Txhua yam tshuaj lom neeg biochemical tshwm sim hauv lub cev yog raug tswj xyuas tshwj xeeb, uas yog ua los ntawm kev ua kom muaj zog lossis inhibitory cuam tshuam ntawm kev tswj cov enzymes. Cov yav tas feem ntau yog nyob rau thaum pib ntawm chains ntawm metabolic transformations thiab txawm pib ib tug ntau theem txheej txheem los yog qeeb nws. Qee qhov kev tawm tsam ib leeg kuj raug tswj hwm. Kev sib tw inhibition yog ib qho ntawm cov txheej txheem tseem ceeb los tswj cov kev ua haujlwm catalytic ntawm enzymes.
Yuav ua li cas yog inhibition?
Lub tshuab ntawm enzymatic catalysis yog raws li kev sib txuas ntawm qhov chaw nquag ntawm cov enzyme rau lub substrate molecule (ES complex), uas ua rau cov tshuaj tiv thaiv nrog kev tsim thiab tso tawm ntawm cov khoom (E + S=ES=EP=E+P).
Inhibition ntawm ib qho enzyme yog txo tus nqi lossis ua tiav ntawm cov txheej txheem catalysis. Hauv qhov nqaimKev nkag siab, lo lus no txhais tau hais tias qhov txo qis hauv kev sib raug zoo ntawm qhov chaw ua haujlwm rau lub substrate, uas yog ua tiav los ntawm kev khi enzyme molecules rau inhibitor tshuaj. Cov tom kawg tuaj yeem ua ntau yam, raws li lawv tau muab faib ua ntau hom, uas sib haum rau cov txheej txheem inhibition ntawm tib lub npe.
hom kev txwv tseem ceeb
Los ntawm qhov xwm txheej, inhibition tuaj yeem yog ob hom:
- Irreversible - ua rau muaj kev hloov pauv tsis tu ncua hauv cov enzyme molecule, depriving nws ntawm kev ua haujlwm (qhov kawg tsis tuaj yeem rov qab los). Nws tuaj yeem yog qhov tshwj xeeb lossis tsis tshwj xeeb. Tus inhibitor khi ruaj khov rau cov enzyme los ntawm covalent kev sib cuam tshuam.
- Reversible - hom tseem ceeb ntawm kev tswj tsis zoo ntawm cov enzymes. Nws yog nqa tawm vim qhov kev hloov pauv tshwj xeeb ntawm cov inhibitor rau cov enzyme protein los ntawm cov nyiaj tsis muaj zog uas tsis yog-covalent, amenable rau kinetic piav qhia raws li Michaelis-Menten kab zauv (nrog rau kev zam ntawm allosteric regulation).
Muaj ob yam tseem ceeb ntawm kev thim rov qab enzyme inhibition: kev sib tw (tej zaum yuav txo qis los ntawm kev nce substrate concentration) thiab tsis sib tw. Hauv qhov kawg, qhov siab tshaj plaws ntawm catalysis txo qis.
Qhov sib txawv tseem ceeb ntawm kev sib tw thiab tsis sib tw inhibition yog nyob rau hauv qhov chaw ntawm kev sib txuas ntawm cov tshuaj tswj hwm rau cov enzyme. Hauv thawj kis, tus inhibitor khi ncaj qha mus rau qhov chaw nquag, thiab hauv qhov thib ob, mus rau lwm qhov chaw ntawm cov enzyme, lossis rau cov enzyme-substrate complex.
Tseem muaj ntau hom kev sib xyaw ua ke, uas khi rau qhov inhibitor tsis tiv thaiv kev tsim ntawm ES, tab sis qeeb catalysis. Nyob rau hauv cov ntaub ntawv no, cov tshuaj regulator yog nyob rau hauv muaj pes tsawg leeg ntawm ob los yog triple complexes (EI thiab EIS). Hauv hom tsis sib xws, cov enzyme tsuas yog khi rau ES.
Ntawm ntawm kev sib tw thim rov qab inhibition ntawm enzymes
Kev sib tw kev sib tw ntawm kev txwv tsis pub yog raws li cov qauv zoo sib xws ntawm cov khoom siv tswj hwm nrog cov substrate. Yog li ntawd, ib tug complex ntawm lub active chaw nrog tus inhibitor yog tsim, conventionally xaiv raws li EI.
Kev thim rov qab kev sib tw inhibition muaj cov yam ntxwv hauv qab no:
- khi rau tus inhibitor tshwm sim ntawm qhov chaw nquag;
- inactivation ntawm cov enzyme molecule yog thim rov qab;
- cov nyhuv inhibitory tuaj yeem txo qis los ntawm kev nce cov concentration ntawm substrate;
- inhibitor tsis cuam tshuam rau qhov siab tshaj plaws ntawm enzymatic catalysis;
- lub EI complex tuaj yeem decompose, uas yog tus cwj pwm los ntawm kev sib cuam tshuam tsis tu ncua.
Nrog cov kev cai no, cov inhibitor thiab cov substrate zoo li sib tw (sib tw) nrog rau ib qho chaw nyob rau hauv lub active center, li no lub npe ntawm tus txheej txheem.
Vim li ntawd, kev sib tw inhibition tuaj yeem txhais tau tias yog cov txheej txheem thim rov qab ntawm inhibition ntawm enzymatic catalysis, raws li qhov tshwj xeeb affinity ntawm qhov chaw nquag rau cov tshuaj inhibitor.
Mechanism of action
Tetheringib qho inhibitor nrog rau qhov chaw nquag tiv thaiv kev tsim cov enzyme-substrate complex tsim nyog rau catalysis. Yog li ntawd, lub enzyme molecule ua inactive. Txawm li cas los xij, qhov chaw catalytic tuaj yeem khi tsis tau tsuas yog rau cov inhibitor, tab sis kuj rau lub substrate. Qhov tshwm sim ntawm kev tsim ntawm ib lossis lwm txoj hauv kev yog nyob ntawm qhov piv ntawm cov concentrations. Yog tias muaj ntau cov substrate molecules, ces cov enzyme yuav hnov mob nrog lawv ntau zaus dua nrog cov inhibitor.
Kev cuam tshuam ntawm tus nqi ntawm cov tshuaj tiv thaiv tshuaj
Qib ntawm inhibition ntawm catalysis thaum lub sijhawm sib tw inhibition yog txiav txim siab los ntawm ntau npaum li cas ntawm cov enzyme yuav tsim EI-complexes. Nyob rau hauv cov ntaub ntawv no, nws muaj peev xwm mus nce lub concentration ntawm lub substrate mus rau xws li ib tug raws li lub luag hauj lwm ntawm inhibitor yuav hloov, thiab tus catalysis tus nqi yuav ncav cuag qhov siab tshaj plaws tus nqi sib xws rau tus nqi V max.raws li kev sib npaug ntawm Michaelis-Menten.
qhov tshwm sim no yog vim muaj zog dilution ntawm inhibitor. Raws li qhov tshwm sim, qhov tshwm sim ntawm cov enzyme molecules khi rau nws raug txo kom xoom, thiab cov chaw ua haujlwm nquag hnov qab tsuas yog nrog cov substrate.
Kinetic dependences ntawm cov tshuaj tiv thaiv enzymatic cuam tshuam nrog kev sib tw inhibitor
Kev sib tw inhibition nce Michaelis tas li (K m), uas yog sib npaug rau cov substrate concentration xav tau kom ua tiav ½ qhov siab tshaj plaws ntawm catalysis thaum pib cov tshuaj tiv thaiv. Tus nqi ntawm cov enzyme hypothetically muaj peev xwm los khi rau lub substrate tseem nyob tas li, thaum tus naj npawb ntawm ES-complexes tsuas yog nyob ntawm qhov concentration ntawm tom kawg (EI complexes tsis tas li thiab tuaj yeem hloov pauv los ntawm substrate).
Kev sib tw inhibition ntawm enzymes yog ib qho yooj yim los txiav txim los ntawm cov duab ntawm lub kinetic dependence ua rau txawv concentrations ntawm lub substrate. Hauv qhov no, tus nqi ntawm Km yuav hloov, thaum Vmax yuav nyob tas li.
Nrog tsis muaj kev sib tw inhibition, qhov tsis sib xws yog qhov tseeb: tus inhibitor khi sab nraum lub chaw ua haujlwm thiab lub xub ntiag ntawm lub substrate tsis tuaj yeem cuam tshuam qhov no hauv txhua txoj kev. Yog li ntawd, qee qhov ntawm cov enzyme molecules yog "tua" los ntawm catalysis, thiab qhov siab tshaj plaws tau txo qis. Txawm li cas los xij, active enzyme molecules tuaj yeem yooj yim khi rau lub substrate ob qho tib si ntawm qis thiab siab concentrations tom kawg. Yog li ntawd, tus Michaelis tas mus li nyob tas li.
Daim duab ntawm kev sib tw inhibition nyob rau hauv lub kaw lus ntawm ob qhov kev sib hloov pauv yog ob peb txoj kab ncaj nraim hla y-axis ntawm qhov taw tes 1 / V max. Txhua txoj kab ncaj nraim sib haum mus rau qee qhov concentration ntawm cov substrate. Cov ntsiab lus sib txawv ntawm kev sib tshuam nrog abscissa axis (1/[S]) qhia txog kev hloov pauv hauv Michaelis tas li.
Kev ua ntawm kev sib tw inhibitor ntawm tus piv txwv ntawm malonate
Ib qho piv txwv ntawm kev sib tw inhibition yog cov txheej txheem ntawm kev txo cov kev ua ntawm succinate dehydrogenase, ib qho enzyme uas catalyzes oxidation ntawm succinic acid (succinate) rau fumaric acid. Ntawm no yog ib qho inhibitormalonate ua, muaj cov qauv zoo sib xws rau succinate.
Ntxiv ib qho inhibitor rau nruab nrab ua rau tsim cov complexes ntawm malonate nrog succinate dehydrogenase. Xws li daim ntawv cog lus tsis ua kev puas tsuaj rau qhov chaw nquag, tab sis thaiv nws txoj kev nkag mus rau succinic acid. Ua kom cov concentration ntawm succinate txo cov nyhuv inhibitory.
siv kho mob
Kev ua ntawm ntau yam tshuaj, uas yog cov qauv sib piv ntawm cov substrates ntawm qee txoj hauv kev metabolic, inhibition uas yog ib feem tsim nyog ntawm kev kho cov kab mob, yog raws li cov txheej txheem ntawm kev sib tw inhibition.
Piv txwv li, txhawm rau txhim kho kev ua haujlwm ntawm cov hlab ntsha hauv cov leeg nqaij dystrophies, nws yuav tsum tau nce qib ntawm acetylcholine. Qhov no ua tiav los ntawm inhibiting cov haujlwm ntawm nws cov hydrolyzing acetylcholinesterase. Cov inhibitors yog quaternary ammonium bases uas yog ib feem ntawm cov tshuaj (proresin, endrophonium, thiab lwm yam).
Antimetabolite yog qhov txawv rau hauv ib pab pawg tshwj xeeb, uas, ntxiv rau cov nyhuv inhibitory, nthuav tawm cov khoom ntawm pseudosubstrate. Nyob rau hauv cov ntaub ntawv no, qhov tsim ntawm EI complex ua rau tsim ib tug biologically inert anomalous khoom. Antimetabolites muaj xws li sulfonamides (siv hauv kev kho cov kab mob kab mob), nucleotide analogs (siv txwv tsis pub cov cell loj hlob ntawm cov qog nqaij hlav cancer), thiab lwm yam.
