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UNC-Chapel Hill ENVR 132 - Study Guide

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t.*xiII.IV.VI.x vn.,al-Zl- 2oo3 tecro(n-e ruPPlemeN+n1 Mnreel*LCnlcul RewNt in Bioche^ktn Md 'uotecular Biolagv l5(l)ri5-70 {2000)Induction, Regulation, Degradation, andBiological Significance of MammalianMetallothioneinsA. T Mites,l G. M. Hawkswarth,l J. H. Beattie,2 and V Radilla3'Departrnent oi Medicine and Therapeutics, Unvefsity of Aberdeen, Polwath Building'Foresterhill Ab€rdeen, AB25 2ZD, ScoUand, UK; ?The Rowett Besearch lnsti'tute.Greenburn Road, Bucksburn, Aberdeen AB21 9SB, Scotland, tlK; rschoo of Applied5q1-anq-.5, The Roberl Gordon University, Aberdeen, AB25 1HG' Scotland' UKCorresponding aulhor: Dr. V. Bodilla, School of Appiied Sciences, The Robert GordonUniversity, Aberdeen, AB25 1HG, Scotland, UKRel6ree: Or. Curlis O. Klaassen, Departmenl ot Pharmacologv, Toxicologv and Therapeutics'Universilv ol Kansas Medic?l Center, Kan$s City, KSTABLE OF CONTENTSDEFINITION AND CLASSIFICATION OF NIT .....,.....,,,, -3636METALLOTH]ONENBIOCIIEMICAI AND PHYSICOCT{EMICAI PROPERTTES OFMT...... ... .. ...........MANTMALIAN VIT ISOFOtu\lS ....... . -. - .. .... .. .3'7btDUcTION AND REGULATION OF MT .................................. . ..... ... 38, T-"-- .--i;.--r . .n,r. - . ....... 19A. i ItursurrlJ'LUIdB. Posttransciptional Control.........-... ..--. ..... 40C. Cell-Specific andMetal-lnducedDifferentialTranscriptionalRegulalion of MT..... .. .. . ... .. .... .... .... 41DEGRADATION OF MT ..................... ... -- .. .. .. . 42BIOLOGICAI ROLES OF MT....... ......... .......... .. . 43A. Merallothionein, Cell Proliferation, and Apoptosis .. - - 43B. Homeostasis of Essenuxl l\letrls .. .... .. -!5C. MT as Free Radical Scavengel ......- ... ...... ...-. . .. ...... .. " 46D. Metal DetoKiJication . ..- ..- .. .... - -- '16MT-i AND OTIrER BRAIN METAILOTHIONEINS ...... .. ............ ... ...... ..48vm.x.X-10.1G9218/00/$ 50O 2000 by CRC Pess LLCARE TI{ERE SEPARATE FLINCTIONS FOR THE DIFFERENTMT ISOFORMS? .....49505lCONCLUSIONSREFERENCESABSTRACT: MTs are small cvsteine-rich met l-binding pro€its found in many speciesand, although there are differences betweelr them' il is of note that they ha\/e a great dealof sequence and sructural homology. Mammalian MIs are 6l or 62 amino acrd polypeP-tides containing 20 conser'r'ed cysteine residues that underyin the bindirg of metals Theexistence of MT across species is indicative of i15 biological demand while the conseraa-tion of cysteines indicates that L\ese are undoubtedly ce.ral to trhe function of this protein'Four MI isoforms have been found so far. MT- 1 MT-2, MT-3 and MT-4. but these alsohave subtypes wirh 17 MT genes ideniiiLed in man, of which 10 are ktown to be funcdonalDiff€rent cells express different Mr isoforms *ith va{'ing levels of expression perhaps asa rcsult of the different funciion of each isofoml Elen dfferent metals induce and bind toMTs to different extents. Over 40 years ofresearch into MT have yielded much info'matronon rhis protein, but have failed !o assiSn lo it a deflrutive biological rcle The fact thatmultiple MT isoforms exist, and the greal vadery of substances and agenis that act asinduc;rs, tunher complicates the search for the biological role of MIs This ,-nic1e revielvsthe current knoqledge on the biocherlxsrry, irduclion regLrlation, and degradation ofthisprolein in man1mals, with a padcular emphasis on human MTs It also conslders thepossibie biological roles ofdis prolein, which include particiPation in cell proliferatron andapoplosis, homeoslasis of essential metals ceilular free radjcal scavengrng and melaldetoxification.I. METALLOTHIONEINMeallothionern lMT, \a as ftrst ldert]fied as a cadfiuum-binding protein in equinelcdney in t957rand was cuosequenLly purified and characterised by Kagi and Vallee.?lMT is characlenzed by irs low molecularweighr 6 ro TlDa\. hrgh metJ content. char-acteristic amino acid composition - highcontent of conser-ved cysteire residues andabsence of aJomalic zmino acids _ specto-scopic feanrres indicaling tetiaiedEl-tbrolatecomplexes and metal thiolate cluslers.a MTis a ubiquitous melai binding protern \rr'ithsfong alfirrry for group lb and []b Lransi-doD metals. MT is a major zinc bindinginlracellular thiol and in many cases repre-qenLs Lhe srngle mos! abundant inudcellul"rprotein thiol. However, despite the accumu-lation of delailed information on bolb thebiochemical and molecular aspec$ of MTstucture and expression, its bioiogical roleis srill not clearly undeBlood more than 40years after its discovery. MT is thoughl !obe involved in the homeostasis of essentialmelalslr0 and melal deloxification.6 rr 16 asoriginally suggested by Piscator in 1964,r7 r3aitiough it also apPears to act as a polentftee radical scavenger.re rrII. DEFINITION ANDCLASSIFICATION OF MTMTs were originally classified accord_ing to the deflnition rha! they should be"polypeprides resembling equine renalmetallothionein in several of their fea-tues".l'MTs were i$tially divided into threeclasses according to their structulzl charac-ren.ucc Clas\ I Mfs are dehned asPol) pepude. with a n:gh degree ofcystelne conser-vation compared to those in equine kidneyCtass II MTs are polypeptides with lesswell conseryed cysEine residues, oniy drs-tant-ly related to equine MT. Class fiI MTsare defined as atypical, nonffanslationa-Ilysynthesized metal thiolate polyPeptides.r? rrThis classification has !ow been supersededby a complex but more smngent evollluon-ary classifi cadon into familjes. subfa,'nilies.suberoups and isoforms.?oThere is considerf,ble sequetce homol-ogy emongst lvlTs from differenl speciesFol erampLe, i! mammals 567o of all lITresidues ale conserved. These compdse all20 cysteine residues ard most ofthe lysines,sennes aod arginines.rs These conser'/edresidues are thought lo play a role in metalbinding.r6 Lysines mey be itrvolved in thederoxrficaion function of lvlTT rs and thosein rhe alpha domam appear lo be lmpoflantn mamtaining the conformational integntyofthe protem23 by interactioo with lhe metalthiolate clusters.'e Snrdies using mutMt MTssuggest *lat the consefl'ed seames in thelvlT sequence could play a role in the stabil-Lry of metal-bindi;tg ligands roThere is also similaity across PhylaNIT ir, Neurospora crasrd contajns only 25amlno acids and while it is signilicantlysmaller than mammaliall MT, its pnmaryculcrure is very sim.der Io the xmino-rer-Tinal half of mammalian MTs.rr Thus. lheclass I MTs display divergent evolution.since the differences in amino


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UNC-Chapel Hill ENVR 132 - Study Guide

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