Cov roj ntsha cov ntshav qab zib hauv lub cev thiab nws cov roj ntsha biochemistry - Ntshav Qab Zib
Tsis muaj ib qho tsis ntseeg, cov roj cholesterol yog qhov zoo tshaj plaws paub lipid rau cov pej xeem; nws tsis muaj npe vim tias cov kev sib txuam ntawm cov ntshav siab thiab cov zaus ntawm tib neeg cov kab mob plawv. Tsawg dua cov xim tau them rau lub luag haujlwm tseem ceeb ntawm cov roj (cholesterol) hauv cov qog ua cell thiab ua lub zog ua ntej cov tshuaj steroid thiab cov kua tsib kua qaub. Cholesterol yog qhov tsim nyog rau ntau tus tsiaj, nrog rau tib neeg, tab sis nws muaj nyob rau hauv cov khoom noj mammalian yog xaiv tau - lub cev lub cev lawv tus kheej tuaj yeem coj nws los ntawm kev yooj yim.
Cov qauv ntawm 27-carbon compound qhia txog ib txoj hauv kev nyuaj rau nws txoj kev xaim hluav taws xob, tab sis txhua yam ntawm nws cov pa roj carbon atoms yog muab los ntawm ib qho ua ntej - acetate. Isoprene blocks - cov intermediates tseem ceeb tshaj plaws los ntawm acetate rau cov roj cholesterol, lawv yog cov ua ntej ntawm ntau cov lipids, thiab cov txheej txheem los ntawm isoprene cov blocks yog cov polymerized yog qhov zoo sib xws hauv txhua txoj kev ua hauv metabolic.
Peb pib los ntawm kev xav txog cov theem tseem ceeb hauv txoj hauv kev ntawm cov roj ntsha biosynthesis los ntawm acetate, tom qab ntawd peb sib tham txog kev thauj cov roj hauv cov ntshav, nws nqus los ntawm cov hlwb, txoj cai ib txwm ntawm cov roj synthesis thiab cov kev cai nyob rau hauv thaum tsis pom zoo los yog thauj. Tom qab ntawd peb saib rau lwm cov tshuaj uas los ntawm cov roj hauv lub cev, xws li cov kua tsib kua qaub thiab cov tshuaj hormones steroid. Thaum kawg, cov lus piav qhia ntawm biosynthetic txoj hauv kev rau kev tsim ntau lub tebchaw - derivatives ntawm isoprene block, nyob rau hauv uas muaj cov xwm txheej thaum ntxov nrog cov roj (synthesis), yuav qhia txog qhov txawv tshaj plaw ntawm isoprenoid hws nyob rau hauv biosynthesis.
Cov roj (cholesterol) yog tsim los ntawm acetyl-CoA hauv plaub theem
Cov roj (cholesterol), zoo li cov saw fatty acids ntev yog tsim los ntawm acetyl-CoA, tab sis cov qauv sib dhos yuav txawv tag. Hauv qhov kev sim thawj zaug, cov tshuaj acetate sau nrog 14 C xws li ntawm cov methyl lossis carboxyl carbon atom ntxiv rau ntxiv rau tsiaj pub tsiaj. Raws li kev faib tawm ntawm daim ntawv lo hauv cov roj (cholesterol) uas raug cais tawm ntawm ob pawg ntawm cov tsiaj (Daim Duab 21-32), cov theem ntawm cov roj (biosynthesis) roj (enzymeatic) tau piav qhia.
Daim duab. 21-32. Qhov uas cov pa roj carbon atoms. Txheeb xyuas thaum lub sijhawm sim siv cov kua hluav taws xob acetate sau npe nrog cov pa roj carbon methyl (dub) lossis carboxyl carbon (xim liab). Hauv cov txheej txheem khov khov, cov nplhaib tau txhais los ntawm cov tsiaj ntawv A rau D.
Qhov kev sib hloov coj qhov chaw nyob hauv plaub theem, raws li qhia hauv Daim Duab. 21-33: (1) kev txhawm rau ntawm peb acetate seem nrog kev tsim ntawm 6-carbon ntu nruab nrab ntawm mevalonate, (2) kev hloov pauv ntawm mevalonate mus rau hauv isoprene block, (3) lub polymerization ntawm rau tsib-carbon isoprene chav nrog tsim ntawm 30-carbon tawm squalene los ua, plaub lub voj voos ntawm cov tshuaj steroid nucleus, tom qab ntawv hloov pauv (oxidation, tshem tawm lossis tsiv teb chaws ntawm cov pab pawg methyl) nrog kev tsim cov roj (cholesterol).
Daim duab. 21-33. Cov duab dav dav ntawm cov roj biosynthesis. Plaub theem ntawm cov khoom cua tau sib tham hauv cov ntawv nyeem. Isoprene cov nyom hauv squalene yog cim los ntawm kab liab kab liab.
Cov theem (1). Synthesis ntawm mevalonate los ntawm acetate. Thawj theem ntawm cov roj biosynthesis ua rau lub hauv paus ntawm cov khoom lag luam nruab nrab mevalonate (Daim duab 21-334). Ob lub acetyl CoA lwg me me rau kom muab acetoacetyl CoA, uas tso nrog tus thib acetyl CoA molecule los tsim rau-lub pob zeb sib xyaws β-hydroxy-β-methylglutaryl-CoA (HM G -CoA). Ob qho tshuaj tiv thaiv thawj no yog catalyzed thiolase thiab NM G -CoA synthase, ua ntu zus. Cytosolic NM G-CoA synthase Qhov kev zom zaubmov sib txawv no txawv ntawm mitochondrial isoenzyme, uas ua rau muaj kev cuam tshuam ntawm NM G -CoA thaum tsim cov ketone lub cev (saib Daim duab 17-18).
Daim duab. 21-34. Qhov tsim ntawm mevalonate los ntawm acetyl-CoA. Qhov chaw ntawm C-1 thiab C-2 mevalonate los ntawm acetyl-CoA tseem ceeb hauv liab dawb.
Qhov thib peb tshuaj tiv thaiv txwv qhov ceev ntawm tag nrho cov txheej txheem. Hauv nws, NM G -CoA txo rau mevalonate, rau cov uas ob ntawm NА D PH lwg me me muab ob qho hluav taws xob. HMG-CoA reductase - integral membrane protein ntawm ER yooj yim, nws pabcuam, raws li peb yuav pom tomqab ntawd, raws li lub ntsiab lus tseem ceeb ntawm kev tswj kev zom zaubmov hauv cov roj cholesterol tsim.
Cov theem (2). Txoj kev hloov pauv ntawm mevalonate rau ob lub isoprene qhib. Ntawm theem tom ntej ntawm kev sib txuas roj (cholesterol), peb pawg phosphate tau hloov pauv los ntawm ATP lwg me me mus rau mevalonate (Daim duab 21-35). Cov phosphate tau cog lus rau hydroxyl pawg ntawm C-3 mevalonate hauv nruab nrab 3-phospho-5-pyrophosphomevalonate yog pawg zoo tawm, hauv cov kauj ruam tom ntej ob qho tib si ntawm cov phosphates thiab cov pab pawg carboxyl uas nyob ib sab tawm, ua rau ob daim ntawv cog lus hauv cov khoom siv roj carbon tsib ∆ 3 -isopentenyl pyrophosphate. Qhov no yog thawj zaug ntawm ob lub isoprenes qhib - cov neeg tseem ceeb hauv cov roj (synthesis). Isomerization ntawm Δ 3 -isopentenylpyrophosphate muab qhov thib ob qhib isoprene dimethylallyl pyrophosphate. Kev sib xyaw ntawm isopentenyl pyrophosphate nyob rau hauv cytoplasm ntawm cov nroj tsuag hlwb tshwm sim raws li txoj kev tau piav ntawm no. Txawm li cas los xij, cog cov tshuaj chloroplasts thiab ntau cov kab mob siv txoj hauv kev ywj pheej ntawm mevalonate. Txoj hauv kev xaiv no tsis pom muaj nyob hauv cov tsiaj, yog li nws yuav ntxim siab thaum tsim cov tshuaj tua kab mob tshiab.
Daim duab. 21-35. Kev hloov pauv ntawm mevalonate rau hauv isoprene block. Rau lub koog ua haujlwm muab sib txuas ua ke rau daim ntawv squalene (saib Daim duab 21-36). Cov pawg tawm ntawm 3-phospho-5-pyrophosphomevalonate muaj qhov tseem ceeb hauv paj yeeb. Hauv cov square nkhaus yog qhov kwv yees hypothetical.
Cov theem (3). Kev tso hws ntawm rau (6) isoprene chav nyob ua squalene. Isopentenyl pyrophosphate thiab dimethylallyl pyrophosphate tam sim no yauv lub taub hau-rau-tw hws, nyob rau hauv uas ib pab pawg pyrophosphate tsiv thiab 10-carbon saw cov qauv. - geranyl pyrophosphate (Daim duab 21-36). (Pyrophosphate txuas rau lub taub hau.) Geranyl pyrophosphate yauv mus rau hauv qab ntawm lub taub hau-rau-tw hws nrog isopentenyl pyrophosphate, thiab 15-carbon intermediate farnesyl pyrophosphate. Thaum kawg, ob lub lwg me me ntawm farnesyl pyrophosphate ua ke "lub taub hau rau taub hau", ob pawg phosphate raug tshem tawm - tsim squalene.
Daim duab. 21-36. Squalene tsim. Cov qauv squalene uas muaj 30 carbon atoms tshwm sim thaum cov hws ua haujlwm los ntawm isoprene (tsib-carbon) cov khoom.
Cov hom tau tshwm sim rau cov intermediates los ntawm cov npe ntawm cov khoom xa tuaj uas lawv tau muab cais tawm thawj. Geraniol, ib feem ntawm cov roj sawv, muaj lub geranium tsw, thiab farnesol, pom nyob rau hauv cov xim ntawm acacia farnesa, muaj cov paj ntawm lub hav aroma. Ntau lub cev nroj tsuag tsw ntxhiab tsw muaj rau cov khoom sib txuas ua los ntawm isoprene block. Squalene, thawj zaug cais los ntawm lub siab ntses (Squalus hom), muaj 30 carbon atoms: 24 atoms hauv cov saw tseem ceeb thiab muaj 6 tus atoms hauv cov hlau hloov.
Cov theem (4). Kev hloov pauv ntawm squalene mus rau plaub lub nplhaib ntawm ib tug steroid nucleusCov. Hauv daim duab. 21-37 nws yog pom meej tias cov qauv squalene saw, thiab sterols - cyclic. Txhua sterols muaj plaub qhov hws ua ke uas ua rau steroid nucleus, thiab tag nrho cov cawv nrog pawg hydroxyl ntawm C-3 atom, li no lub npe lus Askiv sterol. Nyob rau hauv kev txiav txim squalene monooxygenase ib qho pa atom los ntawm O ntxiv rau qhov kawg ntawm lub taub hau squalene 2 thiab epoxide yog tsim. Qhov enzyme no yog lwm qhov sib xyaw ua ke oxidase (ntxiv. 21-1), NADPH txo lwm cov pa oxygen atom los ntawm O 2 mus H2 O. Khoom Siv Ob Chav squalene-2,3-epoxide npaj ua kom pom tseeb tias cov tshuaj tiv thaiv zoo ib yam li qub tuaj yeem hloov cov xov ntawm squalene epoxide rau hauv kev ua voj voog. Hauv cov tsiaj hlwb, qhov kev vam meej no ua rau muaj kev tsim lanosterol uas muaj plaub lub nplhaib yam ntxwv ntawm cov steroid nucleus. Raws li qhov tshwm sim, lanosterol hloov pauv mus rau hauv cov cholesterol los ntawm qhov kwv yees li ntawm 20 cov tshuaj tiv thaiv, uas suav nrog kev tsiv teb tsaws ntawm qee pawg hlau thiab tshem tawm ntawm lwm tus. Cov lus piav qhia ntawm txoj hauv kev zoo no ntawm biosynthesis, ib qho nyuaj tshaj plaws ntawm cov paub, tau ua los ntawm Conrad Bloch, Theodore Linen, John Cornfort thiab George Popiak nyob rau xyoo 1950.
Daim duab. 21-37. Ntiv nplhaib kaw puv tawm linear squalene rau hauv cov tub ntxhais kawm tau cov tshuaj steroid. Thawj theem yog catalyzed los ntawm oxidase nrog cov kev ua haujlwm sib xyaw (monooxygenase), uas nws lub cosubstrate yog N AD PH. Cov khoom lag luam yog ib qho epoxide, uas nyob rau theem tom ntej no yuav ua kom muaj kev kub ntxhov los tsim cov tub ntxhais steroid. Cov khoom kawg ntawm cov kev tawm tsam hauv cov tsiaj txhu cov ntshav yog cov roj cholesterol; hauv lwm yam muaj sia sterols sib txawv me ntsis los ntawm nws tsim.
Cov roj (cholesterol) yog cov yam ntxwv ntawm cov tsiaj ntawm cov tsiaj, nroj tsuag, cov hu ua fungi thiab protists tsim lwm cov sterols zoo sib xws.
Lawv siv tib txoj kev sib txuas ua ke rau squalene-2,3-epoxide, tab sis tom qab ntawd cov kab kev sib txawv me ntsis, thiab lwm yam sterols raug tsim, xws li sigmasterol hauv ntau cov nroj tsuag thiab ergosterol hauv cov hu ua fungi (Daim duab 21-37).
Piv txwv 21-1 Cov Nqi Siv Zog rau Squalene Synthesis
Cov nqi hluav taws xob yog dab tsi (qhia raws li ATP lwg me me) rau kev sib txuas ntawm ib lub squalene lwg me?
Tshuaj. Hauv qhov kev coj los ua ke ntawm squalene los ntawm acetyl-CoA, ATP tsuas yog siv nyob rau theem thaum mevalonate hloov pauv mus rau hauv kev qhib isoprene squalene kev ceev faj. 6 lub tshuab ua haujlwm isoprene lwg me me xav tau los tsim cov tshuaj squalene qauv, thiab peb lub ATP lwg me me yuav tsum tsim kom tau ib qho molecule uas siv lawm. Nyob rau hauv tag nrho, 18 ATP lwg me me tau siv rau qhov kev coj los ua ke ntawm ib qho squalene lwg me.
Kev sib xyaw ntawm cov roj cholesterol hauv lub cev
Hauv txha caj qaum, ntau cov roj uas txhaws tau coj los ua ke hauv lub siab. Qee cov roj (cholesterol) synthesized muaj ntxiv rau hauv daim nyias nyias ntawm hepatocytes, tab sis nws feem ntau yog xa tawm hauv ib qho ntawm nws peb daim ntawv: biliary (bile) roj cholesterol, kua tsib kua tsib los yog cov roj (cholesterol). Bile acids thiab lawv cov ntsev yog hydrophilic derivatives ntawm cov cholesterol, uas tau tsim tawm hauv lub siab thiab pab txhawb kev zom zaub mov ntawm lipids (saib Daim duab 17-1). Lub cev roj (cholesterol) tsim nyob rau hauv daim siab los ntawm kev txiav txim acyl-CoA-cholesterol-acyltransferase (ACAT). Qhov enzyme no hloov pauv ntawm ib hom fatty acid residue los ntawm coenzyme A rau hydroxyl pawg ntawm cov roj (Daim Duab 21-38), hloov cov roj cholesterol mus rau hauv ib daim ntawv ntau dua hydrophobic. Cov roj (cholesterol) esters nyob hauv cov roj lipoprotein zais cia yog thauj mus rau lwm cov ntaub so ntswg uas siv cov roj cholesterol lossis muab khaws cia hauv lub siab.
Daim duab. 21-38. Synthesis ntawm cov roj cholesterol. Etherification ua rau cov roj cholesterol ua tau ntau dua hydrophobic daim ntawv rau kev cia khoom thiab thauj.
Cov roj (cholesterol) yog qhov tsim nyog rau tag nrho cov ntaub so ntswg ntawm kev loj hlob tsiaj ntawm lub cev rau kev sib txuas ntawm daim nyias nyias, thiab qee yam kabmob (piv txwv li cov qog adrenal thiab cov qog sib deev) siv cov roj (cholesterol) ua ntej ua rau cov tshuaj hormones steroid (qhov no yuav tham txog hauv qab). Cholesterol kuj yog qhov ua ntej rau cov vitamin D (saib Daim Duab 10-20, v. 1).
Cov roj (cholesterol) thiab lwm cov lipids muaj cov lipoproteins plasma ntshav
Cov roj (cholesterol) thiab cov roj (cholesterol) esters, zoo li triacylglycerols thiab phospholipids, yog cov tsis ua haujlwm hauv dej, txawm li cas los xij, lawv yuav tsum txav tawm ntawm cov ntaub so ntswg uas lawv tau coj los ua ke rau cov ntaub so ntswg uas lawv yuav khaws lossis noj. Lawv tau nqa los ntawm cov hlab ntsha hauv daim ntawv ntshav lipoproteins ntshav - macromolecular ntau txoj kev cov protein nqa khoom tshwj xeeb (apolipoproteins) nrog phospholipids, cov roj (cholesterol), cov roj (cholesterol) esters thiab cov triacylglycerols tshwm sim hauv cov kev nyuaj no hauv ntau cov kev sib txuas.
Apolipoproteins ("apo" yog hais txog lipid tsis muaj protein ntau nws tus kheej) ua ke nrog lipids los ua ntau feem ntawm lipoprotein hais - cov teeb meem kheej nrog hydrophobic lipids nyob rau hauv plawv thiab hydrophilic amino acid txuas rau saum npoo (Daim duab 21-39, a). Nrog ntau cov sib xyaw ua ke ntawm lipids thiab cov protein, hais ntawm cov khoom sib txawv yog tsim - los ntawm chylomicrons rau lub siab lipoproteins. Cov ntawv no tuaj yeem muab cais tawm los ntawm ultracentrifugation (Cov Lus 21-1) thiab pom raws li siv hluav taws xob tsom (duab 21-39, b). Txhua feem ntawm lipoproteins ua cov haujlwm tshwj xeeb, uas yog txiav txim siab los ntawm qhov chaw ntawm synthesis, lipid muaj pes tsawg leeg thiab cov ntsiab lus apolipoprotein. Tsawg kawg 10 qhov sib txawv ntawm apolipoproteins tau pom nyob hauv tib neeg cov ntshav ntshav (Cov Lus 21-2), uas sib txawv me me, cov tshuaj tiv thaiv nrog cov tshuaj tiv thaiv tshwj xeeb, thiab cov xeeb ceem tau faib tawm hauv cov chav kawm sib txawv ntawm lipoproteins. Cov protein ua ua cov cim taw qhia cov lipoproteins rau cov nqaij tshwj xeeb lossis ua rau cov enzymes ua rau lipoproteins.
Rooj 21-1. Tib neeg cov ntshav lipoproteins
Kev sib xyaw (cov feem ntau,%)
r = 513,000). Ib qhov LDL me me muaj qhov tseem ceeb ntawm kwv yees li 1,500 lwg me ntawm cov roj cholesterol esters, nyob ib ncig ntawm tus tub ntxhais muaj lub plhaub 500 cov roj (cholesterol) ntawm cov roj, 800 molecules ntawm phospholipids thiab ib lub qauv ntawm apoB-100. b - plaub chav kawm ntawm lipoproteins, pom nrog lub tshuab tsom electron (tom qab qhov pom ntawm qhov tsis zoo). Clockwise, pib los ntawm sab saud sab sauv: chylomicrons - nrog lub cheeb ntawm 50 txog 200 nm, PL O NP - los ntawm 28 txog 70 nm, HDL - los ntawm 8 rau 11 nm, thiab LDL - los ntawm 20 txog 55 nm. Cov khoom ntawm lipoproteins tau muab rau hauv rooj. 21-2.
Chylomicrons, raug xa mus rau hauv Sec. 17, txav cov zaub mov triacylglycerols los ntawm cov hnyuv mus rau lwm cov ntaub so ntswg. Cov no yog cov lipoproteins ntau tshaj plaws, lawv muaj qhov ceev tsawg tshaj plaws thiab cov ntsiab lus sib txheeb ntau tshaj plaws ntawm triacylglycerols (saib Daim duab 17-2). Chylomicrons yog cov khoom cua hauv cov txheej txheem ER ntawm epithelial cov kab mob hauv lub plab hnyuv me, tom qab ntawd txav mus los ntawm cov kab mob lymphatic thiab nkag mus rau cov hlab ntshav los ntawm cov leeg ntshav subclavian. Chylomicron apolipoproteins muaj apoB-48 (tshwj xeeb rau chav kawm ntawm lipoproteins), apoE thiab apoC-II (Cov Lus 21-2). AroC-II ua kom cov lipoprotein lipase nyob rau hauv cov hlab ntaws ntawm cov ntaub so ntswg adipose, lub plawv, cov leeg pob txha thiab cov nqaij mos ua kom lub plab, ua kom muaj qhov ntws ntawm cov roj ntsha dawb rau hauv cov ntaub so ntswg. Yog li, chylomicrons hloov cov khoom noj muaj roj fatty acids rau cov ntaub so ntswg, qhov chaw uas lawv yuav tau noj lossis khaws cia li roj (Daim duab 21-40). Chylomicron cov khoom seem (feem ntau yog tso tawm los ntawm triacylglycerols, tab sis tseem muaj cov roj cholesterol, apoE thiab apoB-48) raug thauj los ntawm cov hlab ntsha mus rau lub siab. Hauv lub siab, cov teeb meem khi rau apoE muaj nyob hauv chylomicron cov khoom seem thiab sib kho lawv nqus los ntawm endocytosis. Hauv cov tshuaj hepatocytes, cov khoom seem no tso tawm lawv cov cholesterol thiab raug rhuav tshem hauv lysosomes.
Rooj 21-2. Tib neeg cov ntshav lipoprotein apolipoproteins
Muaj nuj nqi (yog tias paub)
Activates L CAT, sib cuam tshuam nrog ABC thauj neeg
Inhibits L MIV
Muaj zog L CAT, roj thauj / tshem tawm
Cov khi rau LDL receptor
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Pib tshem cov VLDL thiab chylomicron cov khoom seem
Thaum cov zaub mov muaj roj ntau cov rog ntau dua li nws siv tam sim no siv roj, lawv tig mus rau hauv triacylglycerols hauv lub siab, uas ua kom muaj feem nrog cov apolipoproteins tshwj xeeb. cov lipoproteins tsawg heev (VLDL). Kev noj cov paib ntau dhau hauv daim siab tseem tuaj yeem hloov mus rau triacylglycerols thiab xa tawm ua VLDL (Daim duab 21-40, a).Ntxiv nrog rau triacylglycerols, VLDL feem muaj qee qhov nqi ntawm cov roj (cholesterol) thiab cov roj (cholesterol), thiab ntxiv rau apoB-100, apoC-1, apoC-II, apoC III thiab apoE (Cov Lus 21-2). Cov lipoproteins no tseem thauj los ntawm cov ntshav los ntawm daim siab mus rau cov leeg thiab adipose cov ntaub so ntswg, qhov twg, tom qab lipoprotein lipase yog ua haujlwm los ntawm apo-C II, cov roj ntsha dawb tso tawm los ntawm triacylglycerols ntawm VLDL feem. Adipocytes ntes cov roj muaj roj dawb, rov ua rau lawv ua triacylglycerols, uas tau muab cia rau hauv cov hlwb no ua rau cov lipid suav nrog (tshem tawm), myocytes, ntawm qhov tsis sib xws, tam sim ntawd oxidize fatty acids thiaj li tsim lub zog. Feem ntau cov VLDL seem yog tshem tawm los ntawm cov ntshav ncig ntawm hepatocytes. Lawv txoj kev nqus, zoo ib yam li kev nqus ntawm chylomicrons, kho kom haum xeeb los ntawm receptors thiab nyob ntawm muaj cov apoE hauv VLDL cov seem (hauv ntxiv. 21-2 kev sib raug zoo ntawm apoE thiab Alzheimer tus kab mob tau piav qhia).
Daim duab. 21-40. Lipoproteins thiab lipid thauj, thiab - lipids yog thauj los ntawm cov hlab ntshav hauv daim ntawv ntawm lipoproteins, uas tau muab sib xyaw ua ob peb ntu nrog cov kev ua haujlwm sib txawv thiab cov sib txawv ntawm cov protein thiab lipids (tab. 21-1, 21-2) thiab sib raug rau lub cev ntawm cov zauv feem. Cov zaub mov lipids yog sib sau ua ke rau hauv chylomicrons, feem ntau ntawm triacylglycerols muaj nyob hauv lawv tau tawm los ntawm lipoprotein lipase rau hauv adipose thiab cov leeg nqaij hauv cov hlab ntsha. Chylomicron cov seem (uas muaj cov protein thiab roj (cholesterol) feem ntau) yog cov tshuaj los ntawm hepatocytes. Endogenous lipids thiab cov roj cholesterol los ntawm lub siab raug xa mus rau adipose thiab cov leeg nqaij hauv daim ntawv VLDL. Kev tso tawm cov lipids los ntawm VLDL (nrog rau qhov poob ntawm qee cov apolipoproteins) maj mam hloov VLDLP rau LDL, uas muab cov roj (cholesterol) rau cov ntaub so ntswg ntxiv lossis rov los rau lub siab. Daim siab ua rau lub cev tseem tshuav ntawm VLDL, LDL thiab cov seem ntawm chylomicrons los ntawm cov kab mob receptor-mediated endocytosis. Cov roj (cholesterol) seem hauv cov nqaij tshwj xeeb yog thauj rov qab mus rau daim siab hauv daim ntawv ntawm LDL. Hauv lub siab, ib feem ntawm cov roj cholesterol hloov mus rau hauv cov kua tsib ntsev. b - ntshav ntshav ua piv txwv coj tom qab tshaib plab (sab laug) thiab tom qab noj zaub mov nrog cov rog hauv cov ntshav (muaj cai). Chylomicrons tsim los ntawm kev noj cov zaub mov muaj roj ua rau cov ntshav txhaws kom zoo li cov mis hauv lub mis.
Nrog kev poob ntawm triacylglycerols, ib feem ntawm VLDL hloov mus rau VLDL cov seem, tseem hu ua qib nrab ntawm lipoproteins (VLDL), ntxiv tshem tawm ntawm triacylglycerols los ntawm VLDL muab lipoproteins tsawg kawg (LDL) (tab. 21-1). LDL feem, uas yog qhov muaj txiaj ntsig zoo ntawm cov roj (cholesterol) thiab cov roj (cholesterol), thiab tseem muaj apoB-100, hloov cov roj cholesterol mus rau cov ntaub so ntswg tshwj xeeb uas nqa cov tshwj xeeb lees paub lees paub apoB-100 ntawm lawv cov plasma daim nyias nyias. Cov receptors no sib kho cov sib luag ntawm cov cholesterol thiab cov cholesterol (li tau piav qhia hauv qab no).
Txuas Ntxiv 21-2.ApoE alleles txiav txim qhov tshwm sim ntawm Alzheimer tus kab mob
Hauv tib neeg cov pej xeem, muaj peb tus paub sib txawv (peb alleles) ntawm cov gene encoding apolipoprotein E. Ntawm apoE alleles, APOEZ allele yog qhov tshwm sim hauv tib neeg (li 78%), APOE4 thiab APOE2 alleles yog 15 thiab 7%, feem. APOE4 allele tshwj xeeb tshaj yog cov yam ntxwv ntawm cov neeg muaj Alzheimer tus kab mob, thiab qhov kev sib raug zoo no pub rau kwv yees kev tshwm sim ntawm tus kab mob nrog qhov muaj qhov tshwm sim siab. Cov tib neeg uas tau txais kabmob APOE4 muaj qhov pheej hmoo siab ntawm kev pheej hmoo Alzheimer tus kabmob qeeb. Tib neeg homozygous rau APOE4 yog 16 npaug feem ntau yuav muaj tus kab mob, cov hnub nyoog nruab nrab ntawm cov neeg mob tau muaj li 70 xyoo. Rau cov neeg uas tau txais ob daim ntawv ntawm AROEZ, ntawm qhov tsis sib xws, lub hnub nyoog nruab nrab ntawm Alzheimer tus kab mob ntau dua 90 xyoo.
Lub hauv paus molecular rau lub koom haum ntawm apoE4 thiab Alzheimer tus kab mob tseem tsis tau paub. Tsis tas li ntawd, nws tseem tsis tau paub meej tias apoE4 tuaj yeem cuam tshuam kev loj hlob ntawm amyloid cords li cas, uas pom meej tias lub hauv paus rau Alzheimer tus kab mob (saib Daim Duab 4-31, v. 1). Cov kev xav tau tsom mus rau lub luag haujlwm ntawm apoE hauv kev ua kom lub zog ntawm lub cytoskeleton ntawm neurons. Qhov kev pabcuam apoE2 thiab apoEZ khi rau ntau tus lej koom nrog microtubules ntawm cov neurons, thaum apoE4 tsis khi. Qhov no tuaj yeem ua kom nrawm ntawm kev tuag ntawm neurons. Txawm qhov twg cov tshuab no yuav dhau los, cov kev soj ntsuam no ua rau muaj kev cia siab los nthuav peb txoj kev nkag siab ntawm kev ua haujlwm lom ntawm apolipoproteins.
Plaub hom lipoproteins - Cov lipoproteins ntau ntom (HDL), feem no tau ua nyob rau hauv daim siab thiab cov hnyuv hauv cov ntawv uas muaj cov protein me me uas muaj cov roj (cholesterol) me me thiab yuav tsis muaj cov roj (cholesterol) hauv cov roj (daim duab 21-40). HDL feem muaj apoA-I, apoC-I, apoC-II thiab lwm yam apolipoproteins (Cov Lus 21-2), ntxiv rau lecithin-cholesterol-acyltransferase (LC AT), uas ua rau kev tsim cov cholesterol esters los ntawm lecithin (phosphatidylcholine) thiab cov roj (Daim Duab 21-41). L CAT nyob rau saum npoo ntawm cov tshiab tsim HDL hais hloov cov chylomicron cov roj cholesterol thiab phosphatidylcholine thiab VLDL seem rau cov roj cholesterol esters, uas pib tsim lub nucleus, hloov qhov tsim tawm tshiab ntawm discoid HDL hais rau hauv spherical HDL particles. Cov roj (lipoprotein) uas muaj roj (cholesterol) zoo no yuav muab xa rov qab mus rau lub siab, uas cov roj (cholesterol) "tau tso tawm", qee cov roj cholesterol no hloov mus rau hauv cov kua tsib ntsev.
Daim duab. 21-41. Cov tshuaj tiv thaiv raug yuam los ntawm lecithin-cholesterol-acyltransferase (L CAT). Qhov enzyme no tshwm sim nyob rau saum npoo ntawm HDL hais thiab yog tshuab txais los ntawm apoA-1 (ib qho sib xyaw ntawm HDL feem). Cov roj (cholesterol) estrogen yog cov khoom hauv cov HDL uas tsim tshiab, tig lawv los ua HDL paub tab.
HDL tuaj yeem nqus tau hauv daim siab los ntawm receptor-mediated endocytosis, tab sis tsawg kawg ntawm qee cov roj HDL yog xa mus rau lwm cov ntaub so ntswg los ntawm lwm cov txheej txheem. HDL hais tuaj yeem khi rau SR - BI receptor protein ntawm lub plasma membrane ntawm daim siab hlwb thiab hauv cov ntaub so ntswg xws li cov qog adrenal. Cov receptors tsis sib kho endocytosis, tab sis ib feem thiab xaiv cov roj uas txhaws taus thiab lwm cov lipids ntawm HDL feem rau hauv tes. Qhov "depleted" HDL feem rov qab nkag mus rau hauv cov hlab ntshav, qhov twg nws suav nrog cov tshiab ntawm lipids los ntawm chylomicrons thiab VLDL seem. Tib HDL tseem tuaj yeem ntes cov roj (cholesterol) khaws cia hauv cov ntaub so ntswg thiab hloov mus rau lub siab los ntawm rov qab cov roj cholesterol thauj (Daim duab 21-40). Hauv ib qho kev rov qab thauj mus los sib txawv, kev sib cuam tshuam ntawm qhov tshwm sim HDL nrog SR-BI cov neeg txais nyob rau hauv cov roj ntsha muaj roj ntau ntau pib sib kis tau cov roj uas txhaws tawm ntawm lub cell mus rau hauv HDL hais, uas tom qab ntawd hloov cov roj cholesterol rov mus rau lub siab. Hauv lwm qhov txawv ntawm kev thauj rov qab hauv lub xovtooj muaj roj cholesterol, tom qab ntawm HDL, apoA-I cuam tshuam nrog kev thauj khoom nquag, ABC protein. ApoA-I (thiab xav tias HDL) yog nqus tau los ntawm endocytosis, tom qab ntawd zais dua, thauj cov roj (cholesterol), uas thauj mus rau lub siab.
Protein ABC1 yog ib feem ntawm tsev neeg loj uas muaj ntau yam tshuaj, cov tsheb thauj khoom no qee zaum hu ua ABC tsheb thauj khoom, vim lawv txhua tus muaj ATP-khi cov hleb (ATP - khi cov hleb), lawv kuj muaj ob lub transmembrane sau nrog rau (6) transmembrane helices (saib chap. . 11, v. 1). Cov roj ntsha no hloov ntau ions, amino acids, vitamins, steroid hormones thiab ntsev bile dhau los ntawm cov ntshav ua pa. Lwm tus neeg sawv cev ntawm tsev neeg nqa khoom no yog CFTR protein, uas, nrog cystic fibrosis, yog puas lawm (saib ntxiv. 11-3, v. 1).
Cov txheej txheem roj (cholesterol) tau nkag mus rau hauv lub cell los ntawm kev txais cov tshuaj sib kis
Txhua qhov LDL particle hauv cov roj ntsha muaj apoB-100, uas tau lees paub los ntawm cov roj ntsha tshwj xeeb rau cov khoom receptor -LDL txais neeg ntawm daim nyias nyias ntawm cov qe ntshav uas xav tau cov roj (cholesterol). Qhov khi ntawm LDL rau LDL receptor pib mob endocytosis, vim tias LDL thiab nws cov receptor txav mus rau hauv lub cell hauv qhov kawg (daim duab 21-42). Qhov endosome nws thiaj li cuam tshuam nrog lysosome, uas muaj cov enzymes uas hydrolyze cholesterol esters, tso cov roj cholesterol thiab fatty acids mus rau hauv cytosol. ApoB-100 los ntawm LDL kuj tseem tawg los ua cov amino acids uas tso rau hauv cytosol, tab sis LDL cov txais yuav zam kev puas tsuaj thiab rov mus rau cov xovtooj ntawm tes mus koom nrog LDL dua. ApoB-100 kuj tseem muaj nyob rau hauv VLDL, tab sis nws cov ntawv sau sib khi tsis tuaj yeem khi rau LDL receptor; qhov hloov ntawm VLDLP rau LDL ua rau cov vev xaib receptor-binding nkag mus rau hauv apoB-100 siv tau. No cov roj cov ntshav thauj txoj hauv kev thiab nws cov receptor-mediated endocytosis hauv cov nqaij mos tau raug kawm los ntawm Michael Brown thiab Joseph Goldstein.
Michael Brown thiab Joseph Goldstein
Daim duab. 21-42. Kev ntes cov roj (cholesterol) los ntawm receptor-mediated endocytosis.
Cov roj (cholesterol), uas nkag mus rau hauv cov hlwb li no, tuaj yeem nkag mus rau hauv cov qog ua kom rov los yog rov ua kom zoo dua qub los ntawm ACAT (Daim duab 21-38) rau kev cia rau hauv cytosol sab hauv lipid mob. Thaum muaj cov roj cholesterol txaus hauv LDL feem ntawm cov ntshav, cov khoom txuam nrog cov roj (cholesterol) ntau dhau ntawm lub cev yog tiv thaiv los ntawm kev txo tus nqi ntawm nws cov tshuaj.
LDL receptor kuj khi rau apoE thiab ua lub luag haujlwm tseem ceeb hauv kev coj cov chylomicrons thiab VLDL seem los ntawm daim siab. Txawm li cas los xij, yog tias LDL receptors tsis muaj (zoo li, piv txwv li, nyob rau hauv cov nas nas uas muaj qhov tsis txaus LDL receptor), VLDL seem thiab chylomicrons tseem nqus tau los ntawm lub siab, txawm hais tias LDL tsis tau nqus. Qhov no qhia tau tias tseem muaj qee qhov pabcuam kev tiv thaiv kab mob rau cov kabmob receptor-mediated endocytosis ntawm VLDL thiab chylomicron cov seem. Ib qho ntawm cov chaw cia yog cov LRP protein (lipoprotein receptor - ntsig txog protein), uas cuam tshuam rau lipoprotein receptors, uas khi rau apoE thiab ib tug xov tooj ntawm lwm cov ligands.
Ntau qib ntawm cov roj ntsha biosynthesis kev cai
Cov roj ntsha ua kom sib xyaw yog cov txheej txheem nyuaj thiab nquag, yog li nws pom tseeb tias lub cev tau muaj txiaj ntsig muaj cov txheej txheem los tswj cov roj ntsha biosynthesis, uas ua rau nws cov nyiaj ntxiv rau qhov uas los nrog zaub mov. Hauv hom tsiaj, roj ntau ntau yog tswj los ntawm intracellular concentration
roj thiab cov tshuaj hormones glucagon thiab insulin. Cov theem ntawm kev hloov pauv ntawm HMG - CoA rau mevalonate (Daim duab 21-34) txwv qhov nrawm nyob rau hauv cov kev zom zaubmov hauv cov roj (tsim cov ntsiab lus tseem ceeb). Qhov tshuaj tiv thaiv no raug teeb meem los ntawm HMG - CoA reductase. Txoj cai hauv kev teb rau cov kev hloov pauv hauv cov qib roj cholesterol yog kho kom haum los ntawm cov kev cai hloov pauv rau cov gene encoding HMG - CoA reductase. Lub noob no, ua ke nrog ntau dua 20 lwm cov noob caj noob ceg encode enzymes uas koom nrog kev nqus thiab kev sib cais ntawm cov roj cholesterol thiab cov roj ntsha tsis txaus, raug tswj hwm los ntawm tsev neeg me ntawm cov protein hu ua cov protein uas cuam tshuam nrog sterol-txoj cai los ntawm kev tsim cov protein (SREBP, sterol txoj cai khi khi cov protein) Cov. Tom qab ua ke, cov protein no tau nkag mus rau hauv endoplasmic reticulum. Tsuas yog soluble amino-terminal SREBP lub zog ua haujlwm raws li kev hloov khoom siv uas siv cov txheej txheem tau piav qhia hauv Ch. 28 (v. 3). Txawm li cas los xij, cov sau ntawv no tsis muaj kev nkag mus rau lub nucleus thiab tsis tuaj yeem koom nrog hauv kev ua kom muaj ntawm cov gene ntev li ntev tau yog tias nws tseem nyob hauv SREBP molecule. Txhawm rau ua kom muaj kev hloov pauv ntawm HMG caj ces - CoA reductase thiab lwm yam noob, cov kab ntawv hloov tseem muaj sib cais los ntawm SREBP los ntawm proteolytic cleavage. Thaum cov roj (cholesterol) siab, cov kua roj SREBP yog lub cev tsis ua haujlwm, tsau rau ntawm ER nyob rau hauv ib qho nyuaj nrog lwm cov protein hu ua SCAP (SREBP - cleavage activating protein) (Daim duab 21-43). Nws yog SCAP uas khi cov roj (cholesterol) thiab ib tug lej ntawm lwm cov sterols, ua yeeb yam zoo li sterol sensor. Thaum cov theem ntawm cov tshuaj sterol yog qhov siab, SCAP - SREBP complex tej zaum cuam tshuam nrog lwm cov protein, uas ua rau tag nrho cov nyom hauv ER. Thaum cov theem ntawm sterols nyob rau hauv lub cell poob, qhov kev hloov pauv hauv SCAP ua rau poob ntawm kev tuav tseg kev ua, thiab SCAP - SREBP txoj kev tsiv hauv cov hlwv mus rau lub chaw Golgi. Hauv Golgi complex, SREBP cov protein ntau tau muab zwm ob zaug los ntawm ob qhov sib txawv, qhov thib ob tawm ntawm cov amino-davhlau ya nyob rau hauv cytosol. Tus sau no txav mus rau keeb thiab ua kom muaj kev hloov xa ntawm cov hom phiaj noob. Amino-terminal SREBP protein sau muaj luv luv ib nrab-lub neej thiab muaj kev cuam tshuam sai sai los ntawm proteasomes (saib Daim duab 27-48, t. 3). Thaum cov theem ntawm sterol nce siab txaus, qhov kev tiv thaiv proteolytic tso tawm ntawm SR EBP cov protein ntau nrog cov amino terminus tau rov thaiv dua, thiab cov qog proteasome ntawm cov kev ua haujlwm tam sim no ua rau muaj kev cuam tshuam sai ntawm cov phiaj.
Daim duab. 21-43. Kev ua kom zoo ntawm SR EBP. SREB P proteins sib cuam tshuam nrog sterol-kev tswj hwm lub ntsiab lus (xim ntsuab), tam sim ntawd tom qab kev ua kom tiav, tau qhia rau hauv ER, ua ib qho nyuaj nrog S CAP (xim liab). (N thiab C txhais tau hais tias amine thiab carboxyl xaus ntawm cov protein.) Hauv S-CAP ciam xeev, SRE BP proteins tsis ua haujlwm. Thaum cov qib sterol poob qis, SR EBP-S CAP txoj kev tsiv mus rau Golgi complex, thiab cov txheej txheem ntawm SR EBP yog qhov yuav ua tau txuas ntxiv los ntawm ob qhov txawv. Liberated amino acid davhlau ya nyob twg SR EBP protein sau tsiv mus rau nucleus, qhov twg nws ua kom muaj kev hloov pauv ntawm cov tshuaj sterol-tswj cov noob.
Roj hluavtaws ua haujlwm kuj tseem tswj hwm los ntawm ob peb lwm cov txheej txheem (Daim duab 21-44). Kev tswj hwm Hormonal yog kho kom haum xeeb los ntawm cov kev hloov pauv hloov pauv ntawm NM G-CoA reductase. Qhov enzyme no muaj nyob hauv phosphorylated (tsis tsaug zog) thiab dephosphorylated (nquag) cov ntaub ntawv. Glucagon stimulates phosphorylation (inactivation) ntawm enzyme, thiab insulin txhawb dephosphorylation, ua kom cov enzyme thiab haum rau cov synthesis ntawm cov roj cholesterol. High intracellular ntau ntawm cov roj (cholesterol) ua haujlwm rau ASAT, uas ua rau muaj kev tiv thaiv ntau ntawm cov roj (cholesterol) rau hauv kev tso tawm. Thaum kawg, cov roj (qib siab) ntawm cov cell yuav txwv qhov hloov pauv ntawm cov gene uas encodes ib qho LDL receptor, txo cov khoom ntawm qhov receptor no thiab vim li ntawd, kev noj cov cholesterol los ntawm cov ntshav.
Daim duab. 21-44. Kev cai ntawm cov qib roj cholesterol muab qhov sib npaug ntawm qhov sib nqus thiab nqus ntawm cov cholesterol los ntawm cov khoom noj. Glucagon tswj kev phosphorylation (inactivation) ntawm NM G -CoA reductase, insulin txhawb dephosphorylation (kev ua haujlwm). X - cov roj (cholesterol) uas tsis paub tseeb uas ua rau lub cev tiv thaiv tsis tau ntawm NM G -CoA reductase.
Cov roj (cholesterol) tsis muaj kev tswj hwm yuav ua rau muaj mob hnyav rau tib neeg. Thaum tag nrho cov txiaj ntsig ntawm cov roj (synthesized cholesterol) thiab cov roj (cholesterol) uas tau los ntawm cov zaub mov ntau dua qhov tsim nyog rau kev sib sau ua ke, kev sib xyaw ntawm cov kua tsib thiab cov tshuaj steroids, cov kab mob ntshav siab ntxiv hauv cov roj hauv cov ntshav (atherosclerotic plaques) yuav tshwm sim, uas ua rau lawv txhaws (atherosclerosis). Hauv cov teb chaws vam meej, nws yog lub plawv tsis ua haujlwm vim qhov teeb meem ntawm cov hlab ntshav hlab ntsha uas yog qhov tseem ceeb ua rau kev tuag. Kev txhim kho ntawm atherosclerosis cuam tshuam nrog cov roj ntshav siab ntau thiab tshwj xeeb tshaj yog cov roj ntshav siab ntau dhau los ntawm LDL feem; cov ntshav HDL siab, ntawm qhov tsis zoo, muaj feem cuam tshuam rau lub xeev cov hlab ntsha.
Nrog rau cov mob muaj keeb hypercholesterolemia (ib qho kev mob caj ces), cov ntshav roj ntshav nyob hauv cov ntshav muaj ntau heev - mob atherosclerosis zoo rau cov neeg no twb yog menyuam yaus. Vim tias muaj qhov teeb meem LDL receptor, qhov tsis txaus receptor-mediated uptake ntawm LDL cov roj cholesterol. Raws li qhov tshwm sim, cov roj (cholesterol) tsis raug tshem tawm ntawm cov roj ntsha, nws nthuav tawm thiab koom ua ke rau kev tsim cov atherosclerotic plaques. Kev sib txuas ntawm cov roj (endogenous cholesterol) txuas ntxiv, txawm tias muaj cov roj (cholesterol) ntau hauv cov ntshav, vim tias cov roj (cholesterol) tsis tuaj yeem nkag mus rau hauv lub cell los tswj cov tshuaj sib txuas ntxiv (daim duab 21 -44).Rau kev kho mob ntawm cov neeg mob uas muaj kab mob hypercholesterolemia thiab lwm yam kab mob cuam tshuam nrog cov ntshav nce siab kom siab, cov chav kawm qib siab tau siv. Qee qhov ntawm lawv tau los ntawm cov khoom siv hauv ntuj, thaum lwm tus tau tsim los ntawm kev lag luam kws tshuaj. Statins zoo ib yam li mevalonate (ntxiv. 21-3) thiab yog cov muaj kev sib tw ntawm NMS-CoA reductase.
Ntxiv Ntxiv 21-3. CEEB TSHEEJ. Kev lipid hypothesis thiab kev tsim ntawm statins
Coronary heart disease (CHD) yog qhov tseem ceeb ua rau kev tuag nyob hauv cov teb chaws vam meej. Qhov nqaim ntawm cov hlab ntshav ntawm cov hlab ntsha uas nqa ntshav mus rau lub plawv tshwm sim los ntawm kev tsim cov roj ntsha hu ua atherosclerotic plaques; cov plaques no muaj cov roj (cholesterol), fibrillar protein, calcium, platelet clog, thiab cov cell tawg. Nyob rau hauv lub xyoo pua XX. Muaj kev sib cav sib ceg txog txoj kev sib raug zoo ntawm txoj hlab ntshav ntawm txoj hlab ntshav (atherosclerosis) thiab ntshav hauv cov ntshav. Cov kev sib tham no thiab cov kev tshawb fawb nyob rau hauv cov lus qhia no tau ua rau kev tsim cov tshuaj zoo uas txo cov roj (cholesterol).
Xyoo 1913, N.N. Anichkov, tus kws paub txog Lavxias thiab kws paub tshwj xeeb hauv kev sim tshuaj tua kab, tau tshaj tawm txoj haujlwm ua haujlwm uas nws pom tias luav noj nrog cov khoom noj muaj roj cholesterol txhim kho kev puas tsuaj rau cov hlab ntshav uas zoo li atherosclerotic plaques hauv cov hlab ntsha ntawm cov neeg laus. Anichkov tau ua nws qhov kev tshawb fawb rau ntau caum lub xyoos thiab tshaj tawm cov qhabnias hauv cov npe hauv Western zoo. Hmoov tsis zoo, nws cov ntaub ntawv tsis yog lub hauv paus rau tus qauv rau kev txhim kho cov mob atherosclerosis rau tib neeg, txij li lub sijhawm ntawd lub ntsej muag xav tau tias tus kab mob no yog ntuj tsim los ntawm kev laus thiab tsis tuaj yeem tiv thaiv. Txawm li cas los xij, cov pov thawj tau maj mam khaws cia ntawm kev sib raug zoo ntawm cov roj cholesterol thiab kev txhim kho ntawm atherosclerosis (lipid hypothesis), thiab hauv 1960s. Qee cov kws tshawb nrhiav tau hais meej meej tias qhov kab mob no tuaj yeem kho nrog tshuaj. Txawm li cas los xij, qhov kev xav tsis sib xws tau muaj txog thaum kev tshaj tawm xyoo 1984 ntawm kev tshawb pom dav dav txog lub luag haujlwm ntawm cov roj cholesterol ua los ntawm Asmeskas National Institute of Health (Coronary Primary Prevention Trial). Tau pom tseeb tias qhov kev txo qis hauv tsawg zaus ntawm myocardial infarction thiab mob hlab ntsha tawg nrog qhov txo qis hauv cov roj hauv cov ntshav tau ua pov thawj. Hauv txoj kev tshawb fawb no, cov roj (cholesterol), cov tshuaj anion sib pauv roj uas khi cov kua tsib kua qaub, tau siv los txo cov roj (cholesterol). Cov txiaj ntsig tau tsa kev tshawb nrhiav tshiab, muaj zog ntau dua los ntawm kev siv tshuaj kho mob. Kuv yuav tsum hais tias nyob rau hauv lub ntiaj teb scientific, kev ua xyem xyav txog qhov tseem ceeb ntawm lipid hypothesis kiag li tsuas yog ploj nrog kev tawm ntawm statins nyob rau xyoo 1980s - thaum ntxov xyoo 1990.
Tus thawj statin tau nrhiav tau los ntawm Akira Endo ntawm Sankyo hauv Tokyo. Endo tau tshaj tawm nws cov haujlwm hauv xyoo 1976, txawm hais tias nws tau daws cov teeb meem ntawm cov metabolism hauv cov roj cholesterol tau ntau xyoo. Xyoo 1971, nws tau qhia tias cov tshuaj tiv thaiv cov roj (cholesterol synthesis inhibitors) kuj tseem yuav muaj nyob hauv cov neeg tsim tawm cov nceb noj tshuaj tua kab mob uas tau kawm nyob rau lub sijhawm ntawd. Tau ob peb xyoos ntawm kev ua haujlwm hnyav, nws tau soj ntsuam ntau dua 6,000 kab lis kev cai ntawm ntau yam nceb, kom txog thaum nws tuaj txog qhov txiaj ntsig zoo. Lub txiaj ntsig sib txuas tau hu ua compactin. Qhov tshuaj no ua rau cov roj (cholesterol) qis hauv cov dev thiab cov liab. Cov kev tshawb fawb no tau ua tib zoo mloog txog Michael Brown thiab Joseph Goldstein ntawm University of Texas Southwestern Medical School. Brown thiab Goldstein, nrog rau Endo, tau pib kawm sib koom ua ke thiab paub tseeb nws cov ntaub ntawv. Cov kev vam meej loj ntawm thawj qhov kev sim kho mob koom nrog cov tuam txhab ua lag luam hauv kev tsim cov tshuaj tshiab no. Ntawm Merck, ib pab neeg coj los ntawm Alfred Alberts thiab Roy Wagelos tau pib ua qhov kev tshuaj ntsuam tshiab ntawm kev coj noj coj ua nceb thiab, los ntawm kev tshuaj xyuas tag nrho ntawm 18 kab lis kev cai, nrhiav lwm cov tshuaj muaj sia. Cov khoom tshiab hu ua lovastatin. Txawm li cas los xij, tib lub sijhawm, nws tau txais kev ntseeg dav dav tias kev tswj hwm ntawm kev txhaj tshuaj ntau ntawm cov yeeb yam rau cov dev ua rau muaj kev loj hlob ntawm kev mob qog noj ntshav thiab nrhiav cov statins tshiab hauv xyoo 1980s. tau muab ncua lawm. Txawm li cas los xij, los ntawm lub sijhawm ntawd, cov txiaj ntsig ntawm kev siv statins los kho cov neeg mob nrog tsev neeg hypercholesterolemia tau pom meej. Tom qab kev sib tham ntau heev nrog cov kws tshaj lij thoob ntiaj teb thiab Chaw Tswj Xyuas Khoom Noj thiab Tshuaj (FDA, Asmeskas), Merck pib tsim lovastatin. Kev tshawb nrhiav dav nyob rau ob xyoo tom ntej no tsis tau qhia txog cov nyhuv carcinogenic ntawm lovastatin thiab cov tshuaj tshiab uas tshwm sim tom qab nws.
Daim duab. 1. Statins yog inhibitors ntawm NM G-CoA reductase. Kev sib piv ntawm cov qauv ntawm mevalonate thiab plaub yam khoom lag luam tshuaj (statins) uas inhibit qhov kev txiav txim ntawm NM G -CoA reductase.
Statins inhibit qhov kev txiav txim siab ntawm HMG - CoA - reductase, mimicking tus qauv ntawm mevalonate, thiab yog li thaiv qhov synthesis ntawm cov cholesterol. Hauv cov neeg mob hypercholesterolemia tshwm sim los ntawm kev puas tsuaj hauv ib daim qauv ntawm LDL receptor gene, thaum noj cov lovastatin, cov qib roj cholesterol yog txo 30%. Cov tshuaj tseem zoo dua ua ke nrog cov resins tshwj xeeb uas khi cov kua tsib kua qaub thiab tiv thaiv lawv txoj kev thim rov qab los ntawm cov hnyuv.
Tam sim no, cov tshuaj statins feem ntau siv los txo cov ntshav roj ntshav plasma cholesterol. Thaum noj ib qho tshuaj twg, lo lus nug tshwm sim txog lawv qhov kev mob tshwm sim uas tsis xav ua. Txawm li cas los xij, piv txwv li ntawm statins, ntau cov kev mob tshwm sim, hauv kev sib piv, yog qhov zoo. Cov tshuaj no tuaj yeem txhawb cov ntshav khiav, txhim kho uas twb muaj lawm atherosclerotic plaques (yog li kom lawv tsis txhob tawg ntawm phab ntsa ntawm cov hlab ntshav thiab tsis cuam tshuam nrog cov ntshav txaus), inhibit platelet sib sau ua ke, thiab tseem ua rau cov txheej txheem ua kom tsis muaj zog ntawm cov hlab ntshav. Hauv cov neeg mob noj cov tshuaj statins rau thawj zaug, cov kev cuam tshuam no tau nthuav tawm txawm tias ua ntej cov roj cholesterol pib poob qis, thiab muaj feem cuam tshuam nrog kev cuam tshuam ntawm isoprenoid synthesis. Yog lawm, tsis yog txhua sab phiv los ntawm statins yuav muaj txiaj ntsig zoo. Hauv qee cov neeg mob (feem ntau yog ntawm cov noj cov tshuaj statins ua ke nrog lwm cov tshuaj uas txo cov roj (cholesterol)), cov leeg mob thiab cov leeg tsis muaj zog tuaj yeem tshwm sim, thiab qee zaum ua rau hauv daim ntawv zoo. Lwm qhov kev mob tshwm sim ntau ntawm statins kuj tau sau npe, uas, hmoov zoo, tsis tshua muaj tshwm sim. Hauv feem coob ntawm cov neeg mob, noj cov tshuaj statins tuaj yeem tiv thaiv kev txhim kho ntawm cov kab mob plawv. Zoo li lwm yam tshuaj, statins yuav tsum tsuas yog siv raws li koj tus kws kho mob pom zoo.
Nrog rau cov mob muaj keeb muaj HDL cov roj (cholesterol), cov roj (cholesterol) yuav qis heev, nrog rau tus kab mob Tangier, cov roj (cholesterol) yog qhov tseem tsis tau txiav txim siab. Ob qho tib si cuam tshuam tshwm sim los ntawm kev hloov pauv hauv ABC1 protein. HDL-free cholesterol fraction tsis tuaj yeem ntes cov roj (cholesterol) los ntawm ABC1-cov roj ntsha tsis txaus, thiab cov roj-cov roj (cholesterol) uas tsis ua haujlwm yog tshem tawm cov ntshav sai sai ntawm cov ntshav thiab rhuav tshem. Ob qho tag nrho cov mob muaj keeb kwm muaj HDL thiab Tangier muaj tsawg heev (tsawg dua 100 tsev neeg muaj tus kab mob Tangier paub thoob ntiaj teb), tab sis cov kab mob no qhia cov luag haujlwm ntawm ABC1 protein hauv kev tswj cov qib HDL ntshav. Txij li thaum ntshav ntshav qis HDL sib txheeb ze nrog qhov siab ntawm kev mob ntshav siab rau txoj hlab ntshav, ABC1 protein yuav yog lub hom phiaj tseem ceeb rau cov tshuaj uas tsim los tswj cov qib HDL. ■
Cov tshuaj hormones steroid yog tsim los ntawm kev faib cov plaub sab ntawm cov roj thiab nws cov oxidation.
Ib tus neeg tau txais tag nrho nws cov tshuaj hormones steroid los ntawm cov roj (Daim Duab 21-45). Ob chav kawm ntawm cov tshuaj hormones steroid hauv cov adrenal cortex: ntxhia ntxeem cawv,uas tswj cov kev nqus ntawm inorganic ions (Na +, C l - thiab HC O) 3 -) nyob rau hauv lub raum, thiab glucocorticoids, uas pab tswj gluconeogenesis thiab txo qhov mob teb. Cov tshuaj hormones poj niam txiv neej yog tsim nyob rau hauv cov kev ua me nyuam ntawm tus txiv neej thiab poj niam thiab ntawm qhov tso. Ntawm lawv progesterone uas tswj tus poj niam kev muaj me nyuam, androgens (Xws li testosterone) thiab estrogens (estradiol), uas cuam tshuam rau kev txhim kho ntawm cov yam ntxwv ntawm kev sib deev hauv cov txiv neej thiab poj niam, ua ntu zus los. Cov tshuaj hormones steroid muaj cov txiaj ntsig ntawm qhov muaj zog ntau heev thiab yog li ntawd yuav coj los ua ke hauv cov khoom me. Muab piv rau cov kua tsib cov kua tsib, cov roj (cholesterol) tsawg yog ua rau kev tsim cov tshuaj hormones steroid.
Daim duab. 21-45. Qee qhov tshuaj hormones steroid yog tsim los ntawm cov roj (cholesterol). Cov kev teeb tsa ntawm qee cov sib txuas tau pom hauv Daim Duab. 10-19, v. 1.
Kev sib xyaw ntawm cov tshuaj hormones steroid xav kom tshem tawm ob peb lossis tag nrho ntawm cov pa roj carbon atoms hauv "cov hlua sab nraud" ntawm C-17 D-ntiv nplhaib ntawm cov roj (cholesterol). Kev rub tawm hauv ib sab yog tshwm sim hauv mitochondria ntawm cov ntaub so ntswg steroidogenic. Cov txheej txheem tshem tawm muaj hydroxylation ntawm ob sab sib txuas ntawm cov pa roj carbon atoms ntawm ib sab cov hlua (C-20 thiab C-22), tom qab ntawd qhov meej meej ntawm daim ntawv cog lus nruab nrab ntawm lawv (Daim duab 21-46). Qhov tsim ntawm ntau cov tshuaj hormones kuj suav nrog kev qhia ntawm oxygen atoms. Txhua qhov hydroxylation thiab oxidation kev cuam tshuam thaum steroid biosynthesis yog catalyzed los ntawm kev sib xyaw ua haujlwm oxidases (ntxiv. 21-1) uas siv NА D PH, O 2 thiab mitochondrial cytochrome P-450.
Daim duab. 21-46. Cleavage ntawm lub ntsej muag sab hauv kev sib txuas ntawm cov tshuaj hormones steroid. Hauv qhov system oxidase nrog cov kev ua haujlwm sib xyaw uas oxidizes cov roj carbon atoms uas nyob ib sab, cytochrome P-450 ua raws li cov khoom siv hluav taws xob. Kuj tseem koom nrog hauv cov txheej txheem yog hauv cov hluav taws xob thauj cov protein, adrenodoxin thiab adrenodoxin reductase. Qhov no system ntawm sab saw splitting pom nyob rau hauv mitochondria ntawm adrenal cortex, qhov twg active ntau lawm ntawm steroids yuav siv qhov chaw. Pregnenolone yog qhov kev qhia paub ua ntej ntawm lwm cov tshuaj hormones steroid (Daim duab 21-45).
Cov roj ntsha ua kom lub cev roj ntsha tsis taus yog cov koom nrog hauv ntau lwm txoj kev ua rog.
Ntxiv rau nws lub luag haujlwm raws li ib nrab ntawm cov roj ntsha roj ntsha caj dab roj ntshav, isopentenyl pyrophosphate ua haujlwm ua lub luag haujlwm tseem ceeb nyob rau hauv kev sib txuas ntawm cov naj npawb loj ntawm biomolecules uas ua ntau cov kev ua haujlwm lom (Daim duab 21-47). Cov no suav nrog cov vitamins A, E thiab K, cog cov tshuaj pleev xim xws li carotene thiab chlorophyll phytol saw, cov roj hmab ntuj, ntau cov roj tseem ceeb (piv txwv li, cov tshuaj tsw qab ntawm cov txiv qaub roj, eucalyptus, musk), kab tshuaj tua kab menyuam yaus uas tswj hwm metamorphosis, dolichols, uas ua cov lipid-soluble muaj nyob hauv cov khoom sib txuas ua ke ntawm polysaccharides, ubiquinone thiab plastoquinone - cov khoom lag luam hauv tshuab hluav taws xob hauv mitochondria thiab chloroplasts. Tag nrho cov molecules yog isoprenoids hauv kev teeb tsa. Ntau tshaj 20,000 qhov sib txawv isoprenoids tau pom nyob rau hauv cov xwm txheej, thiab ntau pua tus tshiab tau qhia txhua xyoo.
Daim duab. 21-47. Tag nrho daim duab ntawm cov biosynthesis ntawm isoprenoids. Cov qauv ntawm feem ntau ntawm cov khoom kawg nthuav tawm ntawm no tau muab rau hauv chap. 10 (v. 1).
Prenylation (covalent Symptoms ntawm isoprenoid, saib Daim duab 27-35) yog ib qho kev sib koom ua ke uas cov roj ntsha thauj tog rau sab hauv puab ntawm cov qog ntawm tes (saib daim duab 11-14). Hauv qee cov protein, cov lipid uas tau khi yog sawv cev los ntawm 15-carbon farnesyl pawg, hauv lwm tus nws yog 20-carbon geranyl geranyl pawg. Qhov ob hom ntawm lipids txuas cov enzymes sib txawv. Nws yog tau hais tias kev siv tshuaj ua kom lub cev ncaj qha cov protein rau nyias daim nyias nyias raws li cov lipid uas txuas nrog. Prilination ntawm protein yog lwm txoj haujlwm tseem ceeb rau isoprene derivatives - cov neeg koom nrog cov roj (cholesterol) metabolic pathway.
Ntsiab lus ntawm Tshooj 21.4 Cov Khoom Siv Hluav Taws Xob Khoom Noj Roj (Cholesterol), Steroids, thiab Isoprenoids
Olesterol Cov Cholesterol yog tsim los ntawm acetyl-CoA hauv cov tshuaj tiv thaiv uas cuam tshuam los ntawm cov tshuaj nruab nrab xws li β-hydroxy-β-methylglutaryl-CoA, mevalonate, ob lub isoprene dimethylallyl pyrophosphate thiab isopentenyl pyrophosphate. Lub hws ntawm isoprene chav muab cov tsis-cyclic squalene, uas lub pob mus los ua ib txoj kab kev ntiv nplhaib thiab kab ke sab.
Synt Kev sib txuas ntawm cov cholesterol yog nyob rau hauv kev tswj hwm hauv hormonal thiab ntxiv rau, yog qhov cuam tshuam los ntawm kev nce siab ntawm cov roj (intracellular cholesterol), uas tshwm sim los ntawm covalent kev hloov kho thiab kev cai ntawm kev hloov tsheb.
Olesterol Cov roj (cholesterol) thiab cov roj (cholesterol) esters nqa los ntawm cov ntshav vim ntshav lipoproteins plasma. VLDL feem hloov cov roj (cholesterol), cov roj (cholesterol) thiab cov triacylglycerols los ntawm lub siab mus rau lwm cov nqaij, qhov twg cov triacylglycerols los ntawm lipoprotein lipase thiab VLDL hloov dua siab rau LDL. Qhov LDL feem nyob rau hauv cov roj (cholesterol) thiab cov roj (cholesterol) esters yog tsis ncaj los ntawm cov receptors los ntawm endocytosis, thaum B-100 apolipoprotein hauv LDL raug lees paub los ntawm plasma membrane receptors. HDL tshem tawm cov roj cholesterol hauv cov ntshav, hloov mus rau hauv lub siab. Kev noj zaub mov zoo lossis kev mob caj ces hauv cov metabolism hauv cov roj ntsha tuaj yeem ua rau atherosclerosis thiab myocardial infarction.
Hormones Cov tshuaj hormones Steroid (glucocorticoids, mineralocorticoids thiab cov tshuaj hormones poj niam txiv neej) yog tsim los ntawm cov roj (cholesterol) los ntawm kev hloov rau sab caj npab thiab qhia cov pa oxygen atoms rau hauv cov txheej txheem steroid ntawm cov nplhaib. Ntau lwm isoprenoid tebchaw yog tsim los ntawm mevalonate los ntawm kev sib xyaw isopentenyl pyrophosphate thiab dimethylallyl pyrophosphate nrog rau cov roj (cholesterol).
■ Kev ua kom cev xeeb tub ntawm qee cov protein ua rau lawv mus rau qhov chaw muaj kab mob ntawm tes thiab yog qhov tseem ceeb rau lawv lub cev kev lom neeg.
Lo lus nug 48. Kev tswj ntawm cov metabolism hauv cov roj ntsha siab (ox-oxidation thiab biosynthesis). Synthesis of malonyl CoA. Acetyl CoA carboxylase, kev cai ntawm nws txoj haujlwm. Thauj ntawm acyl Co-a los ntawm sab hauv membrane ntawm mitochondria.
Qhov tseem ceeb
tus nqi ntawm phenylalanine yog noj
nyob rau hauv 2 txoj kev:
puv
nyob rau hauv nas,
lem
hauv tyrosine.
Txoj siav
phenylalanine rau tyrosine feem ntau
tsim nyog los tshem tawm ntau heev
phenylalanine, txij li muaj ntau ntau
Nws lom rau hauv hlwb. Kev kawm
tyrosine tsis yog teeb meem
txij li thaum tsis muaj cov amino acid
hauv cov hlwb xyaum tsis tshwm sim.
Qhov tseem ceeb
phenylalanine metabolism pib
nrog nws cov hydroxylation (Daim duab 9-29), hauv
ua rau tyrosine.
Cov tshuaj tiv thaiv no yog catalyzed los ntawm ib qho tshwj xeeb
monooxy-nase - phenylalanine hydra (zsilase,
uas ua haujlwm ua ke nrog kev tsim khoom
tetrahydrobiopterin (N4BP).
Kev ua haujlwm enzyme kuj tseem nyob ntawm
muaj xub ntiag ntawm Fe2.
Hauv
lub siab yog feem ntau ceev nraub qaum
glycogen (saib Ntu 7). Txawm li cas los xij
glycogen nyob rau hauv daim siab yog depleted dhau
18-24 teev ntawm kev yoo mov. Lub hauv paus tseem ceeb
piam thaj li cov xaum khiav tawm
glycogen ua gluconeogenesis,
uas pib ua kom nrawm dua
Daim duab.
11-29. Cov pa loj pauv hloov
lub zog thaum hloov pauv nqus
postabsorbent lub xeev. I
- lub cev ketone, FA - fatty acids.
4-6 h
tom qab cov zaub mov kawg. Muab tshuaj rau sab
glycerol yog siv rau cov piam thaj ua ke,
amino acids thiab lactate. Nyob siab
glucagon kev xav tau raug muab tso ua ke
fatty acids uas yog txo vim
phosphorylation thiab inactivation
acetyl CoA carboxylase thiab tus nqi
p-oxidation nce. Txawm li cas los,
ntxiv rog mov rau daim siab
kua qaub uas thauj
los ntawm cov rog rog. Acetyl-CoA tsim
nyob rau hauv oxidation ntawm fatty acids, nws yog siv
hauv lub siab rau kev ua kom tiav ntawm ketone lub cev.
Hauv
adipose cov ntaub so ntswg nrog nce mloog ntxiv
glucagon txo tus nqi hluavtaws
TAG thiab lipolysis yog txhawb. Cuam Tshuam
lipolysis - kev ua kom tau tawm
yam tshuaj lip TAG lipase
adipocytes nyob rau hauv kev cuam tshuam ntawm glucagon.
Fatty Acids Los Ua Qhov Tseem Ceeb
lub zog ua haujlwm hauv lub siab, cov leeg thiab
adipose ntaub so ntswg.
Yog li
yog li, nyob rau hauv lub sijhawm postabsorption
ntshav qabzib concentration yog tswj
ntawm theem ntawm 80-100 mg / dl, thiab theem ntawm cov rog
kua qaub thiab ketone lub cev nce ntxiv.
Qab zib
ntshav qab zib yog ib yam kab mob uas tshwm sim
vim yog yawg los txheeb ze
insulin tsis txaus.
A.
Lub ntsiab tseem ceeb cov ntaub ntawv hauv qab zib
mob ntshav qab zib
Raws li
Koom Haum Ntiaj Teb
mob ntshav qab zib
dej num raws qhov sib txawv
caj ces yam thiab kuaj mob
ob lub ntsiab: ntshav qab zib
Yam I - insulin-dependant (IDDM), thiab ntshav qab zib
Hom II - tsis muaj cov insulin ywj pheej (NIDDM).
Kev cai
hluavtaws ntawm zhk. Kev cai enzyme
hluavtaws ntawm lcd - acetyl CoA carboxylase.
Qhov enzyme no yog tswj hwm los ntawm ob peb
txoj kev.
Ua kom rov sib cais / cais tawm
enzyme subunit complexes. Hauv
tsis nyob hauv daim ntawv ntawm acetyl CoA carboxylase
sawv cev nyias muaj nyias kev,
txhua qhov uas muaj 4 ntu haujlwm.
Lub tshuab ua kom zog ntawm enzyme yog citrate. Nws txhawb
kev sib xyaw ua ke ntawm cov ceg, raws li qhov tshwm sim
kev ua haujlwm enzyme nce ntxiv
Cov. Inhibitor-palmitoyl-CoA. Nws hu
txoj kev cuam tshuam nyuaj thiab txo qis qis
kev ua enzyme.
Phosphorylation / Dephosphorylation
acetyl CoA carboxylase. Hauv
postabsorption xeev lossis hauv
lub cev ua haujlwm glucagonized
adrenaline los ntawm adenylate cyclase
cov kab ke ua haujlwm los ntawm prokinase A thiab
txhawb nqa subunit phosphorylation
acetyl CoA carboxylase. Phosphorylated
lub enzyme yog qhov ua tsis taus pa thiab kev sib txuas ntawm cov rog
kua qaub daug.
Kev nqus tau
lub sij hawm insulin activates phosphatase,
thiab acetyl-CoA carboxylase mus rau hauv
dephosphorylated xeev. Tom qab ntawv
nyob rau hauv tus ntawm citrate tshwm sim
polymerization ntawm lub protomers ntawm cov enzyme, thiab
nws ua neeg nquag. Ntxiv rau kev ua kom muaj zog
enzyme, citrate ua lwm qhov
ua haujlwm nyob rau hauv cov synthesis ntawm LCD. Kev nqus tau
lub sijhawm hauv mitochondria ntawm lub siab ua haujlwm
accumulates citrate, nyob rau hauv uas
lub acyl residue yog thauj rau
cytosol.
Kev cai
β-oxidation tus nqi.
Β-oxidation-metabolic txoj kev,
khov kho txuas nrog kev ua haujlwm ntawm CPE thiab dav dav
txoj kev ntawm catabolism. Yog li ntawd nws ceev
tswj los ntawm cell xav tau rau
zog i.e. los ntawm cov sib piv ntawm ATP / ADP thiab NADH / NAD, thiab raws li qhov tshuaj tiv thaiv ntawm CPE thiab
hom kev tshwm sim ntawm catabolism. Ceev
idation-oxidation hauv cov ntaub so ntswg yog nyob ntawm qhov muaj
substrate, i.e.
ntawm qhov ntau ntawm cov rog
kua qaub nkag mus rau mitochondria.
Fatty Acid Concentration Dawb
nyob rau hauv cov ntshav ntawm lub nce raws li kev ua kom zoo
lipolysis nyob rau hauv daim ntaub adipose thaum yoo mov
nyob hauv qab ntawm glucagon thiab thaum lub cev
ua haujlwm nyob rau hauv kev cuam tshuam ntawm adrenaline. Hauv no
fatty acids uas dhau los
qhov tseem ceeb ntawm lub zog
rau cov leeg thiab mob siab, los ntawm
β-oxidations yog tsim los ntawm NADH thiab acetyl-CoA inhibiting
pyruvate dehydrogenase ua.
Kev sib pauv ntawm pyruvate sib sau
los ntawm cov kua nplaum mus rau acetyl-CoA maj mam poob.
Cov tshuaj nruab nrab rau lub cev ntau zuj zus
glycolysis thiab, tshwj xeeb, piam thaj-6-phosphate.
Cov piam thaj-6-phosphate inhibits hexokinase
thiab yog li ntawd poob siab
kev siv ntawm cov kua nplaum nyob hauv txheej txheem
glycolysis. Yog li ntawd, tshaj plaws
siv lcd ua lub hauv paus tseem ceeb
lub zog hauv cov leeg thiab lub siab
txuag qabzib rau cov ntaub so ntswg thiab
cov ntshav liab.
Ox-oxidation tus nqi kuj
nyob ntawm enzyme kev ua si
carnitine acyltransferases Kuv.
Hauv lub siab, qhov enzyme no yog tshuaj tiv thaiv.
malonyl CoA, ib yam khoom tsim
nrog biosynthesis ntawm lcd. Nyob rau lub sijhawm nqus mus
glycolysis yog qhib kev ua haujlwm hauv lub siab thiab
tsim kom muaj cov acetyl-CoA nce ntxiv
los ntawm pyruvate. Ua ntej cov tshuaj tiv thaiv
lcd hloov pauv ntawm acetyl-CoA rau malonyl-CoA.
Malonyl-CoA inhibits qhov ox-oxidation ntawm lcd,
uas tuaj yeem siv ua hluavtaws
rog.
Kev kawm
malonyl-CoA los ntawm acetyl-CoA-cai
cov tshuaj tiv thaiv hauv biosynthesis lcd. Thawj cov tshuaj tiv thaiv
hluavtaws lcd hloov pauv ntawm acetyl-CoA rau
malonyl CoA. Catalytic enzyme
cov tshuaj tiv thaiv no (acetyl Coa carboxylase),
belongs rau cov chav kawm ntawm ligases. Nws muaj
covalently khi biotin. Hauv thawj
co2 covalent cov tshuaj tiv thaiv theem
khi rau biotin vim lub zog
ATP, nyob rau theem 2 COO- pauv hloov
ntawm acetyl-CoA los tsim malonyl-CoA.
Acetyl CoA Carboxylase Enzyme Kev Ua
txiav txim qhov nrawm ntawm txhua tus tom qab
hluavtaws kev ua haujlwm lc
citrate ua kom muaj kev enzyme hauv cytosol
acetyl CoA carboxylase. Malonyl CoA nyob rau hauv
nyob rau hauv lem inhibits qhov hloov ntawm siab dua
fatty acids uas yog los ntawm cytosol mus rau matrix
mitochondria inhibiting kev ua si
sab nrauv acetyl CoA: carnitine acyltransferase,
yog li tig tawm lub oxidation ntawm siab dua
fatty acids uas yog.
Acetyl-CoA Oxaloacetate →
HS-CoA Citrate
HSCOA ATP Citrate → Acetyl-CoA ADP Pi Oxaloacetate
Acetyl-CoA
hauv cytoplasm ua haujlwm ua haujlwm pib ua haujlwm
nyob rau hauv kev coj ua ke ntawm lcd, thiab oxaloacetate nyob rau hauv
cytosol muaj kev hloov pauv hauv
ntawm qhov uas pyruvate yog tsim.
Roj biosynthesis
Cov roj ntsha caj hlav hauv lub cev ua kom tshwm sim hauv endoplasmic reticulum. Lub hauv paus ntawm txhua cov pa roj carbon atoms hauv cov qauv molecule yog acetyl-SCoA, uas los ntawm no los ntawm mitochondria hauv citrate, tsuas yog nyob rau hauv cov synthesis ntawm fatty acids. Cov roj hauv cov roj biosynthesis noj 18 ATP lwg me thiab 13 NADPH lwg me me.
Kev tsim cov roj (cholesterol) nyob rau ntau tshaj 30 qhov tshwm sim, tuaj yeem sib sau ua ke nyob rau ntau theem.
1. Cov hluavtaws ntawm mevalonic acid.
Thawj ob lub zog ua kom sib haum ua ke nrog ketogenesis kev ua kom zoo, tab sis tom qab kev sib txuas ntawm 3-hydroxy-3-methylglutaryl-ScoA, lub enzyme nkag mus hydroxymethyl-glutaryl-ScoA reductase (HMG-SCOA reductase), ua rau mevalonic acid.
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