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proteins involved  involved in a number of  cellular  processes Poly (ADP-ribose) polymerase ( polymerase (PARP PARP)) is a family of proteins involving mainly  mainly DNA repair  andprogrammed andprogrammed cell death. death.

Members of PARP famil The PARP PARP family comprises ! members (" putative). They have ha ve all very different structures and functions in the cell. •

PARP1## PARP2 # $PARP (PARP4 (PARP4)# )# Tan%yrase& and &' (PARP&a or TNKS TNKS## and PARP&b PARP1 or TNKS2 ) have a confirmed PARP activity.



PARP3## PARP6 # TIPARP  (or  (or thers include PARP3 *PARP!*)# PARP8 # PARP9 PARP9## PARP10 # PARP11 PARP11## PARP12 # PARP14# PARP14# PARP15 # andPARP16   andPARP16 .

PARP PA RP st structure ructure+edit source , source , edit betaPARP is composed of four domains of interest a  a  DNA&binding domain domain## a caspase&cleaved domain (see domain.. The DNA&binding domain is composed of belo/)# an auto&modification domain# and acatalytic a catalytic domain t/o  0inc finger  motifs. t/o motifs. 1n the presence of damaged DNA (base pair&e2cised)# the DNA&binding domain /ill bind the DNA and induce a conformational shift. shift. 1t has been sho/n that this binding occurs independent of the other domains. This is integral in a programmed cell death model based on caspase caspase  cleavage inhibition cleavage inhibition of PARP. The auto&modification domain is responsible for releasing the protein from the DNA after catalysis. A Also# lso# it plays an integral role in cleavage&induced inactivation.

3unctions +edit source , source , edit betaPARP PA RP is found in the cell4s nucleus. The main role is to detect and signal single&strand DNA brea%s (556) activation is an immediate cellular response to the en0ymatic machinery involved in the556 the 556 repair . PARP activation to metabolic# chemical# or radiation&induced DNA 5 556 56 damage. nce PA PARP RP detects a 556# it binds to the DNA# and# after a structural change# begins the synthesis of a poly (ADP&ribose) (ADP&ribose) chain (PAR) as a signal for the other DNA&repairing DNA&repairing en0ymes such as DNA ligase 111 (7ig111)# DNA polymerase polymerase beta (pol8)# and scaffolding proteins such as 9&ray cross&complementing gene  (9R::). After After repairing# the PAR chains are degraded via Poly(ADP&r Poly(ADP&ribose) ibose) glycohydrolase glycohydrolase  (PAR;). +1t is interesting to note that NAD< NAD< is  is re=uired as substrate for generating ADP&ribose ADP&ribose monomers. The overactivation of PARP PARP may deplete the stores of cellular NAD< and induce a progressive A ATP TP depletion# since glucose o2idation is inhibited# and necrotic cell death. 1n this regard# PARP is inactivated inactivated by caspase&> cleavage (in a specific domain of the en0yme) during programmed p rogrammed cell death. PARP PA RP en0ymes are essential in a number of cellular functions# +'- including e2pression of inflammatory PARP is re=uired for the induction of 1:AM& gene e2pression by smooth muscle cells# in genes+>- PARP response to TN3. TN3.+?-

 Activity+edit source , source , edit betaThe catalytic domain is responsible for Poly (ADP&ribose) polymeri0ation. polymeri0ation. This domain has a highly  that is common to all members of the PARP family. PAR polymer can reach lengths of up conserved motif  that to '"" nucleotides before inducing apoptotic processes. The formation of PAR PAR polymer is similar to the formation of DNA polymer from nucleoside triphosphates. Normal DNA synthesis re=uires that

 

a pyrophosphate pyrophosphate  act as the leaving group# leaving a single phosphate group lin%ing  lin%ing  deo2yribose sugars. sugars.  PAR is synthesi0ed using nicotinamide (NAM) nicotinamide (NAM) as the leaving group. This leaves a pyrophosphate as the lin%ing group bet/een ribose sugars rather than single phosphate groups. This creates some special bul% to a PAR bridge# /hich may have an additional role in cell signaling.

Role in repairing DNA nicks+edit source , source , edit betane important function of PARP PARP is assisting in the repair of single&strand DNA nic%s. 1t binds sites /ith single&strand brea%s through its N&terminal 0inc fingers and fingers and /ill recruit 9R::# 9R::# DNA ligase ligase1111# DNA polymerase beta# polymerase  beta# and a %inase to the nic%. This is called called  base excision repair  ([email protected]). PARP&' has been sho/n to oligomeri0e /ith PARP& PARP& and# therefore# is also implicated in [email protected] The oligomeri0ation has also been sho/n to stimulate PARP catalytic activity. PARP& is also %no/n for its role in transcription through chromatin  by PARylating PARylating histones and rela2ing chromatin structure# thus allo/ing remodeling of  chromatin transcription comple2 to access genes. PARP& and PARP&' are activated by DNA single&strand brea%s# and both PARP& and PARP&' %noc%out mice have severe deficiencies in DNA repair# and increased sensitivity to al%ylating agents or ioni0ing radiation.+-

PARP PA RP activity and lifespan +edit source , source , edit betaPARP activity (/hich is mainly due to PARP) measured in the permeabili0ed mononuclear  leu%ocyte blood leu%ocyte blood cells of thirteen mammalian species (rat# guinea pig# rabbit# marmoset# sheep# pig# cattle# pigmy chimpan0ee# horse# don%ey# gorilla elephant and man) correlates /ith ma2imum lifespan of the species. +- The difference in longevity bet/een the longest& (humans) and shortest&lived species tested (rat) /as &fold. The automodification reaction of human and rat PA PARP& RP& /as analy0ed and human PARP& PARP& /as found to have a t/o&fold higher poly(ADP&ribosyl)ation capacity than the rat en0yme# /hich could account# in part# for the higher PARP PARP activity in humans than rats. +!-

 7ymphoblastoid cell 7ymphoblastoid cell lines established from blood samples of humans /ho /ere centenarians (""

years old or older) have significantly higher PARP PARP activity than cell lines from younger ('" to !" years old) individuals#+B- again indicating a lin%age bet/een longevity and repair capability. individuals# These findings suggest that PARP PARP&mediated &mediated DNA repair capability contributes to mammalian longevity. Thus these findings lend support to the DNA damage theory of aging  aging  /hich assumes that un&repaired +C-+""DNA damage is the underlying cause of aging and a nd that DNA repair capability contributes to longevity. longevity.+C-+

Role of tankyrases+edit source , source , edit betaThe tan%yrases are PARPs that comprise  comprise  an%yrin repeats repeats## oligomeri0ation domain (5AM)# and a PARP cataltic !o"ain (P:D). !o"ain (P:D). Tan%yrases are also %no/n as PARP&a and PARP&b. They /ere named for their interaction /ith the telomere&associated TR3 TR3 proteins and an%yrin repeats. They may allo/ the removal of telomerase&inhibiting comple2es from chromosome ends to allo/ for telomere maintenance. Through their 5AM domain and ANs# they can oligomeri0e and interact /ith many other proteins# such as TR3# TA6B' (TNKS1#P1 ( TNKS1#P1)# )# $R#14# $R#14# 1RAP# NuMa# @6NA&# and Mcl& Mcl&.. They have multiple roles in the cell# vesicular traffic%ing through its interaction in $%&T4 'esicle (;5$s) 'esicle (;5$s) /ith ins(lin)responsi'e a"ino pepti!ase (1RAP). pepti!ase (1RAP). 1t also plays a role in spindle assembly through its interaction /ith n(clear "itotic apparat(s (NuMa)# apparat(s (NuMa)# therefore allo/ing bipolarity. 1n the absence of TNs# mitosis arrest is observed chec%point. TNs can also PARsylate Mcl&7 and Mcl&5 and in pre&anaphase through Mad'  Mad' %inetochore chec%point. inhibit both their pro& and anti&apoptotic function. Relevance of this is not yet %no/n.

 

Role in cell death+edit source , source , edit betaParp can be activated in cells e2periencing stress andEor DNA damage. Activated Activated Parp can deplete the  ATP  AT P of a cell in an attempt to repair the damaged D DNA. NA. A ATP TP depletion in a cel celll leads to lysis lysis and cell death (necrosis). PARP PARP also has the ability to induce programmed cell death# via the production of PAR# /hich stimulates mitochondria to release A13 release A13..+- This mechanism appears to be caspase&independent. :leavage of Parp# by en0ymes such as caspases or cathepsins# typically inactivate Parp. The si0e of the cleavage fragments can give insight into /hich en0yme /as responsible for the cleavage# and can be useful in determining /hich cell death path/ay has been activated.

Role in epigenetic DNA DN A modification+edit source , source , edit betaPARP&mediated PA RP&mediated post&translational post&translational modification of p proteins roteins such as :T:3 can affect the amount of DNA methylation at :p; dinucleotides. This regulates the insulator features of :T:3 can differential differentially ly mar% the copy of DNA inherited from either the maternal or the paternal DNA throug through h the process %no/n as  as genomic imprinting. imprinting. PARP has also been proposed to affect the amount of DNA methylation methylation by directly binding to the DNA methylt methyltransferase ransferase DNMT& DNMT& after attaching poly ADP&ri ADP&ribose bose chains to itself after interaction /ith :T:3 and affecting DNMTFs en0ymatic activity .

source , edit betaPARP PA RP 1nactiva 1nactivation tion+edit source , PARP is inactivated by caspase  caspase cleavage. 1t is believed that normal inactivation occurs in systems /here DNA damage is e2tensive. 1n these cases# more energy /ould be invested in repairing damage than is feasible# so that energy is instead retrieved for other cells in the tissue through programmed cell death. 6esides degradation# there is recent evidence about reversible do/nregulation mechanisms for PARP PARP## among these an *autoregulatory loop*# /hich is driven by PARP itself and modulated by GG transcription  transcription factor.+'the GG Hhile in vitro vitro  cleavage by caspase occurs throughout the caspase family# preliminary preliminary data suggest that acid '?  '? caspase&> and caspase&! are responsible for in vivo  vivo cleavage. :leavage occurs at aspartic acid and  glycine and glycine '#  '# separating PARP PARP into a '?%DA and BC%DA segment. The smaller moiety includes the 0inc finger motif re=uisite in DNA binding. The BC %Da fragment includes the auto&modification domain and catalytic domain. The putative p utative mechanism of P:D activation via PARP PARP inactivation relies on the separation of the DNA&binding region and the auto&modification auto&modification domain. The DNA&binding region is capable of doing so independent of the rest of the protein# cleaved or not. 1t is unable# ho/ever# to dissociate /ithout the auto&modification domain. 1n this /ay# the DNA&binding DNA&binding domain /ill attach to a damaged site and be unable to effect repair# as it no longer has the catalytic domain. The DNA&binding domain prevents other# non&cleaved PARP PARP from accessing the damaged site and initiating repairs. This model suggests that this Isugar plugJ can also begin the signal for apoptosis. en0yme that  that brea%s a phosphodiester bond bond.. Ksually# people  A phosphodiesterase  ([email protected]) is any en0yme phosphodiesterase ([email protected]) spea%ing of p*osp*o!iesterase of p*osp*o!iesterase are  are referring to  to cyclic nucleotide  nucleotide phosphodiesterases# /hich have great clinical significance and are described belo/. Lo/ever# Lo/ever# there are many other families of phosphodiesterases# including phospholipases phospholipases  : and D# autota2in autota2in## sphingomyelin phosphodiesterase## DNases phosphodiesterase DNases## RNases RNases## and restriction endonucleases( endonucleases(/hich all brea% the phosphodiester bac%bone of DNA  DNA or RNA RNA)# )# as /ell as numerous less&/ell&ch less&/ell&characteri0ed aracteri0ed small&molecule phosphodiesterases.

 

The cyclic nucleotide phosphodiesterases phosphodiesterases comprise  comprise a group of en0ymes en0ymes that  that degrade the  the phosphodiester  bond  in the second messenger  moleculescAMP bond  moleculescAMP  and  and c;MP. c;MP. They regulate the locali0ation# duration# and amplitude of cyclic nucleotide signaling /ithin subcellular domains. [email protected] are therefore important regulators of  signal transduction mediated transduction mediated by these second messenger molecules. :ontents hide--    +hide



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Listory+edit source  source , edit betaThese multiple forms (isoforms or subtypes) of phosphodiesterase /ere isolated from rat brain b rain using +-+'polyacrylamide gel electrophoresis in the early C!"s +-+' and /ere soon after/ard sho/n to be selectively +>-+??inhibited by a variety of drugs in brain and other tissues. +>-+

The potential for selective phosphodiesterase inhibitors to inhibitors to be used as therapeutic agents /as predicted as early as C!! by Heiss and Lait. +- This prediction has no/ come to pass in a variety of fields Dia0epam  as a [email protected]? inhibitor  ).  ). (e.g. $iagra  $iagra as a [email protected] inhibitor and Dia0epam

source ,  edit betaNomenclature and classification+edit source , The [email protected] nomenclature signifies the P+, -a"il  /ith  /ith an Arabic numeral# then a capital letter denotes  derived the .ene in t*at -a"il # and a second and final Arabic numeral then indicates the  the  splice 'ariant  derived from a single gene (e.g.# [email protected]:> family # gene :# splicing variant >) +The superfamily of [email protected] en0ymes is classified into  famili families# es# namely  namely  [email protected]&[email protected]# [email protected]&[email protected]# in mammals mammals.. The classification is based on

 

[email protected] substrate specificities by en0yme family. 6oth means it hydroly0es both cAMP and c;MP.



amino acid  acid se=uences



substrate specificities



regulatory properties



pharmacological properties



tissue distribution

Different [email protected] of the same family are functionally related despite the fact that their amino acid se=uences can sho/ considerable divergence. +!- [email protected] have different substrate specificities. 5ome are cAMP& selective hydrolases ([email protected]?# ! and B) others are c;MP&selective c;MP&selective ([email protected]# # and C). thers can hydrolyse both cAMP and c;MP ([email protected]# '# ># "# and ). [email protected]> [email protected]> is  is sometimes referred to as c;MP&inhibited phosphodiesterase. Although [email protected]' can [email protected]' can hydroly0e both cyclic nucleotides# binding of c;MP to the regulatory ;A3&6 domain /ill increase cAMP affinity and hydrolysis to the detriment of c;MP. This mechanism# as /ell as others# allo/s for cross&regulation of the cAMP and c;MP path/ays.

:linical significance+edit source , source , edit betaPhosphodiesterase en0ymes are often targets for pharmacological inhibition due to their uni=ue tissue distribution# structural properties# and functional properties. +B1nhibitors of [email protected] can [email protected] can prolong or enhance the effects of physiological processes mediated c;MP  by inhibition of their degradation by [email protected] by  by cAMP or  cAMP or  c;MP 5ildenafil ($iagra) is an inhibitor of  c;MP&specific phosphodiesterase 5ildenafil ($iagra) phosphodiesterase type # /hich enhances the dysfunction.. 5ildenafil vasodilatory effects of c;MP in the corpus cavernosum and cavernosum and is used to treat erectile dysfunction is also currently being investigated for its myo& and cardioprotective effects# /ith particular interest being given to the compoundFs therapeutic value in the treatment of Duchenne muscular dystrophy +C- and benign prostatic hyperplasia dystrophy  hyperplasia..+"[email protected] inhibitors have been identified as ne/ potential therapeutics in areas such as pulmonary arterial  hypertension arterial hypertension## coronary heart disease disease## dementia# dementia# depression# depression# and schi0ophrenia schi0ophrenia.. :ilosta0ol  inhibits [email protected]> [email protected]>.. This inhibition allo/s  allo/s red blood cells to cells to be more able to bend. This is :ilosta0ol (Pletal) inhibits  claudication## as the cells can maneuver through constricted veins useful in conditions such as intermittent claudication and arteries more easily.

 

9anthines such as caffeine# theobromine# and thyroid hormone are phosphodiesterase inhibitors (enhance lipolysis as inhibition of phosphodiesterase en0yme# thereby preserving cAMP cAMP## also activating %inase en0yme# /hich phosphorylates hormone&sensitive lipase and activates li

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