, bile acid, iron, nucleosides, and peptides. It discusses and compares evolution, biology and mechanism of action of all known abc proteins, including the first structural studies as well as clinical implications.
These transmembrane proteins are involved in a wide variety of cellular processes in both physiologic and pathologic states 4,5. Hence, distinct transport mechanisms for abcg2 and other abcg. The overexpression of drug transporters is one of the most intensively studied mechanisms of drug resistance in many tumors. This chapter concentrates mainly on structural and mechanistic aspects of abc. Highest expression was found in human liver and jejunum. The authors explore and describe the state of the art of research, knowledge, and prospects for the future for this important family of proteins. Identifying the function of transporters in physiological and pathological conditions is garnering significant attention for drug development. It will be useful to anyone trying to stay abreast of the latest findings.
Several mechanisms have been proposed for substrate recognition and transport by abc proteins 22, 23. Efferth has received over 6,000 citations in his career. Zolnerciks and others catalytic and transport cycles of abc. The recent progress on the function and involvement of membranes in bacterial physiology enabling a greater understanding of the molecular details of the cell envelope, its biogenesis and function. Abc transporters use the energy of atp hydrolysis to transport substrates across cell membranes. The most important causes of treatment failure in canine lymphoma include intrinsic or acquired drug resistance. The atpbinding cassette abc transporters are a family of large proteins in membranes and are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of atp hydrolysis. Abc transporters are ubiquitous in all organisms sequenced ranging from 11 in mycoplasma genitalium to 78 in bacillus subtilis quentin et al. Bacterial abc transporters are essential in cell viability, virulence, and pathogenicity.
This comprehensive volume provides an overview on the description of the structure, the genome, normal tissue expression, physiological aspect, and mechanism of action of the abc. The human abc transporter abcg2 breast cancer resistance protein. Comparative aspects of molecular mechanisms of drug. Abc transporters use atp hydrolysis to translocate substrates across cell membranes. In this overview, the importance of studies on bacteria in elucidating many basic principles pertaining to abc. Abc transporters with similar mechanisms include bacterial permeases that pump. The family is defined by homology within the atpbinding cassette abc region, which extends outside of the more typical walker motifs found in all atpbinding proteins. Abc transporters of human physiology and disease, the. The book covers the most recent research into the role of abc transporters in the design of strategies to circumvent drug resistance. Abc transporters often consist of multiple subunits, one or two of which are transmembrane proteins and one or. There are two types of abc transporters, abc importers and abc exporters, that have a common mechanism in transporting substrates because.
Given the important role of abc transporters in refractory epilepsy drug resistance, antiepileptic drugs that are not substrates of abc transporters were used to obtain abc transporter inhibitors with strong specificity, high safety, and few side effects, making them suitable for longterm use. Although we have seen dramatic progress in abc protein studies in the last 20 years, we are still far from a detailed molecular understanding of function. Learn vocabulary, terms, and more with flashcards, games, and other study tools. In escherichia coli almost 5% of the genome is occupied by genes encoding components of these transporters, and there are examples in all species from microbes to man. In the first model i the substrate enters the transporter from the inner leaflet, possibly by diffusing from the cytosol into the inner leaflet, and exits from the outer. These findings advance our understanding of antimrsa drug design and abc transporters. Analysis of cryoelectron microscopy structures of the mycobacterium tuberculosis abc transporter rv1819c suggests that it is a multisolute transporter for hydrophilic molecules. Abc transporters play a critical role in the development of multidrug resistance in cancer.
This concise volume describes the latest, uptodate theory, methodology, and applications of abc transporters in microorganisms. It provides stepbystep protocols and overviews in the field that also allow newcomers to obtain an orientation over a wide spectrum of aspects. Abc transporters and cancer, volume 125 1st edition. Abc transporters are powered by the hydrolysis of atp and transport their substrate via the alternating access mechanism, whereby the protein alternates between a conformation in which the.
Feb 03, 2015 there are 48 abc transporters in humans that can be subdivided by phylogenetic analysis into seven distinct subfamilies ag 8,9. The topics include the structure, physiology, and evolution of abc transporters, as well as their special characteristics in specific microorganisms, including bacteria, yeast, trypanosomes, and malaria parasites. Bacterial efflux transporters are classified into five major superfamilies, based on their amino acid sequence and the energy source used to export their substrates. Biochemical, cellular, and molecular aspects, volume 292 1st edition. Abc atpbinding cassette transporters share a common architecture and a common basic mechanism. Atpbinding cassette abc transporters are responsible for the atppowered translocation of many substrates across membranes. There are 48 abc transporters in humans that can be subdivided by phylogenetic analysis into seven distinct subfamilies ag 8,9. Summary members of the atpbinding cassette abc transporter superfamily. The increasing number of abc transporters more than 2000 abc atpase domains are now in public data banks dassa and bouige, 2001 has led to their classification according to structure and function dassa and. Structural and mechanistic studies of abc transporters. Mechanistic diversity in atpbinding cassette abc transporters.
Abc transporters classified so far can be grouped into exporters and importers with the importers further divided into two classes i and ii, depending on details of their architecture and mechanism 1012. The overall biological relevance of incomplete gene organization of abc. Research progress on the role of abc transporters in the drug. Structure and mechanism of abc transporters sciencedirect. These primary transporters are enzymes that convert energy from various sourcesincluding adenosine triphosphate atp, sunlight, and other redox reactionsto. A mycobacterial abc transporter mediates the uptake of. Abc transporters are found in all known organisms, and approximately 1,100 different transporters belonging to this family have been described in the literature. The atpbinding cassette abc superfamily of genes encode membrane proteins that transport a diverse set of substrates across membranes. Mutations in the gene that codes for one of these abc transporter proteins is believed to be responsible for cystic fibrosis. In prokaryotes, these proteins are critical survival factors that function in the uptake of nutrients and in the secretion of toxins and antimicrobial agents. All abc transporters contain two membranespanning domains that harbor a translocation pathway for a specific substrate. Role of abc transporters in lipid transport and human disease.
This book is devoted to the fascinating superfamily of plant atpbinding cassette abc transporters and their variety of transported substrates. Cancer stem cells cscs are rare tumor cells that exhibit stem cell properties such as selfrenewal capacity and pluripotency. The atpbinding cassette transporters abc transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. Abc transporters make use of the energy of atp binding andor hydrolysis to drive the conformational changes in the transmembrane domain tmd and consequently transports molecules. Gerhard burckhardt, hermann koepsell, in seldin and giebischs the kidney fifth edition, 20. The structure of the human abc transporter abcg2 reveals a novel. This book provides new structural, biochemical, and clinical information on abc transporters. We further show that macb shares its structural architecture with an entire superfamily of abc transporters responsible for fundamental bacterial processes, including cell division and outer membrane biogenesis, suggesting a common mode of operation, and raise the possibility of targeting such proteins for the development of new antibiotics. In one comprehensive volume, this book contains a collection of the most current knowledge on the involvement of abc transporters in drug transport and resistance. Zolnerciks and others catalytic and transport cycles of abc exporters marwan k. Abc transporters, both importers and exporters, contain two transmembrane domains, which form a substrate translocation pathway, and two nucleotidebinding domains nbds, which bind and hydrolyze atp. The available outline of the human genome contains 48 abc genes. Therefore, understanding the mechanisms of abc transporter function is of signi.
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