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fermentebi rogorc katalizatorebi

fermentebi aris cilebi, romlebic asruleben katalizatoris funqcias - zrdian


qimiuri reaqciis siCqares. fermentebi ikavSireben reagentebs (substratebs), gardaqmnian
maT produqtebad da gamoaTavisufleben garemoSi. reaqciis mimdinareobisas
SesaZlebelia xdebodes fermentis modificirebac, magram reaqciis dasrulebisas isini
ubrundebian sawyis mdgomareobas. garda qimiuri reaqciis siCqaris zrdisa, fermentebi
organizmis metabolizmis regulaciaSi mniSvnelovan rols TamaSoben.

fermentebis damakavSirebeli centrebi. fermenti ikavSirebs substrats da gardaqmnis


produqtSi. substrati ukavSirdeba fermentSi arsebul specifiur substratis
damakavSirebel centrs (saiTs). dakavSireba xdeba aminomJavebis radikalebTan
urTierTqmedebis saSualebiT. moculobiTi geometria, romelic saWiroa substratis da
fermentis urTierTqmedebisTvis, ganapirobebs fermentebis specifiurobas substratis
mimarT da gansazRvravs specifiuri produqtis warmoqmnas.

fermentis aqtiuri (katalizuri) centri. substratuli saiTi gadaifareba fermentis


aqtiuri centriT (fermentis is ubani, sadac mimdinareobs reaqcia). aqtiur centrSi
katalizi mimdinareobs im funqciuri jgufebis meSveobiT, romlebsac warmoadgenen
kofermentebi (koenzimebi), mWidrod dakavSirebuli metalebi da ra Tqma unda fermentis
aminomJavuri radikalebi.

aqtivaciis energia da gardamavali mdgomareoba. katalizuri saiTis funqciuri jgufebi


aaqtiureben substratebs da amiT amcireben im energias, romelic saWiroa maRali
energiis mqone mdgomareobis, e.w. gardamavali kompleqsis, warmosaqmnelad.
qimotripsinis magaliTi gviCvenebs fermentuli katalizis meqanizms, romelic moicavs
zogad mJava-fuZe katalizs, kovalenturi intermediatebis warmoqmnas, gardamavali
mdgomareobis stabilizacias.

pH da temperaturuli profili. fermentebs axasiaTebT funqcionirebisTvis


optimaluri pH sazRvrebi, romlebic damokidebulia im funqciuri jgufebis pK-ze,
romlebic monawileoben katalizSi da im urTierTqmedebebSi, romlebic saWiroa sam-
ganzomilebiani struqturis Sesaqmnelad. temperaturis zrda aradenaturirebad
sazRvrebSi iwvevs fermentuli reaqciis siCqaris zrdas.

meqanizmiT ganpirobebuli inhibitorebi. mravali wamlis da toqsinis efeqturoba


damokidebulia maT unarze, daainhibiron romelime fermenti. yvelaze Zlieri
inhibitorebia kovalenturi inhibitorebi, is nivTierebebi, romlebic warmoqmnian
kovalentur kavSirebs fermentis aqtiuri centris reaqtiul jgufebTan da gardamavali
mdgomareobis analogebi, romlebic emsgavsebian gardamavali mdgomareobis kompleqss.

fermentebis nomenklatura. fermentebis dasaxelebis umetesoba mTavrdeba “aza”-Ti.


fermentebs, rogorc wesi, aqvT rogorc miRebuli saxelwodeba, aseve sistematuri
klasifikaciiT miniWebuli saxeli da fermentebis komisiis (Enzyme Commission EC)
mier miniWebuli nomeri.
I. fermentebiT katalizebuli reaqciebi
fermentebi uzrunvelyofen organizmSi mimdinare reaqciebis siCqares, specifiurobas da
regulatorul kontrols. fermentebis udidesi nawili cilebia, romlebic moqmedeben
rogorc katalizatorebi. fermentebis mier katalizirebul reaqciebSi 3 ZiriTadi
safexuria:
1. substratis dakavSireba : E + S-> ES
2. dakavSirebuli substratis gardaqmna produqtad: ES -> EP
3. produqtis gamoTavisufleba:
fermenti ikavSirebs reaqciis substratebs,
aZlevs maT erTmaneTis mimarT reaqciaSi
Sesasvlelad swor geometriul orientacias.
amis Semdeg monawileobs produqtis
warmosaqmnelad saWiro bmebis warmoqmnasa da
gaxleCvaSi, gamoanTavisuflebs produqtebs da
ubrundeba sawyis mdgomareobas.

Reaction catalyzed by glucokinase, an example of enzyme


reaction specificity.
Glucokinase catalyzes the transfer of a phosphate from
ATP to carbon 6 of glucose. It cannot rapidly transfer a
phosphate from other nucleotides to glucose, or from ATP
to closely related sugars such as galactose, or from ATP
to any other carbon on glucose. The only products formed
are glucose 6-phosphate and ADP.

fermentebi ar qmnian axal reaqciebs, isini


ubralod iwveven reaqciebis siCqaris zrdas.
fermentebis katalizuri simZlavre (sxva
sityvebiT, maT mier katalizebuli reaqciis
siCqare, gayofili arakatalizebuli reaqciis
siCqareze) 106-an 1014-is farglebSi meryeobs.
aseTi simZlavris gareSe nervis gamtarianoba, gulis kunTis SekumSva, sakvebis moneleba
iqneboda sicocxlisTvis Seusabamod neli. fermentebis unars, gamoarCion mravali,
erTmaneTis msgavsi nivTierebidan mxolod erTi romelime naerTi, specifiurobas
uwodeben. fermenti gardaqmnis substrats mxolod erT produqtad. fermentebis mier
katalizirebuli reaqciebis rogorc specifiuroba, aseve siCqare ganpirobebulia
specifiuri aminomJavebis unikaluri TanmimdevrobiT, romelic fermentis sam-
ganzomilebian struqturas qmnis.

a. katalizuri saiTi

qimiuri reaqciis katalizirebisTvis fermenti warmoqmnis ferment-substratul


kompleqss katalizur centrSi. rogorc wesi, aqtiuri centri warmoadgens Rrmuls an
naprals, romelic iqmneba polipeptiduri jaWvis erTi an ramdenime ubnis
monawileobiT. aqtiuri centris farglebSi ganlagebuli kofermentebi da
polipeptiduri jaWvis funqciuri jgufebi monawileoben substratis molekulebis
gardaqmnaSi produqtebad.

reaqciis dasawyisSi substratis molekulebi ukavSirdebian maT damakavSirebel


centrebs. damakavSirebeli centris sam-ganzomilebiani struqtura fermentis napralSi
iZleva substratis molekulebis reaqtiuli nawilebis sworad ganlagebis saSualebas.
dakavSirebuli substratebis erTmaneTTan siaxlove da precizuli orientacia
erTmaneTis mimarT ganapirobeben fermentebis katalizur simZlavres.

aqtiuri centri aseve Seicavs funqciur jgufebs, romlebic uSualod monawileoben


reaqciaSi. funqciuri jgufebi ekuTvnis polipeptidur jaWvebs an (da) kofaqtorebs
(metalebi an organuli molekulebi - e.w. koenzimebi). substratis dakavSireba iwvevs
fermentis konformaciis Secvlas, romelsac Tan mosdevs damatebiTi urTierTqmedebebi
substratsa da fermentis funqciur jgufebs Soris (mag. koenzimi SeiZleba
daukavSirdes substrats kovalenturi bmiT an amino mJavis radikalma moaSoros
protoni substrats). aqtivirebuli substratebi da fermenti qmnian e.w. gardamaval
kompleqss, maRali energiis mqone arastabilur eleqtronul konfiguracias, romelic
Sualeduria substratsa da produqts Soris. damatebiTi kavSirebi fermentTan
astabilizeben gardamavali mdgomareobis kompleqss da amcireben misi warmoqmnis
energias.

Reaction in the enzyme active catalytic site.


A. The enzyme contains an active catalytic site, shown in dark blue, with a region or domain where the
substrate binds. The active site also may contain cofactors, nonprotein components that assist in catalysis.
B. The substrate forms bonds with amino acid residues in the substrate binding site, shown in light blue.
Substrate binding induces a conformational change in the active site.
C. Functional groups of amino acid residues and cofactors in the active site participate in forming the
transition state complex, which is stabilized by additional noncovalent bonds with the enzyme, shown in blue.
D. As the products of the reaction dissociate, the enzyme retums to its original conformation.

gardamavali kompleqsi iSleba produqtebad, romlebic disocireben fermentidan.


fermenti, rogorc wesi, ubrundeba sawyis mdgomareobas. Tavisufali fermenti Tavidan
ikavSirebs substratebs da cikli meordeba.

b. substratis damakavSirebeli saiTi.


fermentis specifiuroba (unari, Sevides reaqciaSi mxolod erT substratTan)
ganpirobebulia aminomJavebis specifiuri radikalebis sivrculi ganlagebiT, romelic
qmnis damakavSirebel centrs da axdens substratis aqtivacias reaqciis mimdinareobisas.
ferment-substratuli urTierTqmedeba aRiwereba “klite-gasaRebis” an “inducirebuli
Sesabamisobis” modeliT.

1. substratis dakavSirebis “klite-gasaRebis” modeli


substratis damakavSirebeli saiTi warmoqmnilia aminomJavebis radikalebis mier. isini
qmnian komplementarul samganzomilebian zedapirs, romelic “cnobs”substrats da
ikavSirebs mas mravali hidrofoburi, eleqtrostatikuri urTierTqmedebebiT an
wyalbaduri bmebiT. substratis damakavSirebel centrSi monawile aminomJavebis
radikalebi SeiZleba iyvnen cilis sxvadasxva ubnebidan, rogorc es glukokinazas
magaliTze iqna naCvenebi. substratisgan mcired gansxvavebuli nivTierebac ki steriuli
winaaRmdegobis da muxtebis-repulsirebis gamo ver ukavSirdeba ferments. am modelSi
substratis da misi damakavSirebeli saiTis komplementaroba Zveleburi yaidis
boqlomis da martivi gasaRebis msgavsia.

Glucose binding site in glucokinase.


A. Glucose, shown in blue, is held in its binding site by multiple hydrogen bonds between each hydroxyl group
and polar amino acids from different regions of the enzyme amino acid sequence in the actin fold . The
position of the amino acid residue in the linear sequenceis given by its number. The multiple interactions
enable glucose to induce large conformational changes in the enzyme (Modified frorn Pilkis SJ, Weber lT,
Harisson RW, Bell GI. J Biol Chem. Glucokinase: structaral analysis of a protein involved in susceptibility to
diabetes 1994;21925-21928)
B. Enzyme specificity is illustrated by the comparison of galactose and glucose. Galactose difrers from
glucose only in the position of the -OH goup shown in blue. However, it is not phosphorylated at a significant
rate by the enzyme.Cells therefore require a separate galactokinase for the metabolism of galactose.

2. substratis dakavSirebis “inducirebuli


Sesabamisobis” modeli.
substratsa da damakavSirebel saiTs Soris
komplementaroba sruli suraTis mxolod nawilia.
substratis dakavSirebis Sedegad fermenti
ganicdis konformaciul cvlilebebs
(inducirebuli Sesabamisoba”), rac gadaaadgilebs
aminomJavebis radikalebs aqtiur centrSi da
zrdis dakavSirebisTvis saWiro urTierTqmedebebis
raodenobas (ix. suraTi)
Conformational change resulting from the binding of glucose to hexokinase.
(The figure is actually yeast hexokinase, which is more similar to human
glucokinase than it is to the other human hexokinase isozymes). The shaded
and unshaded areas show the two domains (four subdomains) that form the
actin fold with its ATP-binding cleft.
A. Free enzyme.
B. With glucose bound, the cleft closes, forming the ATP binding site. The
closure of the cleft when glucose binds to hexokinase (or human glucokinase)
is one of the largest “induced fits” known.
inducirebuli Sesabamisobis modeli iTvaliswinebs, im garemoebas, rom substratis
damakavSirebeli centri ar aris rigiduli saketi, aramed fermentis samganzomilebiani
struqturis mier warmoqmnili dinamiuri sivrculi zedapiria. substratis mier
gamowveuli konformaciuli cvlilebis funqcia mdgomareobs imaSi, rom iseTnairad
gadaadgilos aminomJavebis radikalebi aqtiur centrSi, rom gaioldes reaqciis
mimdinareoba, moxdes kosubstratis dakavSirebis gaumjobeseba an mezobeli
suberTeulis gaaqtiureba kooperaciuli urTierTqmedebebiT. glukozas dakavSirebiT
gamowveuli glukokinazas aqtinis foldis konformaciuli cvlileba amis kargi
magaliTia. inducirebuli Sesabamisoba am SemTxvevaSi praqtikulad fermentis mTel
molekulas moicavs, ris Sedegadac ixureba foldSi naprali, rac ATP-is dakavSirebas
aZlierebs, iwvevs aqtiuri centridan wylis gamodevnas (rac SeiZleba reaqciis
mimdinareobis xelSemSleli yofiliyo). amgvarad, katalizur centrSi mravalnairi
urTierTqmedebebi substratsa da ferments Soris ganapirobeben rogorc substratis
gamocnobas, aseve reaqciis Semdeg etaps - gardamavali mdgomareobis kompleqsis
warmoqmnas.

g. gardamavali mdgomareobis kompleqsi.


imisTvis, rom SesaZlebeli gaxdes reaqciis mimdinareoba, substratebma unda ganicadon
aqtivireba. Tu avagebT grafiks, romelic gviCvenebs substratis energetikuli donis
cvlilebas reaqciis msvlelobisas, miviRebT mruds. am mrudis maqsimaluri done
substratis da aseve produqtis sawyis mdgomareobaze maRla mdebareobs (ix. suraTi).
energiis es maqsimaluri done Seesabameba gardamaval mdgomareobas. zogierTi
fermentuli reaqciis SemTxvevaSi am mdgomareobas Seesabameba substratis qimiuri
kavSirebis maqsimaluri daZabva, sxva SemTxvevebSi substratis eleqtronuli
konfiguraciis daWimva da arastabiluri mdgomareoba. energiis donis maqsimumi

Seesabameba substratis
yvelaze arastabiluri
mdgomareobis
konfiguracias da iseT
mdgomareobas, rodesac
cvalebadi substrati
yvelaze mWidrod aris

Energy diagram showing the


energy levels of the substrates
as they progress toward
products in the absence of
enzyme.The substrates must
pass through the high-energy
transition state during the
reaction. Although a favorable
loss of energy occurs during the
reaction, the rate of the reaction
is slowed by the energy barrier
to forming the transition state.
The energy barrier is referred to
as the activation energy.

dakavSirebuli fermentis katalizSi monawile funqciur jgufebTan.


substratisa da gardamavali mdgomareobis energiis doneebs Soris sxvaobas aqtivaciis
energia ewodeba.
gardamavali mdgomareobis Teoriis Tanaxmad, reaqciis siCqare ganpirobebulia im
molekulebis raodenobiT, romlebsac sakmarisi energia gaaCniaT aqtivaciis energiis
gadasalaxavad. fermentebi zrdian reaqciis siCqares aqtivaciis energiis SemcirebiT. es
miiRweva sxvadasxva gzebiT, romlebic qimiuri katalizidan aris cnobili, mag.
gardamavali kompleqsis eleqtronuli stabilizacia, mJave-fuZe katalizi da sxv.
gardamavali mdgomareobis kompleqsis warmoqmnis Semdeg is SeiZleba daiSalos isev
substratis warmoqmniT an daiSalos produqtis warmoqmniT. fermenti ar cvlis
substratis an produqtis sawyis energetikul dones.

II. qimotripsinis katalizuri meqanizmi


qimotripsini fermentebis mier aqtivaciis energiis Sesamcireblad aminomJavebis
radikalebis gamoyenebis strategiebis kargi magaliTia. qimotripsini momnelebeli
fermentia, romelic gamoiyofa nawlavebSi da akatalizebs denaturirebuli cilebis
specifiuri peptiduri bmebis hidrolizs. qimitripsini miekuTvneba serinuli
proteazebis superojaxs, im fermentebis ojaxs, romlebic iyeneben aqtiuri centris
serins proteolizis Sualedur produqtTan kovalenturad dakavSirebuli Sualeduri
produqtis warmosaqmnelad. peptiduri bmis hidrolizis reaqcia aRiwereba, rogorc
wylis OH- -is dakavSireba peptiduri bmis karbonilis jgufis naxSirbadTan, xolo H+-
isa - azotTan, ris Sedegadac xdeba bmis gaxleCva (ix. sur.).

a. fermentis gareSe mimdinare reaqcia.


fermentis gareSe mimdinare reaqciisas wylis uaryofiTad damuxtuli hidroqsilis
jgufi urTierTqmedebs karbonilis jgufis naxSirbadTan, romelsac nawilobriv
dadebiTi muxti gaaCnia. am dros warmoiqmneba arastabiluri oqsianionis
tetrahedraluri gardamavali mdgomareobis kompleqsi, sadac Jangbadis atomi mTlianad
uaryofiTad aris damuxtuli. qimotripsinis gareSe mimdinare reaqciis siZnele aixsneba
hidroqsid-ionebis mcire koncentraciiT wyalSi, romlebsac sakmao energia gaaCniaT
imisTvis, rom warmoqmnan gardamavali mdgomareobis kompleqsi da daukavSirdnen swori
orientaciiT.
radganac gardamavali mdgomareobis kompleqsi ufro stabilurad
ukavSirdeba ferments, vidre substrati, nivTierebebi, romlebic am
kompleqsis msgavni arian, potenciurad ufro Zlieri inhibitorebia, vidre
substratis analogebi. amitom wamali, romelic gardamavali
mdgomareobis analogia, ufro Zlieri da specifiuria fermentis mimarT.
gasaTvaliswinebelia is garemoeba, rom gardamavali mdgomareobis
kompleqsi arastabiluria, amitom maTi analogebis sinTezi am mxriv
SezRudulia. gamosavali aseTi mdgomareobidan aris iseTi naerTebis
sinTezi, romlebic gardamavali mdgomareobis kompleqsis stabilur
modifikacias warmoadgenen, fermentuli reaqciis Sedegad gardaiqmnebian
gardamavali mdgomareobis kompleqsis analogebad da iwveven fermentis
specifiur inhibirebas. aseve SesaZlebelia gardamavali mdgomareobis
kompleqsis analogebiT komplementaruli antisxeulebis gamomuSaveba.

ebzaimebi (katalizurad aqtiuri antisxeulebi) keTdeba gardamavali


mdgomareobis kompleqsis analogis mimarT antisxeulis miRebiT. maT gaaCniaT
aminomJavebis radikalebis iseTi ganlageba variabelur ubnebSi, romelic fermentis
aqtiuri centris msgavsia. Sesabamisad maT SeiZleba fermentuli aqtioba gamoiCinon.
magaliTad, miRebulia ebzaimebi kokainesTerazas (organizmSi Slis kokains)
gardamavali mdgomareobis kompleqsis analogis mimarT. am ebzaimebs gaaCniaT
esTerazuli aqtivoba, organizmSi maTi yovelTviuri ineqcia iwvevs kokainis swraf
daSlas da amcirebs kokainze damokidebulebas.

hidrolizi niSnavs qimiuri kavSiris wyliT liziss (daSlas). proteolizi


cilis peptiduri bmis hidrolizia, romelsac fermentebi, saxelad proteazebi
akatalizeben.

b. qimotripsinis mier katalizirebuli reaqciis katalizis strategia


qimotripsinis mier katalizirebul reaqciaSic warmoiqmneba igive oqsianioni, oRond am
SemTxvevaSi mis warmoqmnaSi monawileobs serinis hidroqsilis jgufi wylis OH--is
anionis nacvlad.

qimotripsinis mier katalizirebuli reaqcia aCqarebulia, radganac


fermentis aqtiuri centris funqciuri jgufebi aaqtiureben moieriSe hidroqsilis
jgufs,
astabilizeben oqsianionur gardamavali mdgomareobis kompleqss,
warmoqmnian kovalentur intermediats da
axdenen warmavali jgufis destabilizacias.

reaqcia mimdinareobs or etapad:


a) denaturirebuli cilis substratis peptiduri kavSiris gaxleCva da kovalenturi
acil-fermentis intermediatis warmoqmna,
b) acil-fermentis intermediatis hidrolizi da substratuli cilis narCenis
gamoTavisufleba.

Fig. 8.8. Chymotrypsin hydrolyzes


certain peptide bonds in proteins. The
scissile bond is shown in blue. The
carbonyl carbon, which carries a
partial positive charge, is attacked by
a hydroxyl group from water. An
unstable tetrahedral oxyanion
intermediate is formed,
which is the transition state complex.
As the electrons retum to the carbonyl
carbon, it
becomes a carboxylic acid, and the
remaining proton from water adds to
the leaving group to form an amine.

1. qimotripsinTan dakavSirebis
specifiuroba
qimotripsini akatalizebs
denaturirebuli cilis fenilalaninis, tirozinis an triftofanis karbonilis mxares
mdebare peptiduri kavSiris hidrolizs. substratis gamomcnobi saiTi warmoadgens
hidrofobur damakavSirebel jibes, romelSic Tavsdeba substratis hidrofoburi
aminomJava da iZleva gasaWreli kavSiris karbonilis jgufs. substratuli cila unda
iyos denaturirebuli imisTvis, rom kargad moergos jibes da xistad damagrdes
fermentis glicinebis radikalebiT. gasaWreli bmis mimarT specifiuroba
ganpirobebulia aseve katalizis Semdgomi stadiebiTac, mag. ser 195-is gadaadgilebiT
moieriSe poziciaSi.

2. acil-fermentis intermediatis warmoqmna qimotripsinSi

reaqciis pirvel stadiaze denaturirebuli cilovani substratis peptiduri bmis gaWra


xdeba, rodesac fermentis aqtiuri centris serinis hidroqsilis jgufi miitans ieriSs
gasaWreli bmis karbonilis jgufze (nukleofiluri katalizi. nukleofili aris
qimiuri jgufi, romelic miizideba dadebiTad damuxtuli birTviT) (Fig. 8.9, Step 2).
aspartati da histidini kooperireben, rom gardaqmnan es hidroqsilis jgufi
(romelsac nawilobrivi uaryofiTi muxti gaaCnia Jangbadze) ufro Zlier
nukleofilur moieriSe jgufad misi uaryofiTi muxtis gazrdis meSveobiT. aqtiuri
centris histidini moqmedebs rogorc fuZe da aclis protons serinis hidroqsilis
jgufs (mJava-fuZe katalizi). protonirebuli histidini stabilizdeba mezoblad
mdebare aspartatis uaryofiTi muxtiT.

aspartat - histidin- serinis kombinacia, romelic cnobilia, rogorc katalizuri


triada, aris fermentis aqtiuri centris aminomJavebis kooperaciulobis magaliTi.
Zlieri nukleofilis Seqmna am muxtis gadamcemi sistemis mier (charge-relay system),
iwvevs igive efeqts, rasac gamoiwvevda hidroqsilis ionebis raodenobis zrda
arafermentul reaqciaSi.
reaqciis Semdeg safexurze xdeba oqsianionis tetrahedraluri gardamavali
mdgomareobis kompleqsis warmoqmna, romelic stabilizdeba wyalbaduri bmebis
meSveobiT fermentis ConCxis NH jgufebTan (Fig. 8.9, Step 3).
oqsianionis tetrahedraluri kompleqsi, iseve, rogorc gardamavali mdgomareobis
kompleqsebis umetesoba, SegviZlia warmovidginoT, rogorc “eleqtronuli deformacia”,
anu eleqtrostatikuri zedapiri, romlis warmoqmnis albaToba ukiduresad mcire
iqneboda fermentis funqciuri jgufebiT stabilizaciis gareSe. gardamavali
mdgomareobis kompleqsis stabilizacia amcirebs mis energetikul dones da zrdis im
molekulebis raodenobas, romlebsac SeuZliaT miaRwion am dones. Sesabamisad izrdeba
reaqciis siCqarec.

serinuli proteazebi sisxlis SededebaSi. proteazebis mier serinis gamoyeneba


aqtiur centrSi xSiri movlenaa da gvxvdeba rogorc monelebis procesebSi monawile
fermentebSi, aseve sisxlis koagulaciaSi monawile proteolizur
fermentebSi. sisxlis Sededebis Sedegad miRebuli Trombi warmoiqmneba
fibrinisgan, sisxlis cilisgan, romelic imyofeba araaqtiuri formis -
fibrinogenis saxiT. serinuli proteaza Trombini Wris peptidur kavSirs
fibrinogenSi da miiReba aqtiuri fibrini. Trombins igive aspartat-histidin-
serinuli katalizuri triada gaaCnia, rac qimotripsins da praqtikulad igive
meqanizmiT muSaobs. Trombini sisxlSi aseve araaqtiuri winamorbedis -
proTrombinis saxiT aris warmodgenili, romelic aseve aqtiurdeba specialuri
serinuli proteazas meSveobiT.

polipeptiduri bmis gaWris Semdeg aqtiuri centris serini warmoqmnis srul


kovalentur bmas karbonilis jgufis naxSirbadTan (kovalenturi katalizi). stabiluri
kovalenturi intermediatis warmoqmna katalizis gavrcelebuli strategiaa im
fermentebisTvis, romlebic aqtiur centrSi serins an cisteins Seicaven.
SemdgomSi xdeba kovalenturi intermediatis hidrolizi (mJave-fuZe katalizi).
fermentebidan disocirebadi produqtebi xSirad destabilizdebian aqtiur centrSi
mimdinare muxtebis repulsirebiT. qimotripsinis SemTxvevaSi peptiduri bmis gaWris
Semdeg warmoqmnili aminojgufi destabilizdeba an, SeiZleba iTqvas, xdeba ,,arakom-
fortuli” aqtiuri centris histidinis mier.

3. reaqciaTa Semdegi Tanmimdevroba ahidrolizebs acil-fermentul intermediats, rom


gamoanTavisuflos peptidis karbonilis bolo (Fig. , Steps 6-9). aqtiuri centris
histidini aaqtiurebs wyals da warmoiqmneba nukleofiluri ieriSis misatanad saWiro
OH-. amas Tan sdevs meore oqsianionuri gardamavali mdgomareobis kompleqsis
warmoqmna. rodesac histidini daubrunebs serins protons, reaqcia dasruldeba da
moxdeba produqtis disociacia.
Fig. . Catalytic mechanism of chymotrypsin. The substrate (a denatured protein) is in the shaded area.
1.As the substrate protein binds to the active site, serine-195 and a histidine (his57) are moved closer
together and at the right orientation for the nitrogen electrons on histidine to attract the hydrogen of serine. Without this change of
conformation on substrate binding, the catalytic triad cannot form.
2. Histidine serves as a general base catalyst as it abstracts a proton from the serine, increasing the nucleophilicity of the serine-
oxygen, which attacks the carbonyl carbon.
3. The electrons of the carbonyl group form the oxyanion tetrahedral intermediate. The oxyanion is stabilized
by the N-H groups of serine-195 and glycine in the chymotrypsin peptide backbone.
4. The amide nitrogen in the peptide bond is stabilized by interaction with the histidine proton. Here the histidine acts as a general acid
catalyst. As the electrons of the carbon-nitrogen peptide bond withdraw into the nitrogen, the electrons of the carboxyanion return to the
substrate carbonyl carbon, resulting in cleavage of the peptide bond.
5. The cleavage of the peptide bond results in formation of the covalent acyl-enzyme intermediate, and the amide half of the cleaved
protein dissociates.
6. The nucleophilic attack by H2O on the carbonyl carbon is activated by histidine, whose nitrogen electrons
atffact a proton from water.
7. The second tetrahedral oxyanion intermediate (the transition state complex) is formed. It is again stabilized
by hydrogen bonds with the peptide backbone bonds of glycine and serine.
8. As the histidine proton is donated to the electrons of the bond between the serine oxygen and the substrate carbonyl group, the
electrons from the oxyanion return to the substrate carbon to form the carboxylic acid, and the acyl-enzyme bond is broken.
9. The enzyme, as it releases substrate, returns to its original state.
g. qimotripsiniT katalizirebuli reaqciis energetikuli diagrama

fermentuli reaqciis mravalsafexurianoba ganapirobebs mravalborcvian energetikul


diagramas (Fig. 8.10). pirveli Cazneqva (CaRrmaveba) warmoiqmneba sawyis stadiaSi
monawile mravali susti Zalis energiis xarjze, romlebic monawileoben ferment-
substratuli kavSiris warmoqmnaSi. reaqciis mimdinareobasTan erTad maRla iwevs
mrudic, radganac saWiroa damatebiTi energia gardamavali mdgomareobis kompleqsis
Sesaqmnelad. am energias uzrunvelyofs sawyisi susti damakavSirebeli Zalebis
Tanmimdevruli Secvla ufro Zlieri kavSirebiT. naxevrad stabiluri kovalenturi
kompleqsis energia ufro dabalia, vidre gardamavali mdgomareobis kompleqsebisa da
amitom warmoiqmneba energetikuli diagramis kidev erTi Cazneqva. saboloo gardamavali
mdgomareobis kompleqss energiis maqsimumi gaaCnia da amitom aris yvelaze
arastabiluri mdgomareoba. aqedan sistema SeiZleba “Cagordes” ukan - substratisken,
an daiSalos produqtis warmoqmniT.

III. katalizSi monawile funqciuri jgufebi.


qimotripsinSi realizebuli katalizuri strategiebi mravali sxva fermentisTvisac
damaxasiaTebelia. erTi maTgani - sivrculi siaxlove da orientacia (proximity and
orientation) substratis dakavSirebidan gamomdinare Tvisebaa da yvela fermentis
moqmedebis meqanizmisTvis aris damaxasiaTebeli. aseve yvela fermentisTvis
damaxasiaTebelia gardamavali mdgomareobis stabilizeba eleqtrostatikuri
urTierTqmedebebiT, magram mxolod fermentebis garkveul nawils axasiaTebs
kovalenturi intermediatebis warmoqmna.
didi sxvaobaa fermentebis mier katalizuri strategiis realizaciisTvis gamoyenebul
funqciur jgufebSi. zogierTi fermentis SemTxvevaSi, rogoric aris qimotripsini,
katalizi agebulia aqtiuri centris aminomJavebis funqciur jgufebze.

Fig. 8.10. A postulated energy diagram for the reaction catalyzed by chymotrypsin.
In the presence of enzyme (Blue); in the absence of enzyme (black). The energy barrier to the transition state is lowered
in the enzyme-calalyzed reaction by the fomation of additional bonds between the substrate and enzyme in the
transition state complex. The energy is provided by substrate binding to the enzyme. The enzyme does not, however,
change the energy levels of the subsfate or product.
sxva fermentebi zrdian reaqciis TanamonawileTa raodenobas kofaqtorebis gamoyenebiT,
romlebic awvdian maT saWiro zomis, formis da Tvisebebis mqone funqciur jgufebs.
kofaqtorebi aracilovani bunebis naerTebia, romlebic monawileoben katalizis
procesSi. isini zogadad sam jgufad iyofian - koenzimebi, metalis ionebi (mag. Fe2+,
Mg2+, or Zn2+) da metalokoenzimebi (mag. hemoglobinis Fe2+-hemis msgavsi)

a. aminomJavebis gverdiTi radikalebis funqciuri jgufebi


praqtikulad yvela polaruli aminomJava monawileobs erT an ramdenime fermentul
katalizSi (ix. tabula). serins, cisteins da lizins SeuZliaT miiRon monawileoba
kovalentur katalizSi.

Table 8-1 Some Functional Groups in the Acive Site


Function of Amino Acid Enzyme Example
CovaIent intermediates
Cysteine-SH Glyceraldehyde 3- phosphate dehydrogenase
Serine-OH Acetylcholinesterase
Lysine-NH2 Aldolase
Histidine-NH Phosphoglucomutase
Acid-base catalysis
Histidine-NH Chymotrypsin
Aspartate-COOH Pepsin
Stabilization of anion formed during the reaction
Peptide backbone-NH Chymotrypsin
Arginine-NH Carboxypeptidase As
Serine-OH Alcohol dehydrogenase
Stabilization of cation formed during the reaction
Aspartate-COO- Lysozyme

histidins, Tavisi pKa-s gamo SeuZlia neitraluri pH-is farglebSi protonis


donorireba an aqceptireba, amitom xSirad gvxvdeba mJava-fuZe katalizis SemTxvevebSi.
polaruli aminomJavebis radikalebis umravlesoba nukleofiluria da, aqedan
gamomdinare, maT aqvT unari nukleofilur katalizSi daastabiluron reaqciis
mimdinareobisas gaCenili dadebiTad damuxtuli jgufebi.

nukleofilebs sruli an nawilobrivi uaryofiTi muxti gaaCniaT (rogorc serinis


Jangbadis atoms serinis OH-Si) an gaaCniaT azoti, romelsac SeuZlia imoqmedos
eleqtronebis donor jgufad Tavisi ori gauwyvilebeli eleqtronebis meSveobiT.
kovalenturi katalizi da mJava-fuZe katalizi mimdinareobs nukleofiluri jgufebis
meSveobiT.
eleqtrofilebi atareben nawilobriv an srul uaryofiT muxts (mag. qimotripsinis
SemTxvevaSi peptiduri ConCxis -NH gamoiyeneba eleqtrofilur jgufad).
zogadad, nukleofiluri da eleqtrofiluri katalizi mimdinareobs maSin, rodesac
fermentis Sesabamisi nukleofiluri da eleqtrofiluri jgufebi axdenen substratis
im, sawinaaRmdegod damuxtuli jgufebis stabilizacias, romlebic reaqciis
mimdinareobisas Cndebian.

b. koenzimebi katalizSi
koenzimebi aracilovani bunebis, rTuli organuli molekulebia, romlebic Tavisi
funqciuri jgufebiT, aminomJavebis radikalebis msgavsad monawileoben katalizSi.
adamianis organizmSi kofermentebi, rogorc wesi (magram ara yovelTvis), sinTezdebian
vitaminebisgan. yoveli koenzimi monawileobs garkveuli struqturuli Tvisebebis mqone
substratebis klasis specifiuri tipis reaqciebis katalizSi. koenzimebi SeiZleba
daiyos or zogad klasad: gamaaqtivebel-transferuli koenzimebi da Jangva-aRdgeniTi
koenzimebi.

radganac vitaminebis umetesoba moqmedebs, rogorc koenzimi, vitaminebis deficiti


aisaxeba am vitaminis koenzimul formaze damokidebuli fermentebis aqtiobaze. ase
magaliTad, wamlebi da toqsinebi, romlebic ainhibireben koenzimebis sinTezisTvis
saWiro cilebs (rogoricaa vitaminebis matransportirebeli cilebi an
biosinTezuri fermentebi) gamoiwveven vitaminis deficitis damaxasiaTebel simptomebs.
aseTi tipis deficits funqciuri deficiti ewodeba, xolo araadeqvaturi miRebiT
gamowveuls ki kvebiTi deficiti..
koenzimebis umetesoba mWidrod aris dakavSirebuli Tavis fermentebTan da reaqciis
mimdinareobisas ar disocireben. magram funqciuri an kvebiTi vitaminuri deficiti
amcirebs koenzimis raodenobas, rac iwvevs ujredSi apoenzimebis (apofermentebis)
(apoenzimi ewodeba ferments, romelsac mocilebuli aqvs koenzimi) gamoCenas.
eTanoli e.w. “antivitaminia”, romelic praqtikulad yvela koenzimis raodenobas
amcirebs. mag. eTanoli ainhibirebs Tiaminis absorbcias, xolo acetaldehidi, romelic
eTanolis daJangviT miiReba, enacvleba piridoqsalfosfats cilasTan dasakavSirebel
adgilas, axdens mis disociacias, riTac zrdis piridoqsalfosfatis degradaciis
siCqares.

1. gamaaqtivebel-transferuli koenzimebi
gamaaqtivebel-transferuli koenzimebi, rogorc wesi, uSualod monawileoben
katalizSi substratis garkveul nawilTan kovalenturi bmis warmoqmniT, ris Semdeg
SeboWili substrati gaaqtiurebulia transferisTvis, wylis mimatebisTvis an romelime
sxva reaqciisTvis. koenzimis is nawili, romelic warmoqmnis substratTan kovalentur
kavSirs, aris misi funqciuri jgufi.

koenzimis gamocalkevebuli nawili ki mWidrod ukavSirdeba ferments.


Tiaminpirofosfati katalizSi koenzimebis monawileobis kargi magaliTia (ix. sur).
adamianis organizmSi is sinTezirdeba vitamin Tiaminisgan pirofosfatis damatebiT.
pirofosfatis damateba aZlevs mas uaryofiTad damuxtul Jangbadis atomebs, romlebic
warmoqmnian qelatur kompleqss Mg2+-is ionebTan da amis Semdeg igi mWidrod
ukavSirdeba ferments. aqtiur centrSi adgils ikavebs qimiurad aqtiuri naxSirbadis
atomi, romelsac disocirebadi protoni gaaCnia. yvela fermentSi, romelic iyenebs
Tiamin pirofosfats, es qimiurad aqtiuri Tiaminis naxSirbadi warmoqmnis kovalentur
kavSirs substratis ketojgufis mezoblad mdebare naxSirbad-naxSirbaduli kavSiris
daSlis paralelurad. magram yoveli Tiaminis Semcveli fermenti specifiuria
substratis an substratebis garkveuli jgufis mimarT.
koenzimebs fermentebis gareSe Zalian mcire aqtiuroba da specifiuroba gaaCniaT.
fermenti aniWebs mas specifiurobas, sivrcul siaxloves da swor orientacias Tavisi
substratuli centris meSveobiT, iseve, rogorc sxva funqcionaluri jgufebis
meSveobiT uzrunvelyofs gardamavali mdgomareobis stabilizebas, mJava-fuZe katalizs
da sxv. magaliTad fermenti aqcevs Tiamins ukeTes nukleofilur moieriSe jgufad
Tavisi fuZe aminomJavas radikalis meSveobiT, romelic acilebs mas disocirebad
protons da qmnis uaryofiTi muxtis mqone Tiaminis naxSirbadis atoms. reaqciis
Semdgom stadiebze fermenti ukan abrunebs protons.

koenzim A (CoA), biotini da piridoqsalfosfati arian aseve gamaaqtivebel-


matransferirebeli koenzimebi, romlebic sinTezirdebian vitaminebisgan. CoA, romelic
sinTezirdeba vitamin pantoTenatidan, Seicavs adenozin -bisfosfats, romelic
Seqcevadad, magram Zlierad ukavSirdeba fermentis Sesabamis saiTs (ix. suraTi). misi
funqciuri jgufia sulfhidruli jgufi molekulis meore boloSi da aris
nukleofili, romelsac SeuZlia ieriSis ganxorcieleba karbonilis jgufebze da acil
TioeTerebis warmoqna (CoA-Si “A” acilis jgufze miuTiTebs)
koenzimebis umetesoba, rogorc aminomJavebis funqciuri jgufebi, regenerirdeba
reaqciis mimdinareobisas. magram CoASH da ramdenime Jangva-aRdgeniTi kofermenti
transformirdeba produqtad, romelic disociirebs fermentidan reaqciis dasrulebis
Semdeg (mag. CoASH gardaiqmneba acyl CoA warmoebulad, xolo NAD+ aRdgeba NADH-
de). miuxedavad amisa, isini klasificirdebian ara substratebad, aramed koenzimebad,
radganac monawileoben Zalian bevr reaqciaSi, maTi sawyisi mdgomareoba regenerirdeba
metaboluri gzis momdevno reaqciebSi, isini warmoiqmnebian vitaminebisgan da maTi
raodenoba ujredSi praqtikulad ucvlelia.
mraval alkoholiks uviTardeba Tiaminis deficiti, radganac alkoholi ainhibirebs
Tiaminis transports nawlavis lorwovani garsis ujredebSi. organizmSi Tiamini
gardaiqmneba Tiaminpirofosfatad (TPP).
TPP moqmedebs rogorc koenzimi iseTi α-ketomJavebis dekarboqsilirebisas, rogoricaa
piruvati da α-ketoglutarati, aseve pentozafosfatebis utilizaciaSi pentoza
fosfatur gzaSi. Tiaminis deficitis Sedegad α-ketomJavebis daJangva arasrulfasovani
xdeba. es iwvevs centraluri da periferiuli nervuli sistemis, kardiovaskularuli
sistemis da sxva organoebis disfunqcias.

Fig. 8.11.The role of the functional group of thiamine pyrophosphate (the reactive carbon shown in blue) in formation of
a covalent intermediate A . A base on the enzyme ( B) abstracts a proton from thiamine, creating a carbanion (general
acid-base catalysis). B. The carbanion is a strong nucleophile and attacks the partially positively charged keto group
on the substrate. C . A covalent intermediate is formed, which is stabilized by resonance forms. The uncharged
intermediaite is the stabilized transition state complex.

biotini, romelic ar Seicavs fosfatur jgufebs, kovalenturad aris dakavSirebuli


ferment karboqsilazebis lizinTan (ix. sur.). mis funqciur jgufs warmoadgens azotis
atomi, romelic energiaze damokidebul reaqciaSi kovalenturad ikavSirebs CO2-is
jgufs. es dakavSirebuli CO2-is jgufi imyofeba aqtivirebul mdgomareobaSi sxva
molekulebze gadasatanad. adamianis organizmSi biotini monawileobs mxolod
karboqsilirebis reaqciebSi.

piridoqsalfosfati sinTezirdeba vitamin piridoqsinisgan, romelic aseve vitamin B6-is


saxeliT aris cnobili (ix. sur.). qimiurad aqtiuri aldehidis jgufi, rogorc wesi,
reaqciaSi monawileobs aminomJavebis aminojgufebTan kovalenturi kavSirebis
warmoqmniT. piridinis dadebiTad damuxtuli azoti iRebs eleqtronebs dakavSirebuli
aminomJavas bmidan da axorcielebs am bmis gaxleCvas. am SemTxvevaSi fermentis funqciaa
substratidan protonebis mocileba da aminomJavasa da piridoqsalis jgufis erT
sibrtyeSi SenarCuneba eleqtronebis gadatanis gasaioleblad.

Fig. 8.12.CoA and biotin, activation-transfer coenzymes. A. Coenzyme A (CoA or CoASH)


and phosphopantetheine are synthesized from the vitamin pantothenate (pantothenic acid).
The active sulfhydryl group, shown in blue, binds to acyl groups (e.g., acetyl, succinyl, or
fatty acyl) to form thioesters. B. Biotin activates and transfers CO2 to compounds in carboxylation reactions.
The reactive N is shown in blue. Biotin is covalently attached to a lysine residue in the carboxylase enzvme.
Fig. 8.13 Reactive sites of pyridoxal phosphate.
The functional group of pyridoxal phosphate is
a reactive aldehyde (shown in blue) that forms
a covalent intermediate with amino groups of
amino acids (a Schiff base). The positively
charged pyridine ring is a strong electron-
withdrawing group that can pull electrons into it
(electrophilic catalysis).

gamaaqtivebel-transferul koenzimebs
axasiaTebs sami saerTo Tviseba:
(1) specifiuri qimiuri jgufis monawileoba fermentTan dasakavSireblad,
(2) gamocalkevebuli da gansxvavebuli funqciuri anu reaqtiuli jgufis arseboba,
romelic uSualod monawileobs erTi tipis reaqciis katalizSi substratTan
kovalenturi bmis warmoqmniT; da
(3) fermentze damokidebuleba substratis mimarT specifiurobis da katalizuri
simZlavris SesaZenad.

2. Jangva-aRdgeniTi koenzimebi
Jangva-aRdgeniT reaqciebSi, romlebsac oqsidoreduqtazebi akatalizeben, mravali
gansxvavebuli koenzimebi monawileobs. zogierT koenzims, rogoricaa

zogadad, koenzimebi aracilovani bunebis organuli kofaqtorebia, romlebic katalizSi


monawileoben. isini SeiZleba iyvnen fermentebTan kovalenturad dakavSirebuli
(mag. biotini), disocirebdnen deficitis SemTxvevaSi (Tiaminpirofosfati), an reaqciis
bolos disocirebdnen, rogorc Cveulebrivi produqti (CoASH). kofaqtorebi,
romlebic kovalenturad an Zalian Zlierad ukavSirdebian arafermentul cilebs,
prosTetuli jgufebis saxeliT arian cnobili. prosTetuli jgufi, rogorc wesi, ar
disocirebs cilisgan, sanam ar moxdeba cilis sruli degradacia.

nikotinamidadenin dinukleotidi (NAD+) da flavinadenindinukleotidi (FAD),


gadaaqvs eleqtronebi wyalbadTan erTad da TamaSobs unikalur rols ATP-is
warmoqmnaSi energetikuli wyaros Jangvis procesebSi.

sxva Jangva-aRdgeniTi koenzimebi moqmedeben metalebTan erTad da gadaaqvT mxolod


eleqtronebi. vitamini E da vitamini C (askorbinis mJava) arian Jangva-aRdgeniTi
koenzimebi, romlebic moqmedeben, rogorc antioqsidantebi da icaven organizms
Jangbadis Tavisufali radikalebiT gamowveuli dazianebebisgan. metabolizmSi Jangva-
aRdgeniTi koenzimebis sxva funqciebze saubari momdevno TemebSi gveqneba.

Jangva-aRdgeniTi koenzimebi misdeven igive principebs, rasac gamaaqtivebel-transferuli


koenzimebi, im gamonaklisiT, rom ar qmnian kovalentur kavSirebs substratTan. yvela
koenzims Tavisi damaxasiaTebeli funqciuri jgufi gaaCnia, romelsac SeuZlia
eleqtronebis aqceptireba da donorireba da aris specifiuri gadasatani eleqtronis
formis mimarT ( mag. hidridioni, wyalbadis atomi, Jangbadi).
koenzimis garkveuli nawili ukavSirdeba ferments. gamaaqtivebel-transferuli
koenzimebis msgavsad, Jangva-aRdgeniTi koenzimebi ar arian kargi katalizatorebi
fermentebis aminomJavebis radikalebis gareSe.

fermenti laqtatdehidrogenaza, romelic akatalizebs eleqtronebis gadatanas


laqtatidan NAD+-ze, am principebis magaliTia (ix. sur ). koenzimi nikotinamidadenin
dinukleotidi (NAD+) sinTezdeba vitamin niacinisgan (romelic warmoqmnis
nikotinamidur birTvs) da ATP-gan (romelic awvdis AMP-ur nawils). molekulis
AMP-uri nawili mWidrod ukavSirdeba ferments da iwvevs konformaciul cvlilebas.

rodesac nivTiereba iJangeba, is kargavs eleqtronebs. amis Sedegad daJangul naxSirbads


naklebi H atomi an meti O atomi gaaCnia. nivTierebis aRdgena niSnavs eleqtronebis
miRebas, rac mis struqturaSi gamoixateba rogorc H atomebis raodenobis zrda an O
atomebis dakleba. laqtatis daJangvisas piruvatamde (ix. sur.) laqtati kargavs or
eleqtrons hidridionis saxiT da gamoTavisufldeba protoni(H+). NAD+ aqceptirebs
hidridions da aRdgeba NADH-de. ketojgufis mqone naxSirbadis atomi amjerad ufro
daJangul mdgomareobaSia, radganac naxSirbadsa da Jangbads Soris orive eleqtroni
Jangbads miekuTvneba, xolo laqtatis C-H kavSiris ori eleqtroni Tanabrad
ganawilebulia naxSirbadsa da wyalbads Soris.
Jangva-aRdgeniTi reaqciebis fermentebs oqsidoreduqtazebs uwodeben. maT qve klasSi
Sedian dehidrogenazebi, radganac gadaaqvT wyalbadi (wyalbadis atomi an hidrid atomi)
substratidan eleqtronebis iseT aqceptorze, rogoricaa mag. NAD+ .

Fig. 8.14 The coenzyme NAD+


accepting a hydride ion, shown in
blue, from lactate. NAD+- dependent
dehydrogenases catalyze the
transfer of a hydride ion (H:) from a
carbon to NAD+ in oxidation
reactions such as the oxidation of
alcohols to ketones or aldehydes to
acids. The positively charged
pyridine ring nitrogen of NAD+
increases the electrophilicity of the
carbon opposite it in the ring. This
carbon then accepts the negatively
charged hydride ion. The proton from
the alcohol group is released into
water. NADP functions by the same
mechanism, but it is usually involved
in pathways of reductive synthesis.

NAD+ -is funqciur jgufs


warmoadgens nikotinamidis
birTvis dadebiTad
damuxtuli azotis
sapirispiro mxares mdebare
naxSirbadi. naxSirbadis es
atomi aqceptirebs hidrid
ions (wyalbadis atomi, romelsac ori eleqtroni gaaCnia) substratis specifiuri
naxSirbadis atomisgan. amis Semdeg substratis alkoholuri (spirtuli) jgufidan
disocirebs H+ da warmoiqmneba keto jgufi (C = O). fermentis roli am SemTxvevaSi
aris histidinis azotis miwodeba, romelic daikavSirebs laqtatidan disocirebul
protons da gauadvilebs NAD+-s wyalbadis meore atomis orive eleqtronianad
mierTebas. sabolood NADH disocirebs.

g. metalebis ionebis monawileoba katalizSi

metalis ionebi, romlebsac dadebiTi muxti gaaCniaT, monawileoben katalizSi rogorc


eleqtrofilebi (eleqtronebis mimzidveli jgufebi). isini xels uwyoben substratis
dakavSirebas, an astabilizeben reaqciis msvlelobisas warmoqmnil anionebs. maT aseve
SeuZliaT eleqtronebis aqceptireba an donorireba Jangva-aRdgeniT reaqciebSi.

zogierTi metalis unari, daikavSiron mravali ligandi Tavis koordinaciul sferoSi,


aZlevs maT saSualebas miiRon monawileoba substratebis da koenzimebis fermentebTan
dakavSirebaSi. mag. Mg2+ monawileobs Tiaminpirofosfatis uaryofiTad damuxtuli
fosfatis jgufebis fermentis anionur an fuZe aminomJavebis radikalebTan
dakavSirebaSi (ix. sur ). ATP-is fosfaturi jgufebi, rogorc wesi, ukavSirdebian
fermentebs Mg2+-iT an qelatirebiT.

zogierT fermentSi metalebi ikavSireben anionur substratebs an reaqciis


intermediatebs, rom Secvalon maTi muxtis ganawileba da amiT SeaqvT Tavisi wili
katalizis simZlavreSi. alkoholdehidrogenaza, romelsac gadaaqvs eleqtronebi
eTanolidan NAD+-ze da warmoqmnis acetaldehidsa da NADH-s, aris amis magaliTi
(ix. sur. ). alkoholdehidrogenazas aqtiuri centris gaaqtiurebuli serini iRebs
protons eTanolis -OH jgufidan, ris Sedegadac uaryofiTi muxti rCeba Jangbadze. es
muxti stabilizdeba Zn-is mier. miRebuli eleqtronuli konfiguracia iZleva
hidridionis gadatanis saSualebas NAD+-ze. Zn-is funqcia alkoholdehidrogenazaSi
igivea, rac histidinis funqcia laqtatdehidrogenazaSi.

d. kofaqtorebis arakatalizuri roli


zogierTi fermentisTvis kofaqtorebi asruleben arakatalizur, struqturul
funqcias, ikavSireben ra fermentis calkeul ubnebs mesameuli struqturis
warmosaqmnelad. isini SeiZleba iyvnen aseve fermentebis substratebic, romlebic
iSlebian reaqciis Sedegad.

IV. optimaluri pH da temperatura


Tu avagebT romelime fermentis siCqaris damokidebulebas xsnaris pH-ze, umetes
SemTxvevaSi miRebuli grafiki gviCvenebs siCqaris zrdas pH-is Zalze mJave
mniSvnelobebidan fiziologiuramde da siCqaris Semcirebas fiziologiuri pH-dan
Zalze tutovanamde (ix. sur). am mrudis forma mJave areSi, rogorc wesi,
damokidebulia aqtiuri centris (an substratis) funqciuri jgufebis ionizaciaze.
tute areSi aqtiurobis dakargva dakavSirebulia fermentis aminomJavebis Seusabamo
ionizaciasTan.
Fig. 8.15. Liver alcohol dehydrogenase
catalyzes the oxidation of ethanol (shown in
blue) to acetaldehyde. The active site of
liver alcohol dehydrogenase contains a
bound zinc atom, and a serine side chain
-OH and a histidine nitrogen that participate
in the reaction. The histidine pulls an H+ off
the active site serine, which pulls the H+ off
of the substrate -OH group, leaving the
oxygen with a negative charge that is
stabilized by zinc.

kuWis parietuli ujredebi axdenen kuWSi HCl-is sekrecias, rac qmnis pH-s 1-sa da 2-s
Soris. Zlier mJavuri garemo SesaZlebels xdis umetesi cilebis denaturacias,
radganac xdeba aminomJavebis protonireba da Sesabamisad mcirdeba wyalbaduri bmebis
warmoqmnis unari, rac saWiroa mesameuli struqturis Camosayalibeblad. denaturaciis
gareSe cilebis mravali peptiduri bma iqneboda miuwvdomeli proteazebisTvis,
momnelebeli fermentebisTvis. kuWis fermenti -pepsini gamonaklisia im gagebiT, rom misi
pH-optimumi daaxloebiT 1,6-ia da is aqtiuria kuWis wvenis mJave areSi. rodesac
denaturirebuli cilebi gadadian kuWidan nawlavebSi, maTTan erTad gadasuli kuWis
wvenis pH izrdeba da 6-ze meti xdeba. amis mizezia bikarbonatis sekrecia pankreasis
mier. am pH-ze erTvebian qimotripsini da sxva pankreasuli proteazebi.

Fig. 8.16. pH profile of an enzyme. The


rate of the reaction increases as the pH
increases from 6 to 7.4. The exact shape
of the curve depends on the protonation
state of active site amino acid residues or
on the hydrogen bonding required for
maintenance of three-dimensional
structure in the enzyme. For the enzyme
shown in the figure, the increase of
reaction rate corresponds to
deprotonation of the active site histidine.
At a pH above 8.5, deprotonation of an
amino-terminal -NH3+ alters the
conformation at the active site and the
activity decreases. Other enzymes might
have a lower pH maximum, a broader peak, or retain their
activity in the basic side of the curve.
adamianis fermentebis umetesoba optimalur siCqares avlens daaxloebiT 37ºC-ze.
temperaturis zrda 0oC-an 37oC-de zrdis aseve reaqciis siCqares substratis
vibraciuli energiis zrdis xarjze. adamianis fermentebis umetesobis siCqaris
maqsimumi 37oC-is farglebSi aixsneba ufro maRali temperaturis dros maTi
denaturaciiT (meoreuli da mesameuli struqturis dakargva)

V. meqanizmze dafuZnebuli inhibitorebi

inhibitorebi arian nivTierebebi, romlebic amcireben fermentuli reaqciis siCqares.


meqanizmze dafuZnebuli inhibitorebi baZaven katalizuri reaqciis Sualedur safexurs
an monawileoben masSi. maT Soris gulisxmoben aseve gardamavali mdgomareobis
analogebs da nivTierebebs, romlebic Seuqcevadad reagireben aqtiuri centris
funqciur jgufebTan.

a. kovalenturi inhibitorebi

kovalenturi inhibitorebi warmoqmnian kovalentur an ukiduresad mWidro kavSirebs


aqtiuri centris funqciur jgufebTan. es funqciuri jgufebi gaaqtivebulia sxva
aminomJavebTan urTierTqmedebis gamo da amitom ufro mizanmimarTulad modificirdebian
wamlebiT da toqsinebiT, vidre aqtiuri centrisgan daSorebuli aminomJavebi.

letaluri nivTiereba diizopropilftorfosfati (DFP) organofosforuli naerTia,


romelic gamoiyeneboda prototipad momwamvlel gaz zarinSi da iseT
organofosforul toqsinebSi, rogoricaa inseqticidebi malTioni da paraTioni (ix.
sur. ). DFP-is toqsikuri efeqti dakavSirebulia acetilqolinesTerazas aqtiur
centrSi kovalenturi intermediatis warmoqmnasTan, ris gamoc fermenti veRar axdens
neirotransmiter acetilqolinis degradacias.

kovalenturi kavSiris warmoqmnis Sedegad DFP-iT inhibireba praqtikulad Seuqcevadia.


DFP aseve ainhibirebs sxva fermentebsac, romlebic iyeneben serins hidrolizuri
daSlisTvis, magram letaluri efeqti amas ar mosdevs.

Fig. 8.17 A. Acetylcholinesterase normally catalyzes inactivation of the neurotransmitter acetylcholine in a


hydrolysis reaction. The active site serine foms a covalent intermediate with a portion of the substrate during
the course of the reaction. B. Diisopropyl phosphofluoridate( DFP), the ancestor of current organophosphorus
nerve gases and pesticides, inactivates acetylcholinesterase by forrning a covalent complex with the
active site serine that cannot be hydrolysed by water. The resült is that the enzyme cannot carry out its
normal reaction, and acetylcholine accumulates.
aspirini (acetilsalicilis mJava) kargad cnobili farmakologiuri preparatia,
romlis moqmedebis meqanizmi dafuZnebulia ferment prostaglandinendoperoqsidsinTazas
(cikloqsigenaza) aqtiuri saiTis serinis kovalentur acetilirebaze. aspirini waagavs
prostaglandinis winamorbedis,am fermentis fiziologiuri substratis, nawils.

b. gardamavali mdgomareobis analogebi da naerTebi, romlebic reaqciis Sualeduri


stadiebis msgavni arian.
gardamavali mdgomareobis analogebi fermentebis yvelaze Zlieri da specifiuri
inhibitorebi arian, radganac substratze da produqtze ufro Zlierad ukavSirdebian
fermentebs. wamlebis sinTezi, romelTa struqtura zustad imeorebs gardamaval
mdgomareobas SeuZlebelia, gamomdinare am naerTebis arastabilurobidan. magram,
radganac katalizis procesSi nivTiereba ganicdis eleqtronuli konfiguraciis
safexurebriv cvlilebebs, SesaZlebelia iseTi naerTis sinTezi, romelic ufro
stabiluri intermediatis analogi iqneba.

1. penicilini
penicilini, antibiotiki, aris gardamavali mdgomareobis kompleqsis analogi, romelic
Zalian mWidrod ukavSirdeba ferment glikopeptidiltransferazas, romelic
baqteriuli ujredis kedlis Sesaqmnelad aris saWiro.
glikopeptidiltransferaza penicilinTan akatalizebs
nawilobriv reaqcias da qmnis kovalentur bmas
sakuTari aqtiuri centris serinTan. reaqcia
SesaZlebelia im msgavsebis gamo, romelic arsebobs

Fig. 8.18 The antibiotic penicillin inhibits the bacterial enzyme


glycopeptide transpeptidase.
The transpeptidase is a serine protease involved in cross-linking
components of bacterial cell walls and is essential for bacterial
growth and survival. It normally cleaves the peptide bond between
two D-alanine residues in a polypeptide. Penicillin contains a strained
peptide bond within the β-lactam ring that resembles the transition
state of the normal cleavagere action, and thus penicillin binds very
readily in the enzyme active site. As the bacterial enzyme attempts to
cleave this penicillin peptide bond, penicillin becomes irreversibly
covalently attached to the enzyme's active site serine, thereby
inactivating the enzyme.

penicilinis β-laqtamur birTvsa da transpeptidazuri


reaqciis gardamavali mdgomareobis kompleqss Soris.
penicilinis msgavsi aqtiuri centris inhibitorebi,
romlebic Sedian fermentTan nawilobriv reaqciaSi da
warmoqmnian Seuqcevad inhibitorebs, “suiciduri inhibitorebis” ("suicide inhibitors)
saxeliT arian cnobilni.

2. alopurinoli
alopurinoli nikrisis qariT daavadebuli pacientebisTvis gamoiyeneba. is amcirebs
SardmJavas warmoqmnas qsantinoqsidazas inhibirebis Sedegad. es inhibireba aris
magaliTi fermentis, romelic gardaqmnis wamals gardamavali mdgomareobis analogad.
qsantinoqsidaza saWiroa hipoqsantinis qsantinad da qsantinis SardmJavad
gardasaqmnelad da CarTulia purinebis degradaciis metabolur gzaSi. fermenti Seicavs
molibden-sulfidur kompleqss (Mo-S), romelic ikavSirebs substratebs da
gadaaqvs Jangva-aRdgeniTi reaqciisTvis saWiro eleqtronebi. qsantinoqsidaza Jangavs
alopurinols oqsipurinolad, romelic warmoqmnis Zalian Zlier kavSirs aqtiuri
centris molibden-sulfidur kompleqsTan. amis Sedegad fermenti ganicdis suicids da
veRar akatalizebs bunebriv reaqcias, SardmJavas warmoqmnas.

d. mZime metalebi
mZime metalebis (vercxliswyali (Hg), tyvia (Pb), alumini (Al) an rkina (Fe))
toqsikuroba dakavSirebulia maT unarTan mWidrod daukavSirdnen fermentebis
funqciur jgufebs. mZime metalebi araspecifiurni arian fermentebis mimarT da amiT
aris gamowveuli maTi maRali toqsikuroba. vercxliswali, magaliTad imdenad bevr
ferments ainhibirebs (rogorc wesi aqtiuri centris sulfhidrilur jgufebTan
dakavSirebis xarjze), rom xSirad SeuZlebelia imis dadgena, Tu romeli konkretuli
fermentis gamo ganviTarda toqsikozi. tyvia, rogorc wesi, enacvleba fermentebSi
arsebul metalebs da amiT iwvevs maTi funqciis dakargvas. tyviis mier gamowveuli
darRveva da nevrologiuri toqsikozi SeiZleba iyos dakavSirebuli mis unarTan -
Caenacvlos Ca2+-is ions regulatorul cilebSi- Ca2+-kalmodulinsa da proteinkinaza
C-Si.

Fig. 8.19. Allopurinol is a suicide inhibitor of xanthine oxidase. A. Xanthine oridase catalyzes the
oxidation of hlpoxanthine to xanthine, and xanthine to uric acid (uate) in the pathway for degadation of purine
nucleotides. B. The oxidations are Performed by a molybdenum-oxo-sulfide coordination complex in the
active site that complexes with the group being oxidized. Oxygen is donated from water. The enzyme can
work either as an oxidase (O2 accepts the 2e- and is reduced to H2O2), or as a dehydrogenase (NAD+
accepts the 2e- and is reduced to NADH). C. Xanthine oxidase is able to perform the fust oxidation step and
convert allopurinol to alloxanthine (oxypurinol). As a result, the enzyme has committed suicide; the oxypurinol
remains bound in the molybdenum coordination sphare, where it prevents the next step of the reaction.
fermentebis klasifikacia. fermentebis komisiam dayo fermentebis mier katalizirebuli
reaqciebi eqvs mTavar klasad, da TiToeuls mianiWa nomer: (1) oqsidoreduqtazebi; (2)
transferazebi; (3) hidrolazebi; (4) liazebi; (5) izomerazebi da (6)ligazebi.
TiToeuli es farTo klasi Sedgeba qveklasebisgan da miniWebuli aqvT sistemuri
saxelwodebac da gavrcelebulic (mag. dehidrogenazebi da kinazebi).

oqsidoreduqtazebi. Jangva-aRdgeniTi reaqciebi farTed aris gavrcelebuli metabolur


gzebSi da katalizdebian fermentebiT, romlebic oqsidoreduqtazebis farTe klasSi
Sedian. Jangva-aRdgenis procesSi erTi substrati mainc iRebs eleqtronebs da xdeba
aRdgenili, xolo meore substrati kargavs eleqtronebs da xdeba daJanguli. eRti
tipis reaqciebSi, romelsac dehidrogenazebi akatalizeben eleqtronebis gadatana xdeba
hidrid ionis (H:-) an wyalbadis atomis saxiT. am dros , rogorc wesi, monawileoben
Jangva-aRdgeniTi kofermentebi, rogoric arian mag. NAD+/NADH-is wyvili. amave klasis
sxva qveklasi iyenebs donorad O2-s. am dros Jangbadis erTi an arive atomi
gadaitaneba aqceptorze. Jangbadi xdeba aRdgenili, xolo aqceptori ki daJanguli (mag.
ix. qsantin oqsidaza). aseT reaqciebSi monawile fermentebs uwodeben hidroqsilazebs,
rodesac Jangbadis erTi atomi gadaitaneba substratze, xolo meore warmoqmnis wyals,
an oqsidazebs, rodesac orive atomi Seva wylis SemadgenlobaSi. im SemTxvevaSi Tu
Jangbadis orive atomi ukavSirdeba aqceptors - uwodeben oqsigenazebs. oqsidazebis da
hidroqsilazebis umetesoba saWiroebs metalis ionebs, mag. Fe2+ , Tavisi funqciis
Sesasruleblad.

transferazebi. transferazebi akatalizeben jgufebis gadatanis reaqciebs- funqciuri


jgufebis gadatanas erTi molekulidan meoreze. Tu gadasatani jgufi e.w.
maRalenerguli fosfatia, ferments uwodeben kinazas; Tu gadasatania naXSirwylis
naSTi -glikozil transferaza;
cximovani acilis jgufis SemTxvevaSi
aciltransferaza.
am jgufis calke qveklasia
transaminazuri reaqcia, rodesac
erTi aminomJavis amino jgufi
gadaitaneba α-ketomJavaze da
warmoiqmneba axali aminomJava da
donori aminomJavis Sesabamisi α-
ketomJava. fermentebs, romlebic aseT
reaqciebs akatalizeben
aminotransferazebs an transaminazebs
uwodeben. rodesac transferazebi
gansakuTrebiTi mniSvnelobis naerTs
warmoqmnian, maT SeiZleba sinTazac
uwodon. mag. glikogen sinTazas
gadaaqvs glikozilis naSTi UDP-
glucose-dan glikogenis jaWvis
daboloebaze. misi sistematuri
saxelia UDP-glucose-glycogen
glycosyltransferase.

Transamination reactions. Pyridoxal phosphate (PLP) on


aspartate aminotransferase transfers an amino group
from aspartate
to the a-keto acid (α-ketoglutarate) to form a new amino acid (glutamate). The enzyme used to be called glutamate-oxaloacetate
transaminase.

hidrolazebi. hidrolizur reaqciebSi C-O, C-N an C-S kavSirebi ixliCebian wylis


OH- da H+ saxiT mimatebisas bmaSi monawile atomebTan. fermentebis klasis saxeli
damokidebulia gasaxleCi bmis saxelze. xSirad am klasis fermentebs Tavisi
trivialuri saxelebiT moixsenieben (mag. qimotripsini, romelic aris hidrolaza,
romelic akatalizebs peptiduri bmebis gaxleCvas).

liazebi. am klasSi Sedian gansxvavebuli fermentebis jgufebi, romlebic xleCen C-C,


C-O da C-N kavSirebs Jangva-aRdgeniTi an hidrolizisgan gansxvavebuli gzebiT.
zogierT ferments, romlebic xleCen kavSirebs uwodeben aldolazebs,
dekarboqsilazebs Tu naxSirorJangi gamoiyofa C-C bmis gaxleCvis Semdeg, an
Tiolazebs, Tu nukleofilis rols cisteinis an CoASH-is gogirdi gamoiyeneba.
am farTe klasSi Sedian dehidratazebic da mravali sinTazac. dehidratazebi aclian
wylis elementebs momiJnave naxSirbadebs da warmoqmnian ormag bmebs. rogorc es iyo
transferazebis SemTxvevaSi, zogierT ferments, romlis reaqciis mimarTuleba
fiziologiur pirobebSi mniSvnelovani naerTisTvis C-C kavSiris warmoqmnaa -sinTazas
uwodeben (mag. citrat sinTaza).

Aldolases catalyze carbon-carbon cleavage in reactions that are usually reversible.


In glycolysis, the enzyme fructose 1,6-bisphosphate aldolase cleaves a carbon-carbon bond in fructose 1,6-bisphosphate. A ldolases
have a lysine epsilon amino group in the active site that participates in the reaction.

izomerazebi. mravali bioqimiuri reaqcia molekulaSi arsebuli atomebis gadaadgilebaa,


rac warmoqmnis sawyisis izomerebs. fermentebi, romlebic kavSirebis struqturis
gadalagebas ewevian arian izomerazebi, rodesac am dros xdeba fosfatis gadatana erTi
atomidan meoreze - arian mutazebi.

ligazebi. ligazebi warmoqmnian C-C, C-S, C-O da C -N kavSirebs, reaqciebSi, romlebsac


aucileblad Tan unda sdevdes ATP-is an sxva nukleotidis maRalenerguli kavSiris
gaxleCva. karboqsilazebi, mag. umateben CO2-s sxva molekulas da am dros ixarjeba
ATP-is energia. karboqsilazebis umetesobas Wirdeba biotini, rom Seasrulon Tavisi
funqcia. sxva ligazebs uwodeben sinTeTazebs (mag. fatty acyl CoA synthetase).
sinTeTazebi gansxvavdebian aqamde naxsenebi sinTazebisgan, imiT rom maTTvis aucilebelia
maRalerguli fosfaturi bmis energiis gamoyeneba, xolo sinTazebis SemTxvevaSi
gamoiyeneba sxva formis energia.

Isomerases rearrange atoms within a molecule. In the pathway of glycolysis, triose phosphate isomerase converts dihydroxyacetone
phosphate to glyceraldehydes 3-phosphate by rearranging hydrogen atoms. No other substrates or products of the reaction exist.
pacienti daibada fermentis kongenitaluri (Tandayolili) mutaciiT, romelic Zalzed cvlis mis unars daikavSiros
acilireba- transferirebis koenzimi am cvlilebis Sedegad:
(A) fermenti veRar daikavSirebs reaqciis substrats
(B) fermenti veRar warmoqmnis gardamavali mdgomareobis kompleqs.
(C) fermenti gamoiyenebs sxva gamaaqtivebel-transferul koenzims
(D) fermenti gamoiyenebs aqtiuri centris funqciur jgufs koenzimis nacvlad
(E) reaqcia warimarTeba Tavisufali koenzimis mier, Tu davuSvebT, rom sakvebiT sakmao raodenobis vitaminur
prekursori miewodeba

pacients glukokinazas kongenitaluri (Tandayolili) mutaciiT prolini Secvlili aqvs


leiciniT, romelic mdebareobs spiralis zedapirze, aqtiuri centrisgan daSorebiT, magram aqtinis foldis “hinge”
(saxsari)ubanSi. am mutaciasTan dakavSirebiT mosalodnelia
(A) ar eqneba gavlena reaqciis siCqareze, radganac ar imyofeba aqtiur centrSi
(B) ar eqneba gavlena reaqciis siCqareze, radganac prolinic da leicinic arapolaruli aminomJavebia
(C) ar eqneba gavlena substratis molekulebis raodenobaze, romlebic miaRweven gardamaval mdgomareobas
(D) SesaZlebelia Seicvalos ATP-s dakavSireba an reaqciis mimdinareobis Semdgomi safexuri
(E) SeiZleba warmarTos reaqcia alternatuli meqanizmiT

pacients ganuviTarda nawlavuri baqteriebis gaZlierebuli zrda, ramac gamoiwvia nawlavuri SigTavsis pH-is
Semcireba 6,5 5,5-de. pH-is es cvlileba
(A) moaxdens im cilebis denaturacias, romlebmac nawlavebamde miaRwies natiuri intaqturi struqturiT
(B) daarRvevs wyalbadur bmebs, romlebic saWiroa mesameuli struqturis SesanarCuneblad
(C) daainhibirebs fermentebs, romlebic saWiroeben histidins mJava-fuZe katalizisTvis
(D) daainhibirebs nawlavur fermentebs, romlebic substratis dasakavSireblad saWiroeben aqtiuri centris lizins
(E) eqneba mcire gavlena hidrolazebze

zemoT moyvanili reaqcia klasificirdeba, rogorc


(A) jgufebis gadatana
(B) izomerizacia
(C) naxSirbadis atomebs Soris bmis gaxleCva
(D) naxSirbadis atomebs Soris bmis warmoqmna
(E) Jangva-aRdgeniTi reaqcia

fermenti, romelic am reaqcias akatalizebs aris


(A) kinaza
(B) dehidrogenaza
(C) glikoziltransferaza
(D) transaminaza
(E) izomeraza