Editing ABC transporter (section)

== Function ==

ABC transporters utilize the energy of ATP binding and hydrolysis to transport various [[Substrate (biochemistry)|substrates]] across cellular [[cell membrane|membranes]]. They are divided into three main functional categories. In prokaryotes, ''importers'' mediate the uptake of [[nutrient]]s into the cell. The substrates that can be transported include [[ion]]s, [[amino acid]]s, [[peptide]]s, [[sugar]]s, and other molecules that are mostly [[hydrophilic]]. The membrane-spanning region of the ABC transporter protects hydrophilic substrates from the lipids of the membrane [[lipid bilayer|bilayer]] thus providing a pathway across the cell membrane. [[Eukaryotes]] do not possess any importers. ''Exporters'' or ''effluxers'', which are present both in prokaryotes and eukaryotes, function as pumps that extrude toxins and drugs out of the cell. In [[gram-negative bacteria]], exporters transport lipids and some [[polysaccharide]]s from the [[cytoplasm]] to the [[periplasm]]. The third subgroup of ABC proteins do not function as transporters, but are rather involved in translation and DNA repair processes.<ref name=davidson/>

=== Prokaryotic ===

Bacterial ABC transporters are essential in cell viability, [[virulence]], and pathogenicity.<ref name=":0" /><ref name=davidson/> Iron ABC uptake systems, for example, are important effectors of virulence.<ref name="pmid7927795">{{cite journal | vauthors = Henderson DP, Payne SM | title = Vibrio cholerae iron transport systems: roles of heme and siderophore iron transport in virulence and identification of a gene associated with multiple iron transport systems | journal = Infection and Immunity | volume = 62 | issue = 11 | pages = 5120–5 | date = Nov 1994 | pmid = 7927795 | pmc = 303233 | doi =  10.1128/IAI.62.11.5120-5125.1994}}</ref> [[Pathogens]] use [[siderophores]], such as [[Enterobactin]], to scavenge iron that is in complex with high-affinity iron-binding proteins or [[erythrocytes]]. These are high-affinity iron-chelating molecules that are secreted by bacteria and reabsorb iron into iron-siderophore complexes. The chvE-gguAB [[gene]] in ''Agrobacterium tumefaciens'' encodes [[glucose]] and [[galactose]] importers that are also associated with virulence.<ref name="pmid2118656">{{cite journal | vauthors = Cangelosi GA, Ankenbauer RG, Nester EW | title = Sugars induce the Agrobacterium virulence genes through a periplasmic binding protein and a transmembrane signal protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 17 | pages = 6708–12 | date = Sep 1990 | pmid = 2118656 | pmc = 54606 | doi = 10.1073/pnas.87.17.6708 | bibcode = 1990PNAS...87.6708C | doi-access = free }}</ref><ref name="pmid9079938">{{cite journal | vauthors = Kemner JM, Liang X, Nester EW | title = The Agrobacterium tumefaciens virulence gene chvE is part of a putative ABC-type sugar transport operon | journal = Journal of Bacteriology | volume = 179 | issue = 7 | pages = 2452–8 | date = Apr 1997 | pmid = 9079938 | pmc = 178989 | doi =  10.1128/jb.179.7.2452-2458.1997}}</ref> Transporters are extremely vital in cell survival such that they function as protein systems that counteract any undesirable change occurring in the cell. For instance, a potential lethal increase in [[osmosis|osmotic]] strength is counterbalanced by activation of osmosensing ABC transporters that mediate uptake of solutes.<ref name="pmid15519310">{{cite journal | vauthors = Poolman B, Spitzer JJ, Wood JM | title = Bacterial osmosensing: roles of membrane structure and electrostatics in lipid-protein and protein-protein interactions | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1666 | issue = 1–2 | pages = 88–104 | date = Nov 2004 | pmid = 15519310 | doi = 10.1016/j.bbamem.2004.06.013 | s2cid = 21763870 | url = https://pure.rug.nl/ws/files/3624524/2004BiochimBiophysActaPoolman.pdf }}</ref> Other than functioning in transport, some bacterial ABC proteins are also involved in the regulation of several physiological processes.<ref name=davidson/>

In bacterial efflux systems, certain substances that need to be extruded from the cell include surface components of the bacterial cell (e.g. capsular polysaccharides, [[lipopolysaccharides]], and [[teichoic acid]]), proteins involved in bacterial pathogenesis (e.g. [[hemolysis]], [[heme]]-binding protein, and alkaline [[protease]]), heme, [[hydrolytic enzymes]], S-layer proteins, competence factors, [[toxins]], [[antibiotics]], [[bacteriocins]], peptide [[antibiotics]], drugs and siderophores.<ref name=davidsonchen>{{cite journal | vauthors = Davidson AL, Chen J | title = ATP-binding cassette transporters in bacteria | journal = Annual Review of Biochemistry | volume = 73 | pages = 241–68 | year = 2004 | pmid = 15189142 | doi = 10.1146/annurev.biochem.73.011303.073626 }}</ref> They also play important roles in biosynthetic pathways, including extracellular polysaccharide biosynthesis<ref name="pmid9575204">{{cite journal | vauthors = Zhou Z, White KA, Polissi A, Georgopoulos C, Raetz CR | title = Function of Escherichia coli MsbA, an essential ABC family transporter, in lipid A and phospholipid biosynthesis | journal = The Journal of Biological Chemistry | volume = 273 | issue = 20 | pages = 12466–75 | date = May 1998 | pmid = 9575204 | doi = 10.1074/jbc.273.20.12466 | doi-access = free | hdl = 2434/611267 | hdl-access = free }}</ref> and [[cytochrome]] biogenesis.<ref name="pmid8181727">{{cite journal | vauthors = Poole RK, Gibson F, Wu G | title = The cydD gene product, component of a heterodimeric ABC transporter, is required for assembly of periplasmic cytochrome c and of cytochrome bd in Escherichia coli | journal = FEMS Microbiology Letters | volume = 117 | issue = 2 | pages = 217–23 | date = Apr 1994 | pmid = 8181727 | doi = 10.1111/j.1574-6968.1994.tb06768.x | doi-access = free }}</ref>

=== Eukaryotic ===

Although most eukaryotic ABC transporters are effluxers, some are not directly involved in transporting substrates. In the [[cystic fibrosis]] transmembrane regulator ([[Cystic fibrosis transmembrane conductance regulator|CFTR]]) and in the [[sulfonylurea]] receptor (SUR), ATP hydrolysis is associated with the regulation of opening and closing of ion channels carried by the ABC protein itself or other proteins.<ref name=goffeau/>

Human ABC transporters are involved in several diseases that arise from [[Polymorphism (biology)|polymorphisms]] in ABC genes and rarely due to complete loss of function of single ABC proteins.<ref name=pohl>{{cite journal | vauthors = Pohl A, Devaux PF, Herrmann A | title = Function of prokaryotic and eukaryotic ABC proteins in lipid transport | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1733 | issue = 1 | pages = 29–52 | date = Mar 2005 | pmid = 15749056 | doi = 10.1016/j.bbalip.2004.12.007 }}</ref> Such diseases include [[Mendelian]] diseases and complex genetic disorders such as cystic fibrosis, [[adrenoleukodystrophy]], [[Stargardt disease]], [[Tangier disease]], immune deficiencies, progressive familial intrahepatic [[cholestasis]], [[Dubin–Johnson syndrome]], [[Pseudoxanthoma elasticum]], persistent [[hyperinsulinemic hypoglycemia]] of infancy due to focal adenomatous [[hyperplasia]], X-linked [[sideroblastic anemia|sideroblastosis and anemia]], age-related [[macular degeneration]], familial hypoapoproteinemia, Retinitis pigmentosum, [[corneal dystrophy|cone rod dystrophy]], and others.<ref name=goffeau/> The human ABCB (MDR/TAP) family is responsible for [[multiple drug resistance]] (MDR) against a variety of structurally unrelated drugs. ABCB1 or MDR1 [[P-glycoprotein]] is also involved in other biological processes for which lipid transport is the main function. It is found to mediate the secretion of the steroid [[aldosterone]] by the adrenals, and its inhibition blocked the migration of [[Dendrite (non-neuronal)|dendritic]] immune cells,<ref name="pmid11502161">{{cite journal | vauthors = Randolph GJ | title = Dendritic cell migration to lymph nodes: cytokines, chemokines, and lipid mediators | journal = Seminars in Immunology | volume = 13 | issue = 5 | pages = 267–74 | year = 2001 | pmid = 11502161 | doi = 10.1006/smim.2001.0322 }}</ref> possibly related to the outward transport of the lipid [[platelet activating factor]] (PAF). It has also been reported that ABCB1 mediates transport of [[cortisol]] and [[dexamethasone]], but not of [[progesterone]] in ABCB1 transfected cells. MDR1 can also transport [[cholesterol]], short-chain and long-chain analogs of [[phosphatidylcholine]] (PC), [[phosphatidylethanolamine]] (PE), [[phosphatidylserine]] (PS), [[sphingomyelin]] (SM), and [[glucosylceramide]] (GlcCer). Multispecific transport of diverse endogenous lipids through the MDR1 transporter can possibly affect the transbilayer distribution of lipids, in particular of species normally predominant on the inner plasma membrane leaflet such as PS and PE.<ref name=pohl/>

More recently, ABC-transporters have been shown to exist within the [[placenta]], indicating they could play a protective role for the developing fetus against [[xenobiotic]]s.<ref name=pmid16460798>{{cite journal | vauthors = Gedeon C, Behravan J, Koren G, Piquette-Miller M | title = Transport of glyburide by placental ABC transporters: implications in fetal drug exposure | journal = Placenta | volume = 27 | issue = 11–12 | pages = 1096–102 | year = 2006 | pmid = 16460798 | doi = 10.1016/j.placenta.2005.11.012 }}</ref> Evidence has shown that placental expression of the ABC-transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are increased in preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis.<ref name="Journal of Clinical Endocrinology and Metabolism v 107">{{Cite journal |last1=Scott |first1=Hailey |last2=Martinelli |first2=Lilian M. |last3=Grynspan |first3=David |last4=Bloise |first4=Enrrico |last5=Connor |first5=Kristin L. |date=2022-03-24 |title=Preterm Birth Associates With Increased Placental Expression of MDR Transporters Irrespective of Prepregnancy BMI |journal=The Journal of Clinical Endocrinology and Metabolism |volume=107 |issue=4 |pages=1140–1158 |doi=10.1210/clinem/dgab813 |issn=1945-7197 |pmid=34748636|s2cid=243863723 |doi-access=free }}</ref> To a lesser extent, increasing maternal BMI also associated with increased placental ABC-transporter expression, but only at preterm.<ref name="Journal of Clinical Endocrinology and Metabolism v 107" />