Cholesterol biosynthesis ndi kuphatikiza kwachilengedwe - shuga
Mosakayikira, cholesterol ndichidziwitso chodziwika bwino kwa anthu onse; sichidziwitso chifukwa cha kuphatikizana kwakukulu pakati pa cholesterol yamwazi yambiri komanso kuchuluka kwa matenda amtima wamunthu. Chisamaliro chochepa chakulipidwa ku gawo lofunikira la cholesterol ngati gawo lama membrane am'm cell komanso chotsatira cha mahomoni a steroid ndi bile acid. Cholesterol ndiyofunikira nyama zambiri, kuphatikiza anthu, koma kupezeka kwake mu chakudya cham'madzi ndikosankha - maselo amthupi enieniwo amatha kusinthanitsa ndi am'mbuyomu osavuta.
Kapangidwe ka kaboni 27 kameneka kamaonetsa njira yake yovuta, koma ma atomu ake onse a kaboni amaperekedwa ndi wotsogolera wina - acetate. Malo a Isoprene - zofunika kwambiri zapakati kuyambira acetate kupita ku cholesterol, ndizomwe zimayambira zamadzimadzi ambiri achilengedwe, ndipo njira zomwe mabatani a isoprene amaphatikizidwira ndi ofanana m'njira zonse za metabolic.
Timayamba poganizira magawo akuluakulu munjira ya cholesterol biosynthesis kuchokera ku acetate, kenako timakambirana za kayendedwe ka cholesterol kudzera m'magazi, kuyamwa kwake ndi maselo, kuyika kwachilendo kwa kaphatikizidwe ka cholesterol ndi kayendedwe ka milandu mukamayimitsidwa kapena kuyendetsa. Kenako timayang'ana zinthu zina zomwe zimachokera ku cholesterol, monga bile acids ndi mahomoni a steroid. Pomaliza, kufotokozera kwa njira ziwiri zamapangidwe opangira zinthu zambiri - zotumphukira za malovu a isopren, momwe muli magawo oyambirira a cholesterol, zimawonetsa kusinthasintha kwakukulu kwa isoprenoid conduction mu biosynthesis.
Cholesterol imapangidwa kuchokera ku acetyl-CoA m'magawo anayi
Cholesterol, ngati ma acid amafuta amtali, amapangidwa kuchokera ku acetyl-CoA, koma mawonekedwe amsonkhano ndi wosiyana kotheratu. Poyesa koyamba, ma acetate olembedwa ndi 14 C mwina atomu ya methyl kapena carboxyl adawonjezeredwa kuti azidyetsa nyama. Kutengera ndikugawika kwa cholesterol yopatulidwa m'magulu awiri a nyama (mkuyu. 21-32), magawo a enzymatic a cholesterol biosynthesis adafotokozedwa.
Mkuyu. 21-32. Gwero la maatomu a kaboni a cholesterol. Kudziwitsidwa pazoyeserera pogwiritsa ntchito radioactive acetate yolembedwa ndi methyl kaboni (chakuda) kapena carboxyl kaboni (ofiira). M'malingaliro opendekera, mphete zimasonyezedwa ndi zilembo A mpaka D.
Kuphatikizika kumachitika m'magawo anayi, monga akuwonetsera mkuyu. 21-33: (1) kubwezeretsanso kwa zotsalira zitatu za ma acetate kuti apange mkatikati mwa kaboni sikisi wa mevalonate, (2) kutembenuka kwa mevalonate kukhala mabatani a isoprenia, (3) polymerization ya magawo asanu ndi awiri a isoprenini a galasi kuti apange squalene 30-carbon linear, (4) cyclization of squalene mphete zinayi za steroid nucleus, ndikutsatiridwa ndi kusintha kosiyanasiyana (oxidation, kuchotsedwa kapena kusuntha kwa magulu a methyl) ndikupanga cholesterol.
Mkuyu. 21-33. Chithunzi chojambulidwa cha cholesterol biosynthesis. Magawo anayi a kaphatikizidwe amakambidwa mu lembalo. Zilumba za Isoprene mu squalene zimalembedwa ndi mizere yofiira yopyapyala.
Gawo (1). Kaphatikizidwe ka mevalonate kuchokera ku acetate. Gawo loyamba la cholesterol biosynthesis limatsogolera pakupanga chinthu chapakatikati kupitilira (Mkuyu. 21-34). Ma molekyulu awiri a acetyl CoA amalola kupatsa acetoacetyl CoA, yomwe imagwirizana ndi molekyulu ya acetyl CoA yachitatu kupanga gulu la ma carbon sikisi β-hydroxy-β-methylglutaryl-CoA (HM G -CoA). Izi ziwiri zoyambirira zimachitika thiolase ndi NM G -CoA synthase, motsatana. Cytosolic NM G-CoA synthase Njira ya metabolic iyi imasiyana ndi mitochondrial isoenzyme, yomwe imathandizira kapangidwe ka NM G -CoA panthawi yopanga matupi a ketone (onani mkuyu. 17-18).
Mkuyu. 21-34. Mapangidwe a mevalonate kuchokera ku acetyl-CoA. Gwero la C-1 ndi C-2 mevalonate kuchokera ku acetyl-CoA limawonetsedwa pinki.
Kusintha kwachitatu kumachepetsa kuthamanga kwa njira yonse. Mmenemo, NM G -CoA imafupikitsidwa kukhala mevalonate, momwe mamolekyu awiri onse a NUE D PH amapereka ma elekitoni awiri. Kuyambiranso kwa HMG-CoA - kuphatikiza membrane mapuloteni osalala a ER, amathandizira, monga momwe tidzaonera pambuyo pake, monga gawo lalikulu la kayendedwe ka kagayidwe ka cholesterol.
Gawo (2). Kutembenuka kwa mevalonate kukhala isoprene iwiri yokhazikitsidwa. Pa gawo lotsatira la kapangidwe ka cholesterol, magulu atatu a phosphate amasamutsidwa kuchokera ku mamolekyulu a ATP kupita ku mevalonate (mkuyu. 21-35). Phosphate yomangiriridwa ku gulu la hydroxyl ku C-3 mevalonate pakati 3-phospho-5-pyrophosphomevalonate ndi gulu labwino kusiya, mu gawo lotsatira zonsezi phosphates ndi oyandikana ndi boxboxyl achokapo, ndikupanga mgwirizano wapawiri pamtundu wa kaboni kasanu ∆ 3 -isopentenyl pyrophosphate. Ili ndiye gawo limodzi mwa ma isoprenes awiri ophatikizidwa - otenga nawo mbali kwambiri pakuphatikizika kwa cholesterol. Isomerization wa Δ 3 --isopentenylpyrophosphate imaperekanso isopren yachiwiri yokhazikitsidwa dimethylallyl pyrophosphate. Kuphatikizika kwa isopentenyl pyrophosphate mu cytoplasm ya maselo a chomera kumachitika molingana ndi njira tafotokozera apa. Komabe, ma chloroplasts a chomera ndi mabakiteriya ambiri amagwiritsa ntchito njira yopanda mevalonate. Njira ina siyipezeka mu nyama, choncho ndizosangalatsa popanga mankhwala atsopano.
Mkuyu. 21-35. Kutembenuka kwa mevalonate kukhala mabatani a isoprene. Magawo asanu ndi amodzi omwe adakhazikitsidwa amaphatikizana ndikupanga squalene (onani Chithunzi 21-36). Magulu omwe asiya a 3-phospho-5-pyrophosphomevalonate amawonetsedwa bwino kwambiri. M'mabakiketi mabedi ndizovomerezeka zapakati.
Gawo (3). Kuperekera kwa magawo asanu ndi limodzi a isopren kuti apange squalene. Isopentenyl pyrophosphate ndi dimethylallyl pyrophosphate tsopano limadutsa mutu-to-mchira, momwe gulu limodzi la pyrophosphate limasunthira ndikupanga mafayilo 10 a kaboni - geranyl pyrophosphate (Mkuyu. 21-36). (Pyrophosphate imamatirira kumutu.) Geranyl pyrophosphate amadutsa mutu wotsatira mpaka mchira wake ndi isopentenyl pyrophosphate, ndi mafomu apakati 15 a kaboni farnesyl pyrophosphate. Pomaliza, mamolekyulu awiri a farnesyl pyrophosphate amaphatikiza "mutu mpaka mutu", magulu onse a phosphate amachotsedwa - kupangidwa squalene.
Mkuyu. 21-36. Mapangidwe a squalene. Kapangidwe ka squalene kamene kali ndi maatomu 30 a kaboni kumachitika panthawi yotsatiridwa ndi ma isopren (ma kaboni asanu).
Mayina odziwika kwa omwe ali pamtunduwu amachokera ku mayina a magwero omwe adzipatula koyamba. Geraniol, yemwe amapanga mafuta a rose, ali ndi fungo la geranium, ndipo farnesol, wopezeka m'mitundu ya acacia farnesa, ali ndi kakombo ka pfungo labwino. Mafungo ambiri azomera zachilengedwe ndi amisipatimenti yomwe imapangidwa kuchokera ku mabatani a isoprene. Squalene, woyamba kupatulidwa ku chiwindi cha shark (Mitundu ya squalus), imakhala ndi ma atomu 30 a kaboni: maatomu 24 ali mu unyolo waukulu ndi maatomu asanu ndi limodzi mmalo achitsulo.
Gawo (4). Kusintha kwa squalene kukhala mphete zinayi za steroid nucleus. Mu mkuyu. 21-37 zikuwoneka bwino kuti mawonekedwe a squalene unyolo, ndi ma sterols - cyclic. Ma sterol onse ali ndi mphete zinayi zopendekera zomwe zimapanga maukadaulo a steroid, ndipo onsewa ndi ma alcohols okhala ndi gulu la hydroxyl ku atomu ya C-3, motero dzina lachi Ngerezi sterol. Pogwira ntchito squalene monoo oxygenase atomu imodzi ya okosijeni kuchokera ku O imawonjezedwa mpaka kumapeto kwa unyolo wa squalene 2 ndipo epoxide imapangidwa. Enzyme iyi ndi oxidase wina wosakanikirana (kuwonjezera. 21-1), NADPH imachepetsa atomu ina ya oxygen kuchokera ku O 2 kwa H2 O. Zomangira Zapawiri squalene-2,3-epoxide Anakonza kuti kuchitapo kanthu mochititsa chidwi kusanduke gulu la squalene epoxide kukhala dongosolo la ma cyclic. M'maselo a nyama, kuzungulira uku kumabweretsa mapangidwe a lanosterol yomwe imakhala ndi mphete zinayi zokhala ndi ma nucleus a steroid. Zotsatira zake, lanosterol imasinthidwa kukhala cholesterol kudzera pazokambirana zingapo pafupifupi 20, zomwe zimaphatikizapo kusamukira kwamagulu ena azitsulo ndi kuchotsedwa kwa ena. Kufotokozera kwa njira yodabwitsayi ya biosynthesis, imodzi yovuta kwambiri podziwika, idapangidwa ndi Conrad Bloch, Theodore Linen, John Cornfort ndi George Popiak kumapeto kwa 1950s.
Mkuyu. 21-37. Kutsekedwa kwa mphete kumatembenuza squalene wotsogola kukhala chinthu cholochedwa chaidididid. Gawo loyamba limapangidwa ndi oxidase yokhala ndi ntchito yosakanikirana (monoo oxygenase), yomwe cosubstrate yake ndi N AD PH. Mankhwalawa ndi epoxide, omwe mu gawo lotsatira amayenda kuti apange maziko a steroid. Zomaliza zomaliza kupezeka m'maselo a nyama ndi cholesterol; mu zinthu zinanso zosiyanasiyana zomwe zimapangidwa mosiyanasiyana zimapangidwa.
Cholesterol ndi mawonekedwe a sterol a maselo a nyama, zomera, bowa ndi ma protocrant amapanga zitsulo zina zofanana kwambiri.
Amagwiritsa ntchito njira yomweyi ya squalene-2,3-epoxide, koma njira zimasunthira pang'ono, ndipo ma sterol ena amapangidwa, monga sigmasterol muzomera zambiri ndi ergosterol mu bowa (mkuyu. 21-37).
Mwachitsanzo 21-1 Mphamvu Zotsatsa za squalene Synthesis
Kodi mtengo wamagetsi (wotchulidwa ngati mamolekyulu a ATP) wopanga molekyu imodzi ya squalene ndi uti?
Njira Zothetsera. Mu kapangidwe ka squalene kuchokera ku acetyl-CoA, ATP imangokhala pa siteji pomwe mevalonate imasinthidwa kukhala activated isoprene squalene precursor. Ma molekyulu asanu ndi limodzi a isoprene amafunikira kuti apange molekyu ya squalene, ndipo mamolekyulu atatu a ATP amafunikira kuti apange mamolekyulu amodzi onse. Zokwanira, mamolekyulu 18 a ATP amathera kuphatikizidwa ndi molekyulu imodzi ya squalene.
Kuphatikiza kolesterol m'thupi
Mu vertebrates, cholesterol yambiri imapangidwa mu chiwindi. Ena mwa cholesterol ophatikizidwa pamenepo amaphatikizidwa ndi nembanemba ya hepatocytes, koma imatumizidwa kumayiko amodzi mwa mitundu yake itatu: biliary (bile) cholesterol, bile acids kapena cholesterol esters. Ma acid akhungu ndipo mchere wawo ndi ma hydrophilic ofanana ndi cholesterol, omwe amapangidwa m'chiwindi ndikuthandizira kukumba kwa lipids (onani mkuyu. 17-1). Esters of cholesterol Kupangidwa mu chiwindi ndi zochita acyl-CoA-cholesterol-acyltransferase (ACAT). Ma enzyme amenewa amathandizira kusintha kwa otsalira a mafuta kuchokera ku coenzyme A kupita ku gulu la hydroxyl la cholesterol (mkuyu. 21-38), ndikusintha cholesterol kukhala mawonekedwe a hydrophobic ochulukirapo. Ma cholesterster a cholesterol omwe ali ndi tinthu tating'onoting'ono ta lipoprotein amatengedwa kupita kuzinthu zina pogwiritsa ntchito cholesterol kapena kusungidwa mu chiwindi.
Mkuyu. 21-38. Kaphatikizidwe wama cholesterol. Etherification imapangitsa kuti cholesterol ikhale mtundu wina wa hydrophobic wosungirako ndi zoyendera.
Cholesterol ndiyofunikira ku ziwalo zonse za nyama zomwe zikukula pazomwe zimapangidwa, ndipo ziwalo zina (mwachitsanzo, tiziwalo timene timatulutsa ma adrenal ndi glands) zimagwiritsa ntchito cholesterol monga poyambira mahomoni a steroid (izi zidzafotokozedwa pansipa). Cholesterol ndiwotsimikiziranso vitamini D (onani Chithunzi 10-20, v. 1).
Cholesterol ndi lipids zina zimakhala ndi lipoprotein ya plasma
Ma cholesterol ndi cholesterol esters, ngati ma pracylglycerols ndi phospholipids, samaphatikizika ndi madzi, komabe, ayenera kuchoka pamatumba omwe adapangidwa kuti apangidwe ndi minofu yomwe amasungidwa kapena kuwonongedwa. Amanyamulidwa ndimagazi amtundu wa magazi plopma lipoproteins - macromolecular zovuta za mapuloteni ena onyamula (ma apolipoproteins) ndi ma phospholipids, cholesterol, cholesterol esters ndi ma pracylglycerols omwe amapezeka m'malo awa m'magulu osiyanasiyana.
Apolipoproteins ("apo" amatanthauza mapuloteni wopanda lipid palokha) kuphatikiza ndi lipids kuti apange tizigawo ting'onoting'ono ta lipoprotein tinthu tating'onoting'ono tokhala ndi ma hydrophobic lipids pakati ndi maukosi a hydrophilic amino acid pamtunda (mkuyu. 21-39, a). Ndi mitundu yosiyanasiyana ya ma lipids ndi mapuloteni, ma tinthu tosiyanasiyana timapangidwa - kuchokera pa ma chylomicrons kupita pamlingo wapamwamba wa lipoprotein. Tinthu tating'onoting'ono timatha kulekanitsidwa ndi ultracentrifugation (Table 21-1) ndikuwoneka pogwiritsa ntchito ma elekitirofoni a elekitironi (Chithunzi 21-39, b). Gawo lirilonse la lipoproteins limachita ntchito inayake, yomwe imatsimikiziridwa ndi malo a kaphatikizidwe, kapid ndi kapangidwe kake ka apolipoprotein. Apolipoprotein osachepera 10 amapezeka m'magazi am'magazi a anthu (Gome 21-2), lomwe limasiyana, zimachitika ndi ma antibodies ena, komanso kapangidwe kogawidwa m'magulu osiyanasiyana a lipoproteins. Mapuloteniwa amakhala ngati zinthu zotsogolera ma lipoprotein kuzinthu zinazake kapena ma enzymes omwe amapanga lipoproteins.
Gawo 21-1. Ma plopma lipoproteins
Kuphatikizika (kachigawo kambiri,%)
r = 513,000). Tinthu tating'onoting'ono ta LDL tili ndi ma molekyulu pafupifupi 1,500 a ma cholesterol esters, kuzungulira pakati pali chipolopolo cha mamolekyulu 500 a cholesterol, mamolekyulu 800 a phospholipids ndi molekyu imodzi ya apoB-100. b - magulu anayi a lipoprotein, akuwoneka ndi maikulosikopu yama elekitoni (pambuyo pa kuwonetsa kwa). Clockwise, kuyambira kuchokera kumtunda kumanzere: ma chylomicrons - ndi awiri 50 mpaka 200 nm, PL O NP - kuyambira 28 mpaka 70 nm, HDL - kuyambira 8 mpaka 11 nm, ndi LDL - kuyambira 20 mpaka 55 nm. Zomwe milomo ya lipoprotein imaperekedwa ili patebulo. 21-2.
Chylomicrons, wotchulidwa mu Sek. 17, kusuntha chakudya chamtundu wamatumbo kuchokera m'matumbo kupita kuzinthu zina. Awa ndi ma lipoprotein akulu kwambiri, ali ndi kachulukidwe kocheperako komanso kamtundu wapamwamba kwambiri wama triacylglycerols (onani mkuyu. 17-2). Ma Chylomicrons amapangidwa mu ER ya epithelial maselo akukhazikika m'matumbo ang'ono, kenako ndikudutsa mu dongosolo la lymphatic ndikulowa m'mitsempha yamagazi kudzera m'mitsempha yamanzere ya subclavian. Ma chylomicron apolipoproteins ali ndi apoB-48 (apadera pa kalasi iyi ya lipoproteins), apoE ndi apoC-II (Gawo 21-2). AroC-II imayendetsa lipoprotein lipase mu capillaries ya adipose minofu, mtima, chigoba minofu ndi lactating gland mammary, kuonetsetsa kutuluka kwa mafuta acids omasuka mu izi. Chifukwa chake, ma chylomicrons amasamutsa mafuta acids kumisempha, komwe amamwa kapena kusungidwa ngati mafuta (mkuyu. 21-40). Zotsalira za Chylomicron (makamaka zomasulidwa ku ma pracylglycerols, komabe okhala ndi cholesterol, apoE ndi apoB-48) zimatengedwa ndi magazi kupita ku chiwindi. Mu chiwindi, ma receptors amamangiriridwa apoE omwe ali m'mazere a chylomicron ndi kuyimira kuyamwa kwawo ndi endocytosis. Mu hepatocytes, zotsalira izi zimatulutsa cholesterol yomwe imakhala ndikuwonongeka m'miyala.
Gawo 21-2. Mankhwala apolipoprotein a plasma lipoprotein
Ntchito (ngati ikudziwika)
Yogwira L CAT, imagwirizana ndi ABC transporter
Zoletsa L CAT
Amayendetsa L CAT, mayendedwe a cholesterol / chilolezo
Zimamangiriza ku LDL receptor
Ma Chylomicrons, VLDL, HDL
Ma Chylomicrons, VLDL, HDL
Ma Chylomicrons, VLDL, HDL
Iyamba chilolezo cha VLDL ndi zotsalira za chylomicron
Zakudya zikakhala ndi mafuta ochulukirapo kuposa momwe zimagwiritsidwira ntchito ngati mafuta, zimasandulika kukhala ma triacylglycerols mu chiwindi, omwe amapanga kachigawo kena ndi apolipoproteins otsika kwambiri lipoproteins (VLDL). Mafuta ochulukirapo mu chiwindi amatha kusinthidwanso kukhala ma triacylglycerols ndikugulitsidwa ngati VLDL (mkuyu. 21-40, a).Kuphatikiza pa ma pracylglycerols, kachigawo ka VLDL kamakhala ndi kuchuluka kwama cholesterol ndi cholesterol esters, komanso apoB-100, apoC-1, apoC-II, apoC III ndi apoE (Table 21-2). Ma lipoprotein amenewa amatengedwanso ndi magazi kuchokera ku chiwindi kupita ku minofu ndi minofu ya adipose, pomwe, lipoprotein lipase ikadzayambitsidwa ndi apo-C II, mafuta achilengedwe aulere amamasulidwa kuchokera ku triacylglycerols ya chidutswa cha VLDL. Ma Adipocytes amalanda mafuta acids aulere, ndikusinthanso kukhala ma triacylglycerols, omwe amasungidwa m'maselo awa m'njira ya lipid inclusions (madontho), myocyte, m'malo mwake, nthawi yomweyo amadzola mafuta acids kuti apange mphamvu. Zotsalira zambiri za VLDL zimachotsedwa pakufalitsidwa ndi hepatocytes. Kuyamwa kwawo, kofanana ndi kuyamwa kwa ma chylomicrons, amalumikizidwa ndi ma receptors ndipo zimatengera kukhalapo kwa apoE m'malo otsalira a VLDL (kuwonjezera. 21-2, ubale pakati pa apoE ndi matenda a Alzheimer's).
Mkuyu. 21-40. Lipoproteins ndi lipid mayendedwe, ndipo - lipids imayendetsedwa ndi kuthamanga kwa magazi mwa mawonekedwe a lipoproteins, omwe amaphatikizidwa m'magawo angapo omwe amagwira ntchito zosiyanasiyana komanso mawonekedwe osiyanasiyana a mapuloteni ndi lipids (tabu. 21-1, 21-2) ndipo imagwirizana ndi kusala kwa izi. Zakudya zam'madzi zam'madzi zimapangidwira mu ma chylomicrons, ambiri mwa ma triacylglycerols omwe amapezeka mkati mwake amatulutsidwa ndi lipoprotein lipase mu adipose ndi minofu minofu m'mapilaries. Zotsalira za Chylomicron (zomwe zimakhala ndi mapuloteni komanso cholesterol) zimagwidwa ndi hepatocytes. Endo native lipids ndi cholesterol ku chiwindi amaperekedwa ku adipose ndi minofu minofu mu mawonekedwe a VLDL. Kutulutsidwa kwa lipids kuchokera ku VLDL (pamodzi ndi kutayika kwa ma apolipoproteins) pang'onopang'ono kumasintha VLDLP ku LDL, yomwe imapereka cholesterol ku minofu yowonjezera kapena imabwezeretsa chiwindi. Chiwindi chimagwira zotsalira za VLDL, LDL ndi zotsalira za chylomicrons ndi receptor-mediated endocytosis. Cholesterol owonjezera m'misempha yowonjezera imatumizidwa kubwerera ku chiwindi mu mawonekedwe a LDL. Mu chiwindi, gawo la cholesterol limasanduka mchere wa bile. b - zitsanzo zamagazi a m'magazi otengedwa pambuyo panjala (kumanzere) ndikatha kudya chakudya chamafuta ambiri (kumanja). Ma Chylomicrons omwe amapangidwa ndikudya zakudya zamafuta amapereka kuti madzi am'madziwo akhale ngati mkaka.
Ndi kutayika kwa ma pracylglycerols, gawo la VLDL limasinthidwa kukhala zotsalira za VLDL, zomwe zimatchedwanso lipermrotein dermity lipoproteins (VLDL), kuchotsedwa kwina kwa pracylglycerols ku VLDL kumapereka otsika ochepa lipoproteins (LDL) (tabu 21-1). Gawo la LDL, lomwe limalemera kwambiri ku cholesterol ndi cholesterol esters, komanso lili ndi apoB-100, limasunthira cholesterol kumisempha yowonjezera yomwe imakhala ndi ma receptor enieni omwe amazindikira apoB-100 pama membrane awo a plasma. Ma receptor awa amalumikizira kuchuluka kwa mafuta a cholesterol ndi cholesterol esters (monga tafotokozera pansipa).
Zowonjezera 21-2.PaliEEE amatchula za matenda a Alzheimer's
Mwa anthu, pali mitundu itatu (mitundu itatu) yodziwika bwino ya gene encoding apolipoprotein E. Mwa maumbulidwe a paleE, APOEZ allele ndiyomwe imapezeka kwambiri mwa anthu (pafupifupi 78%), ma APOE4 ndi APOE2 milandu ndi 15 ndi 7%, motero. Kuwala kwa APOE4 kumakhala makamaka ndi anthu omwe ali ndi matenda a Alzheimer's, ndipo ubalewu umalola kuneneratu za matendawa pafupipafupi. Anthu omwe atengera APOE4 ali pachiwopsezo chachikulu chotenga matenda a Alzheimer's. Anthu omwe ali ndi homozygous APOE4 ali ndi mwayi wotenga matendawa nthawi 16, anthu wamba odwala amakhala ndi zaka 70. Kwa anthu omwe amatenga makope awiri a AROEZ, m'malo mwake, pafupifupi zaka zapakati pa matenda a Alzheimer ndizoposa zaka 90.
Zomwe zimayambira pakubwera kwa matenda a apoE4 ndi matenda a Alzheimer's sizikudziwika mpaka pano. Kuphatikiza apo, sizikudziwika kuti apoE4 imakhudza bwanji kukula kwa zingwe za amyloid, zomwe zikuwoneka kuti ndizomwe zimayambitsa matenda a Alzheimer's (onani mkuyu. 4-31, v. 1). Malingaliro amayang'ana gawo lomwe lingakhalepo la apoE pakukhazikitsa kapangidwe ka cytoskeleton of neurons. Mapuloteni a apoE2 ndi apoEZ amamangiriza mapuloteni angapo omwe amagwirizana ndi ma microtubules a neurons, pomwe apoE4 samamanga. Izi zimathandizira kumwalira kwa ma neuron. Chilichonse chomwe makinawa amatha, izi zimapereka chiyembekezo chofutukula kumvetsetsa kwathu kwachilengedwe cha ma apolipoproteins.
Mtundu wachinayi wa lipoproteins - lipoproteins yapamwamba (HDL), kachigawo kameneka kamapangidwa m'chiwindi komanso m'matumbo aang'ono mu mawonekedwe a tinthu tating'onoting'ono tambiri timene timakhala ndi cholesterol yaying'ono komanso opanda mafuta a cholesterol esters (mkuyu. 21-40). Kachigawo ka HDL kali ndi apoA-I, apoC-I, apoC-II ndi ma apolipoprotein ena (Table 21-2), komanso lecithin-cholesterol-acyltransferase (LC AT), omwe amathandizira mapangidwe a cholesterol esters kuchokera ku lecithin (phosphatidylcholine) ndi cholesterol (mkuyu. 21-41). L CAT pamtundu wa tinthu tating'onoting'ono tatsopano vya HDL timasintha chylomicron cholesterol ndi phosphatidylcholine ndi zotsalira za VLDL kukhala ma cholesterol esters, omwe amayamba kupanga tinthu tating'onoting'ono, ndikusintha tinthu tating'onoting'ono tatsopano vya HDL tokhala tinthu tambiri tokhala ngati HDL. Lipoprotein wolemera kwambiri wa kolesteroloyo umabwezeretsedwa ku chiwindi, komwe "amatsitsidwa", cholesterol ina imasinthidwa kukhala mchere wa bile.
Mkuyu. 21-41. Zomwe zimachitika ndi lecithin-cholesterol-acyltransferase (L CAT). Enzimuyi ilipo pamtunda wa ma tizidutswa ta HDL ndipo imayendetsedwa ndi apoA-1 (gawo la kachidutswa ka HDL). Ma estlesterol esters amadziunjikira mkati mwa tinthu tating'onoting'ono tatsopano vya HDL, timasandulika kukhala HDL yokhwima.
HDL imatha kumizidwa m'chiwindi ndi receptor-mediated endocytosis, koma ena mwa cholesterol cha HDL amaperekedwa ku minofu ina ndi njira zina. Tizilombo ta HDL titha kumangiriza ku mapuloteni a SR - BI receptor pa membrane wa plasma wama cell a chiwindi komanso mu minofu ya steroidogenic monga gren adrenal. Izi zolandilira sizimayimira endocytosis, koma kusuntha kwa cholesterol ndi lipids zina za gawo la HDL mu cell. Gawo loti "latha" HDL limalowanso m'magazi, pomwe limakhala ndi zigawo zatsopano za lipids kuchokera ku ma chylomicrons ndi zotsalira za VLDL. HDL yemweyo imatha kugwiranso cholesterol yomwe imasungidwa mu minyewa yowonjezera ndikuyiyendetsa ku chiwindi ndi sinthani mayendedwe a cholesterol (Mkuyu. 21 mpaka 40). Mu imodzi mwanjira zosinthira, mayendedwe a HDL omwe amapezeka ndi ma SR-BI zolandila m'maselo okhala ndi cholesterol amayamba kuyambitsa cholesterol kuchokera mu cell kulowa mu ma cell a HDL, omwe amasintha cholesterol kubwerera chiwindi. Mtundu wina wamayendedwe obwereranso mu cell cholesterol wolemera, utatha mtundu wa HDL, apoA-I ndimayanjana ndi transporter yogwira, mapuloteni a ABC. ApoA-I (ndipo mwina HDL) imakamizidwa ndi endocytosis, kenako imasungidwanso, yodzaza ndi cholesterol, yomwe imatengedwa kupita ku chiwindi.
Protein ABC1 ndi gawo limodzi la banja lalikulu laonyamula mankhwala ambiri, onyamula awa nthawi zina amatchedwa onyamula mabungwe a ABC, popeza onse amakhala ndi makaseti omanga a ATP (ATP - makaseti omangirira), amakhalanso ndi madera awiri a transmembrane omwe amakhala ndi ma eyala 6 a transmembrane (onani chap. . 11, v. 1). Mapuloteni awa amasinthira ma ion ambiri, ma amino acid, mavitamini, mahomoni a steroid ndi mchere wamadzimadzi kudzera mwa michere ya plasma. Woyimira wina wa banja lonyamula izi ndi protein ya CFTR, yomwe, yokhala ndi cystic fibrosis, imakhala yowonongeka (onani. 11-3, v. 1).
Ma cholembera a cholesterol amalowa mu khungu kudzera mu endocytosis yolumikizira pakati
Chidutswa chilichonse cha LDL m'magazi chimakhala ndi apoB-100, chomwe chimadziwika ndi mapuloteni ena olandirira pansi -Ma LDL receptors pa nembanemba yama cell omwe amafunikira kugwira cholesterol. Kumangidwa kwa LDL ku LDL receptor kumayambitsa endocytosis, chifukwa chomwe LDL ndi cholandilira chake chimasunthira mu cell mkati mwa endosome (mkuyu. 21-42). Endosome imaphatikizana ndi lysosome, yomwe imakhala ndi ma enzymes omwe hydrolyze cholesterol esters, imatulutsa cholesterol ndi mafuta acids mu cytosol. ApoB-100 kuchokera ku LDL imaphwanyanso ndikupanga ma amino acid omwe amasungidwa mu cytosol, koma LDL receptor imapewera kusokonezedwa ndikubwerera kumalo osungirako cell kuti iwonenso nawo gawo la LDL. ApoB-100 ilinso mu VLDL, koma tsamba lolumikizira lomwe limagwira silingathe kumanga ku LDL receptor; kusinthidwa kwa VLDLP kupita ku LDL kumapangitsa kuti cholumikizira cholumikizira chikhalepoB-100 kupezeka. Njira yotengera magazi ku cholesterol imeneyi ndi endocytosis-mediated endocytosis mu minofu yolimbana nayo yaphunziridwa ndi Michael Brown ndi Joseph Goldstein.
Michael Brown ndi Joseph Goldstein
Mkuyu. 21-42. Kugwidwa kwa cholesterol ndi endeptor-mediated endocytosis.
Cholesterol, yomwe imalowa m'maselowa motere, imatha kuphatikizidwa ndi ziwalo kapena kupangidwanso ndi ACAT (mkuyu. 21-38) kuti isungidwe mu cytosol mkati mwa lipid m'malovu. Pakakhala cholesterol yokwanira yomwe ilipezeka m'chigawo cha magazi cha LDL, kudziunjikira kwa cholesterol yochulukirapo kumalepheretsedwa ndi kuchepa kwa kapangidwe kake.
Receptor ya LDL imamangiridwanso kwa apoE ndipo imagwira gawo lalikulu pakulandidwa kwa ma chylomicrons ndi zotsalira za VLDL ndi chiwindi. Komabe, ngati ma LDL receptors sakupezeka (monga, mwachitsanzo, mu mbewa yolumikizira ya jini ya LDL receptor), zotsalira za VLDL ndi ma chylomicrons zimadziwikirabe ndi chiwindi, ngakhale LDL simakhudzidwa. Izi zikuwonetsa kukhalapo kwa pulogalamu yothandizira yosungirako ya receptor-mediated endocytosis ya VLDL ndi zotsalira za chylomicron. Chimodzi mwa malo osungira ndi mapuloteni a LRP (lipoprotein receptor - protein), omwe amagwirizana ndi lipoprotein receptors, omwe amamangiriza pomwepoE ndi ma ligand ena angapo.
Magawo angapo a cholesterol biosynthesis malamulo
Cholesterol synthesis ndi njira yovuta komanso yodula, motero zikuonekeratu kuti thupi ndilothandiza kukhala ndi makina owongolera cholesterol biosynthesis, yomwe imabwezeretsanso kuchuluka kwake kuphatikiza pazomwe zimadza ndi chakudya. Mu zolengedwa zoyamwitsa, kupanga cholesterol kumayendetsedwa ndi intracellular concentration
cholesterol ndi mahomoni glucagon ndi insulin. Gawo la kutembenuka kwa HMG - CoA kukhala mevalonate (mkuyu. 21-34) imachepetsa kuthamanga mu njira ya metabolic ya mapangidwe a cholesterol (mfundo yayikulu ya malamulo). Izi zimachititsidwa ndi HMG - CoA reductase. Malangizo potsatira kusintha kwamankhwala a cholesterol amathandizidwa ndi pulogalamu yapamwamba yolembetsera mtundu wa HMG - COA reductase. Jini, limodzinso ndi ma gene enanso opitilira 20 omwe amaphatikizidwa ndi mayamwidwe amafuta a cholesterol ndi mafuta osapangika, limayang'aniridwa ndi banja laling'ono lamapuloteni omwe amatchedwa mapuloteni omwe amagwirizana ndi sterol-reglement element protein protein . Pambuyo pa kaphatikizidwe, mapuloteni awa amabweretsedwa mu endoplasmic reticulum. Gawo lokha kusungunuka amino-terminal SREBP limagwira ntchito ngati cholembera pogwiritsa ntchito njira zomwe zafotokozedwa mu Ch. 28 (v. 3). Komabe, tsamba ili lilibe gawo la maukonde ndipo silitenga nawo gawo poyambitsa jini malinga lingokhala mu molekyulu ya SREBP. Pofuna kukhazikitsa mtundu wa HMG gene - redease ya CoA ndi majini ena, tsamba lomwe limagwira ntchitoyo limasiyanitsidwa ndi SREBP yonse ndi proteinolytic cleavage. Cholesterol chikakhala chambiri, mapuloteni a SREBP satha ntchito, okhazikika pa ER mu zovuta ndi puloteni ina yotchedwa SCAP (SREBP - cleavage activating protein) (mkuyu. 21-43). Ndi SCAP yomwe imamanga cholesterol ndi ma sterols ena angapo, ndikuchita ngati sensor ya sensor. Mkulu wa sterol akakhala wokwera, SCAP - SREBP tata mwina imalumikizana ndi mapuloteni ena, omwe amasunga zovuta zonse mu ER. Momwe ma sterols mu cell amatsikira, kusinthika kwa chisinthiko ku SCAP kumabweretsa kutayika kwa ntchito, ndipo SCAP - SREBP zovuta zimasamukira mkati mwa vesicles kupita ku Golgi. Mu zovuta ku Golgi, mapuloteni a SREBP amapukutidwa kawiri ndi mapuloteni awiri osiyanasiyana, cholembera chachiwiri ndikutulutsa amino-terminal domain mu cytosol. Tsambali limasunthira ku nucleus ndikuthandizira kusintha kwa mitundu ya chandamale. Pulogalamu yamapuloteni ya amino-terminal SREBP ili ndi theka lalifupi-moyo ndipo imawonongeka mwachangu ndi proteinasomes (onani mkuyu. 27-48, t. 3). Mulingo wa sterol ukakwera mokwanira, kutulutsidwa kwa mapuloteni a SR EBP okhala ndi amino terminus kumatsekedwanso, ndikuwonongeka kwa proteinasome komwe kumagwira ntchito kumabweretsa kutsekedwa kwachangu kwa mitundu yomwe mukufuna.
Mkuyu. 21-43. Kutsegula kwa SR EBP. Mapuloteni a SREB P omwe amalumikizana ndi chinthu cholowetsedwa ndi sterol (mtundu wobiriwira), atangopanga kapangidwe, amaphatikizidwa mu ER, amapanga zovuta ndi SAP (mtundu wofiira). (N ndi C akuimira malembedwe a amine ndi carboxyl.) Mu boma la S-CAP, mapuloteni a SRE BP ndi osagwira. Mkulu wa sterol akatsika, mawonekedwe a SR EBP-S CAP amasamukira ku Golgi tata, ndipo mapuloteni a SR EBP amaponderezedwa motsatana ndi mapuloteni awiri osiyanasiyana. The anamasulidwa amino acid terminal SR EBP protein domain amasamukira ku maukonde, komwe amachititsa kuti zikhale zolembedwa zolamulidwa ndi sterol.
Kuphatikizika kwa kholesterol kumayendetsedwanso ndi njira zina zingapo (mkuyu. 21-44). Kuwongolera kwa mahormoni kumalumikizidwa ndi kusinthidwa kophatikizana kwa NM G-CoA reductase. Enzyme iyi ilipo mu mitundu ya phosphorylated (yosagwira) ndi dephosphorylated (yogwira). Glucagon imathandizira phosphorylation (inactivation) ya enzyme, ndipo insulini imalimbikitsa dephosphorylation, kuyambitsa enzyme ndikukondera kapangidwe ka cholesterol. Kukhathamiritsa kwakukulu kwa cholesterol kumayambitsa ASAT, komwe kumawonjezera esterization wa cholesterol kuti apatsidwe. Pomaliza, ma cholesterol ambiri am'mlengalenga amalepheretsa kulembedwa kwa jini lomwe limalowa mu LDL receptor, kuchepetsa kupanga kwa cholandilira ichi, motero, kukhudzidwa kwa cholesterol m'magazi.
Mkuyu. 21-44. Kuwongolera kuchuluka kwa cholesterol kumapereka malire pakati pa kaphatikizidwe ndi kuyamwa kwa cholesterol pazakudya. Glucagon imathandizira phosphorylation (inactivation) ya NM G -CoA reductase, insulin imalimbikitsa dephosphorylation (activation). X - mafuta osadziwika a cholesterol metabolites omwe amachititsa proteinolysis ya NM G -CoA reductase.
Cholesterol yosagwiritsiridwa ntchito imatha kudwala kwambiri mwa anthu. Pamene kuchuluka kwathunthu kwa cholesterol wophatikizika ndi cholesterol yomwe imapezeka pazakudya kupitirira kuchuluka kwa kufunikira kwa membrane msonkhano, kaphatikizidwe ka mchere wa bile ndi mankhwala osakanikirana, mapangidwe amomwe amapezeka a cholesterol m'mitsempha yamagazi (atherosranceotic plaques) amawonekera, zomwe zimayambitsa kufalikira kwawo. M'mayiko otukuka, mtima ndi chifukwa chakutseka kwa mitsempha ya m'mimba yomwe imayambitsa kufa. Kukula kwa atherosulinosis kumalumikizidwa ndi kuchuluka kwa mafuta m'thupi komanso makamaka ndi cholesterol yambiri yololedwa ndi kachigawo ka LDL; kuchuluka kwa magazi a HDL, m'malo mwake, kumakhudza malo amitsempha yamagazi.
Ndi cholowa cholandilira hypercholesterolemia (vuto lakabadwa), kuchuluka kwa cholesterol yamagazi ndikokwera kwambiri - atherosclerosis yayikulu imayamba mwa anthuwa kale paubwana. Chifukwa cha cholakwika cholakwika cha LDL, kupezeka kwapakati pa cholesterol cha LDL kumachitika. Zotsatira zake, cholesterol sichimachotsedwa m'magazi, imadziunjikira ndikuthandizira kupanga mapangidwe atherosselotic. Kuphatikizika kwa cholesterol ya amkati kumapitirirabe, ngakhale ndi cholesterol yowonjezera m'magazi, popeza cholesterol chowonjezera sichingalowe mu cell kuti ikulamulire syntracellular synthesis (mkuyu. 21 -44).Zochizira odwala omwe ali ndi cholowa hypercholesterolemia ndi matenda ena ogwirizana ndi seramu cholesterol, makalasi a statin amagwiritsidwa ntchito. Zina mwazo zimapezeka kuchokera ku zinthu zachilengedwe, pomwe zina zimapangidwa ndi makampani opanga mankhwala. Ma Statin ndi ofanana ndi mevalonate (onjezani. 21-3) ndipo ndi othandizira kupikisana nawo a NMS-CoA reductase.
Zowonjezera 21-3. MEDICINE. Lipid hypothesis ndi kulengedwa kwa ma statins
Matenda a mtima a Coronary (CHD) ndiyomwe imayambitsa kufa kwa anthu otukuka. Kuchepetsa kwamitsempha yama coronary komwe kumayendetsa magazi kupita kumtima kumachitika chifukwa cha kupangika kwa ma deposits amafuta otchedwa atherosranceotic plaques; mapopawa amakhala ndi cholesterol, mapuloteni a fibrillar, calcium, mapulogalamu am'magazi, komanso zidutswa za cell. M'zaka za XX. Panali kutsutsana kwakukulu pa ubale womwe umalepheretsa magazi kutsutsana (atherosulinosis) ndi cholesterol yamagazi. Zokambirana izi ndi kufufuza mwachangu kwawoko kwapangitsa kuti pakhale mankhwala ogwira mtima omwe amachepetsa cholesterol.
Mu 1913, N.N. Anichkov, wasayansi wodziwika bwino ku Russia komanso katswiri pankhani yofufuza zam'tsogolo, adafalitsa buku lomwe adawonetsa kuti akalulu omwe amapatsidwa chakudya chamafuta a cholesterol amayamba kuwonongeka m'mitsempha yamagazi yomwe imafanana ndi malo a atherosclerotic m'matumba a anthu okalamba. Anichkov adachita kafukufuku wake kwazaka zambiri ndikufalitsa zotsatira zake m'magazini odziwika bwino aku Western. Tsoka ilo, deta yake sinakhale maziko a chitukuko cha atherosclerosis mwa anthu, popeza nthawi imeneyo malingaliro anali ofala akuti matendawa amabwera chifukwa cha ukalamba ndipo sangathe kupewedwa. Komabe, umboni pang'onopang'ono unasonkhanitsa ubale pakati pa serum cholesterol ndi kukula kwa atherosulinosis (lipid hypothesis), komanso m'ma 1960. ofufuza ena anena mosapita m'mbali kuti matendawa amatha kuthandizidwa ndimankhwala. Komabe, malingaliro osiyana ndi omwe adalipo mpaka kufalitsa mu 1984 za zotsatira za kafukufuku wambiri wokhudza udindo wa cholesterol wochititsidwa ndi US National Institute of Health (Coronary Primary Prevention T kesi). Kuchulukitsidwa kwakukulu kwa kuchuluka kwa kuphwanya kwa myocardial ndi stroko ndi kuchepa kwa cholesterol yamagazi kunawonetsedwa. Phunziroli, cholesterol, anion exchange resin yomwe imamanga asidi acid, idagwiritsidwa ntchito kutsitsa cholesterol. Zotsatirazi zalimbikitsa kufunafuna kwa mankhwala atsopano, amphamvu kwambiri. Ndiyenera kunena kuti mu sayansi yasayansi, kukayikira pazowoneka ngati lipid hypothesis idasoweka pokhapokha ndikuyamba kwa ma statins kumapeto kwa 1980s - koyambirira kwa 1990s.
Statin yoyamba idapezeka ndi Akira Endo ku Sankyo ku Tokyo. Endo adafalitsa ntchito yake mu 1976, ngakhale adathana ndi vuto la kagayidwe ka cholesterol kwa zaka zingapo. Mu 1971, adanenanso kuti cholesterol synthesis inhibitors ikhoza kukhalanso yopanga bowa opanga maantibayotiki omwe amaphunziridwa nthawi imeneyo. Kwa zaka zambiri akugwira ntchito yayikulu, adasanthula zikhalidwe zopitilira 6,000 zama bowa osiyanasiyana, mpaka adapeza zotsatira zabwino. Pomwe ankapangira amatchedwa compactin. Izi zimachepetsa cholesterol mwa agalu ndi anyani. Maphunzirowa adakopa chidwi cha a Michael Brown ndi a Joseph Goldstein aku University of Texas Southwestern Medical School. Brown ndi Goldstein, pamodzi ndi Endo, adayamba kafukufuku wophatikizira ndikutsimikizira zomwe adachita. Kupambana kwakukulu kwa mayeso oyamba azachipatala kunakhudza makampani opanga mankhwala pakupanga mankhwalawa. Ku Merck, gulu lotsogozedwa ndi Alfred Alberts ndi Roy Wagelos adayambitsa zikhalidwe zatsopano za bowa ndipo, atafufuza zikhalidwe 18, anapeza mankhwala ena ogwirira ntchito. Vutoli limatchedwa lovastatin. Komabe, panthawi imodzimodzi, ankakhulupirira kuti kuphatikiza mitundu yayikulu ya compactin kwa agalu kumabweretsa kukula kwa khansa komanso kusaka ma statins atsopano mu 1980s. wayimitsidwa. Komabe, pofika nthawi imeneyi, phindu logwiritsa ntchito ma statins pochiza odwala omwe ali ndi hypercholesterolemia linali likuwonekera kale. Pambuyo poyankhulana ndi akatswiri apadziko lonse lapansi ndi Food and Drug Administration (FDA, USA), Merck adayamba kupanga lovastatin. Kafukufuku wowonjezera m'zaka makumi awiri zotsatira sanawululire zakukhudzana ndi mtundu wa lovastatin komanso mtundu watsopano wa mankhwala omwe adayamba pambuyo pake.
Mkuyu. 1. Statin ndi zoletsa za NM G-CoA reductase. Kuyerekeza kapangidwe ka mevalonate ndi zinthu zinayi zopanga mankhwala (ma statins) zomwe zimalepheretsa zochita za NM G -CoA reductase.
Madera choletsa ntchito ya HMG - CoA - kuchepetsa, kutsata kapangidwe ka mevalonate, potero kutsekereza kaphatikizidwe ka cholesterol. Odwala omwe ali ndi hypercholesterolemia yoyambitsidwa ndi vuto limodzi mu jini la LDL receptor, mutatenga lovastatin, kuchuluka kwa cholesterol kumachepetsedwa ndi 30%. Mankhwalawa ndi othandizanso kuphatikiza ndi ma resini apadera omwe amamanga ma bile acid ndikuletsa kutulutsira kwawo m'matumbo.
Pakadali pano, ma statin nthawi zambiri amagwiritsidwa ntchito kuti muchepetse magazi a m'magazi. Mukamamwa mankhwala aliwonse, funso limabuka za zovuta zawo. Komabe, pankhani ya ma statins, zovuta zambiri, mosiyana, zimakhala zabwino. Mankhwalawa amathandizira kutsika kwa magazi, kukonza malo omwe alipo kale aherosselotic (kuti asasunthike kuchoka ku makoma amitsempha yamagazi komanso osasokoneza kayendedwe ka magazi), kutsutsana ndi kuphatikizana kwa ma cellular, komanso kufooketsa njira zotupa m'makoma amitsempha yamagazi. Odwala omwe amatenga ma statins kwa nthawi yoyamba, zotsatirazi zimawonekera ngakhale milingo ya cholesterol isanayambe kutsika, ndipo mwina imagwirizanitsidwa ndi chopinga cha isoprenoid synthesis. Inde, sikuti mbali zonse za ma statins ndizopindulitsa. Odwala ena (nthawi zambiri amakhala pakati pa omwe amamwa ma cellins kuphatikiza mafuta ena omwe amachepetsa cholesterol), kupweteka kwa minofu ndi kufooka kwa minofu kumatha kuchitika, ndipo nthawi zina mwamphamvu. Zotsatira zoyipa zambiri za ma statin zimalembedwanso, zomwe, mwamwayi, sizimachitika kawirikawiri. Ochuluka mwa odwala, kutenga ma statins kungalepheretse kukula kwa matenda a mtima. Monga mankhwala ena aliwonse, ma statin amayenera kugwiritsidwa ntchito monga momwe adokotala amafotokozera.
Popeza chibadwa cha HDL cholesterol sichinabadwe, kuchuluka kwa cholesterol kumakhala kochepa kwambiri, ngati tili ndi matenda a Tangier, cholesterol sikuti imatsimikizika. Mavuto onse amtunduwu amachokera pakusintha kwa mapuloteni a ABC1. Gawo lopanda cholesterol la HDL lopanda HDL silingatenge cholesterol kuchokera ku maselo osalimba a ABC1, ndipo maselo omwe amadzazidwa ndi cholesterol amachotsedwa mwachangu m'magazi ndikuwonongeka. Kutengera kwina konse kwa matenda a HDL ndi Tangier ndikosowa kwambiri (mabanja osakwana 100 omwe ali ndi matenda a Tangier amadziwika padziko lonse lapansi), koma matendawa akuwonetsa udindo wa mapuloteni a ABC1 pakuwongolera kuchuluka kwa plasma ya HDL. Popeza milingo yochepa ya plasma HDL imakhudzana ndi kuwonongeka kwa mitsempha ya coronary artery, protein ya ABC1 ikhoza kukhala chandamale chothandiza kwa mankhwala omwe amapangidwa kuti athe kuwongolera milingo ya HDL. ■
Mahomoni a Steroid amapangidwa pogawa gawo la cholesterol ndi oxidation yake.
Munthu amalandira mahomoni ake onse a steroid kuchokera ku cholesterol (mkuyu. 21-45). Magulu awiri a mahomoni a steroid amapangidwa mu adrenal cortex: mineralcorticoids,omwe amayang'anira kuyamwa kwa ma ion anorganic (Na +, C l - ndi HC O 3 -) mu impso, ndipo glucocorticoids, omwe amathandizira kuyang'anira gluconeogeneis ndikuchepetsa kuyankha kwakutupa. Mahomoni ogonana amapangidwa m'maselo a abambo ndi abambo ndi placenta. Pakati pawo progesterone yomwe imayang'anira mzere wobereka, androgens (mwachitsanzo testosterone) ndi estrogens (estradiol), zomwe zimakhudza kukhazikitsidwa kwa chikhalidwe chachiwiri chogonana mwa amuna ndi akazi, motsatana. Ma mahomoni a Steroid amatha kugwira ntchito mozama kwambiri ndipo motero amapangidwa pang'ono. Poyerekeza ndi mchere wa bile, mafuta ochepa a cholesterol amawonongeka popanga mahomoni a steroid.
Mkuyu. 21-45. Ma hormone ena a steroid amapangidwa kuchokera ku cholesterol. Mapangidwe a zina mwazomwe zimapangidwira akuwonetsedwa ku mkuyu. 10-19, v. 1.
Kuphatikiza kwama mahomoni a steroid kumafuna kuchotsedwa kwa ma atomu angapo a kaboni mu "mbali yina" ya C-17 D-mphete ya cholesterol. Kuchotsa kwam'mbali kumachitika mu mitochondria ya steroidogenic zimakhala. Njira yochotsera imakhala ndi hydroxylation ya maatomu awiri oyandikana ndi khosi yam'mbali (C-20 ndi C-22), ndiye mgwirizano wamgwirizano pakati pawo (mkuyu. 21-46). Kupangidwe kwamahomoni osiyanasiyana kumaphatikizanso kuyambitsa ma atomu a oxygen. Makina onse a hydroxylation ndi oxidation nthawi ya sodium biosynthesis amathandizidwa ndi oxidases wosakanikirana (kuwonjezera. 21-1) omwe amagwiritsa ntchito NBU D PH, O 2 ndi mitochondrial cytochrome P-450.
Mkuyu. 21-46. Mafuta am'mbali amodzi mwa kuphatikiza kwamahomoni a steroid. Munthawi ya oxidase iyi yomwe ili ndi ntchito yosakanikirana yomwe imapangitsa ma atomu a kaboni oyandikana, cytochrome P-450 imakhala yonyamula ma elekitironi. Zina zomwe zimakhudzidwa ndi njirayi ndi mapuloteni onyamula ma elekitironi, adrenodoxin ndi adrenodoxin reductase. Kugawikanso kwa ma keteni am'mbali kunapezeka mu mitochondria ya adrenal cortex, pomwe kupanga kwa mankhwala a steroid kumachitika. Pregnenolone ndizotsogola kwa mahomoni ena onse a steroid (mkuyu. 21-45).
Cholesterol biosynthesis intermediates amakhudzidwa ndi njira zina zambiri za metabolic.
Kuphatikiza paudindo wawo ngati gawo la cholesterol biosynthesis, isopentenyl pyrophosphate amagwira ntchito monga wothandizira wothandizira pakupanga kuchuluka kwakukulu kwama biomolecules omwe amagwira ntchito zosiyanasiyana zachilengedwe (mkuyu. 21- 47). Izi zikuphatikiza mavitamini A, E ndi K, mitundu yazomera monga carotene ndi chlorophyll phytol unyolo, mphira wachilengedwe, mafuta ambiri ofunikira (mwachitsanzo, mafuta onunkhira a mafuta a mandimu, bulugamu, musk), timadzi tating'onoting'ono tomwe timayendetsa metamorphosis, dolichols, amagwira ntchito ngati lipid-sungunuka mumapangidwe ovuta a polysaccharides, ubiquinone ndi plastoquinone - ma elekitironi onyamula ku mitochondria ndi chloroplasts. Ma mamolekyu onsewa ndi ma isoprenoids omwe amapangidwa. Zoposa 20,000 zopezeka ma isoprenoids zapezeka mwachilengedwe, ndipo mazana mazana atsopano amatchulidwa chaka chilichonse.
Mkuyu. 21-47. Chithunzi chonse cha biosynthesis ya isoprenoids. Mapangidwe azinthu zambiri zomalizira zomwe zaperekedwa pano amaperekedwa mu chap. 10 (v. 1).
Prenylation (kuphatikiza kophatikizana kwa isoprenoid, onani mkuyu. 27-35) ndi njira yotchuka yomwe mapuloteni amawonjezera mkati mwa mamiliyoni a cell ya mammalian (onani mkuyu. 11-14). M'mapuloteni ena, lipid yolumikizidwa imayimiriridwa ndi gulu la carbon-farnesyl la 15, mwa ena ndi gulu la geranium la 20-carbon geranyl. Mitundu iwiriyi ya lipids imalumikiza ma enzyme osiyanasiyana. Ndizotheka kuti ma prenylation amakhudzana ndi mapuloteni osiyanasiyana kumitundu yosiyanasiyana malingana ndi omwe lipid imalumikizidwa. Prilination ya mapuloteni ndi gawo lina lofunika kwa ma isoprene omwe amapezeka - omwe akuchita nawo njira yolesterol.
Chidule cha Gawo 21.4 Biosynthesis ya Cholesterol, Steroids, ndi Isoprenoids
■ Cholesterol imapangidwa kuchokera ku acetyl-CoA mogwirizana m'njira zotsatizana kudzera mwa β-hydroxy-β-methylglutaryl-CoA, mevalonate, awiri ophatikizidwa a isoprene dimethylallyl pyrophosphate ndi isopentenyl pyrophosphate. Kupatsika kwa magawo a isoprene kumapereka squalene yopanda cyclic, yomwe imayenda mozungulira kuti ipange dongosolo lolimbirana mphete ndi steroid mbali yamtambo.
■ Kuphatikizika kwa cholesterol kumayendetsedwa ndi kuwongolera kwa mahomoni ndipo, kuphatikiza,, kumalephereka ndikuwonjezera kuchuluka kwa cholesterol ya intracellular, yomwe imachitika chifukwa chosinthika ndikuwongolera.
■ Ma cholesterol ndi cholesterol esters amatengedwa ndi magazi monga plasma lipoproteins. Gawo la VLDL limasunthira cholesterol, cholesterol esters ndi triacylglycerols kuchokera pachiwindi kupita kuzinthu zina, komwe ma triacylglycerols amamangidwa ndi lipoprotein lipase ndipo VLDL imasinthidwa kukhala LDL. Gawo la LDL lolemedwa mu cholesterol ndi cholesterol esters limagwidwa mosadziwika ndi ma receptors ndi endocytosis, pomwe apolipoprotein B-100 mu LDL imadziwika ndi plasma membrane receptors. HDL imachotsa cholesterol m'mwazi, ndikuyiyendetsa ku chiwindi. Mavuto okhudzana ndi zakudya kapena zolakwika zamtundu wa cholesterol metabolism zimatha kubweretsa atherosclerosis ndi infaration ya myocardial.
Ma mahomoni a Steroid (glucocorticoids, mineralocorticoids ndi mahomoni ogonana) amapangidwa kuchokera ku cholesterol posintha chingwe cham'mbali ndikulowetsa ma atomu a oxygen kukhala dongosolo la ma mphete. Mitundu ina yambiri ya isoprenoid imapangidwa kuchokera ku mevalonate ndi conduction ya isopentenyl pyrophosphate ndi dimethylallyl pyrophosphate limodzi ndi cholesterol.
Kusintha kwa mapuloteni ena kumawatsogolera kumalo omwe amamangidwa ndi ma membrane am'mimba ndipo ndikofunikira pantchito yawo yachilengedwe.
Funso 48. Kuyang'anira kagayidwe ka mafuta ochulukirapo (β-oxidation ndi biosynthesis). Kaphatikizidwe ka malonyl CoA. Acetyl CoA carboxylase, kayendedwe ka zochitika zake. Transport cha acyl Co-kudzera mkati mwa membrane wa mitochondria.
Kwakukulu
kuchuluka kwa phenylalanine kumatha
m'njira ziwiri:
kuyatsa
m'magologolo,
kutembenukira
mu tyrosine.
Kutembenuka
phenylalanine kuti tyrosine makamaka
Chofunika kuchotsa zochuluka
phenylalanine, popeza kutsika kwakukulu
Zoopsa m'maselo. Maphunziro
tyrosine ilibe kanthu
kuyambira kusowa kwa amino acid
m'maselo kwenikweni sizichitika.
Kwakukulu
phenylalanine kagayidwe kamayamba
ndi hydroxylation (mkuyu. 9-29), mu
chifukwa cha tyrosine.
Izi zimathandizira ndi eniake
monooxy-nat - phenylalanine hydra (zsilase,
yemwe amagwira ntchito ngati wopanga-bwino
tetrahydrobiopterin (N4BP).
Ntchito ya enzyme imatanthauzanso
kupezeka kwa Fe2.
Mu
chiwindi chimathandizira kwambiri kuti chiwonjezeke
glycogen (onani gawo 7). Komabe masheya
glycogen mu chiwindi yatha
Maola 18-18 akusala kudya. Gwero lalikulu
glucose pamene m'matangadza
glycogen amakhala gluconeogenesis,
zomwe zimayamba kuthamanga kudzera
Mkuyu.
11-29. Kusintha kwakukulu kwa metabolic
mphamvu posintha kuyamwa
boma la postabsorbent. CT
- matupi a ketone, FA - mafuta acids.
4-6 h
itatha chakudya chomaliza. Magawo
glycerol amagwiritsidwa ntchito kupangira shuga.
ma amino acid ndi mkaka wa m'mawere. Pamwamba
glucagon concentration synthesis
mafuta acids amachepetsa chifukwa
phosphorylation ndi inactivation
acetyl CoA carboxylase ndi mtengo
p-oxidation ukuwonjezeka. Komabe,
kuchuluka mafuta ku chiwindi
ma acid omwe amayendetsedwa
ku malo ogulitsa mafuta. Acetyl-CoA ipangidwe
mu oxidation wamafuta acids, amagwiritsidwa ntchito
mu chiwindi kwa kapangidwe ka matupi a ketone.
Mu
minofu ya adipose yokhala ndi ndende zambiri
glucagon yafupika kaphatikizidwe
TAG ndi lipolysis imakhudzidwa. Kukondoweza
lipolysis - activation
mahomoni a TAG lipase
adipocytes mothandizidwa ndi glucagon.
Mafuta Acids Amakhala Ofunika
mphamvu magwero a chiwindi, minofu ndi
minofu ya adipose.
Chifukwa chake
motero, mu nthawi ya postabsorption
Magazi a shuga amachepetsa
pamlingo wa 80-100 mg / dl, komanso mulingo wamafuta
acid ndi matupi a ketone amayamba.
Shuga
shuga ndi matenda omwe amapezeka
chifukwa cha mtheradi kapena wachibale
kusowa kwa insulini.
A.
Njira zazikulu zamatenda a shuga
matenda ashuga
Malinga ndi
Bungwe Ladziko Lonse
matenda azaumoyo
zolembedwa malinga ndi kusiyana
zokhudzana ndi majini komanso zamankhwala
mitundu iwiri yayikulu: matenda ashuga
Lembani I - wodwala insulin (IDDM), komanso matenda ashuga
Type II - non-insulin Independent (NIDDM).
Malangizo
kapangidwe ka zhk
kaphatikizidwe wa lcd - acetyl CoA carboxylase.
Enzyme iyi imayang'aniridwa ndi angapo
njira.
Kuyambitsa / kudzipatula
enzyme subunit zovuta. Mu
mawonekedwe a acetyl CoA carboxylase
zikuyimira maofesi osiyana,
lirilonse lomwe lili ndi 4 zogonjera.
Woyambitsa enzyme ndi citrate. Zimalimbikitsa
kuphatikiza kwa maofesi, chifukwa
Pomwe ntchito ya enzyme imawonjezeka
. Inhibitor-Palmitoyl-CoA. Amayitana
kudzipatula kovuta ndi kuchepa
ntchito ya enzyme.
Phosphorylation / Dephosphorylation
acetyl CoA carboxylase. Mu
dziko la postabsorption kapena
ntchito zolimbitsa thupi
adrenaline kudzera adenylate cyclase
makina amayatsidwa ndi prokinase A ndi
tsitsani phokoso lothandizidwa ndi subunit phosphorylation
acetyl CoA carboxylase. Phosphorylated
enzyme imagwira ntchito ndipo kuphatikiza kwamafuta
ma acid amasiya.
Absorbent
nthawi insulin imayambitsa phosphatase,
ndi acetyl-CoA carboxylase imalowa
dephosphorylated boma. Kenako
motsogozedwa ndi citrate kumachitika
polymerization of the protomers a enzyme, ndipo
amakhala wakhama. Kuphatikiza pa kuyambitsa
enzyme, citrate imachita ina
ntchito mu kapangidwe ka LCD. Absorbent
nthawi mu mitochondria maselo a chiwindi
amadziunjikira citrate, momwe
zotsalira za acyl zimatengedwera kupita nazo
cytosol.
Malangizo
Mitengo ya id-oxidation.
Njira ya id-oxidation-metabolic,
zolumikizidwa zolimba ndi ntchito ya CPE ndi yonse
njira zamatsenga. Chifukwa chake kuthamanga
yoyendetsedwa ndi kufunikira kwa khungu kwa
mphamvu i.e. malinga ndi kuchuluka kwa ATP / ADP ndi NADH / NAD, komanso kuchuluka kwa CPE ndi
njira yodziwika ya catabolism. Kuthamanga
β-oxidation mu zimakhala zimatengera kupezeka
gawo lapansi, i.e.
pa kuchuluka kwamafuta
ma acid omwe amalowa mu mitochondria.
Kulimbikitsa Mafuta Aulere Acid
m'magazi amadzuka pakuyambitsa
lipolysis mu adipose minofu pa kusala
mchikakamizo cha glucagon komanso munthawi yakuthupi
ntchito motsogozedwa ndi adrenaline. Mwa awa
mafuta acids amakhala
gwero lalikulu lamphamvu
chifukwa cha minofu ndi chiwindi,
Ma β-oxidations amapangidwa ndi NADH ndi acetyl-CoA zoletsa
pyruvate dehydrogenase zovuta.
Kusintha kwa mapangidwe a pyruvate
kuyambira glucose mpaka acetyl-CoA amachepetsa.
Ma metabolites apakati amadziunjikira
glycolysis ndipo, makamaka, shuga-6-phosphate.
Glucose-6-phosphate amaletsa hexokinase
chifukwa chake amataya mtima
kugwiritsa ntchito shuga pang'onopang'ono
glycolysis. Chifukwa chake, wamkulu
kugwiritsa ntchito lcd ngati gwero lalikulu
mphamvu mu minofu minofu ndi chiwindi
timasunga shuga m'matumbo amitsempha ndipo
maselo ofiira amwazi.
Mlingo wa id-oxidation nawonso
zimatengera ntchito ya enzyme
carnitine acyltransferases I.
Mu chiwindi, enzyme iyi imaletseka.
malonyl CoA, chinthu chopangidwa
ndi biosynthesis wa lcd. Mu nyengo ya mayamwa
glycolysis imayikidwa m'chiwindi ndipo
Kupanga kwa acetyl-CoA kumawonjezeka
kuchokera ku pyruvate. Choyamba kaphatikizidwe
kutembenuka kwa lcd kwa acetyl-CoA kukhala malonyl-CoA.
Malonyl-CoA ikuletsa the-oxidation wa lcd,
angagwiritsidwe ntchito kaphatikizidwe
mafuta.
Maphunziro
malonyl-CoA kuchokera ku acetyl-CoA-yoyang'anira
zimachitika biosynthesis lcd. Choyamba
kaphatikizidwe ka lcd wa acetyl-CoA kuti
malonyl CoA. Enzyme yothandizira
izi (acetyl Coa carboxylase),
a gulu la ligases. Ali
womangika biotin. Poyamba
co2 mgwirizano wogwira magawo
chimamangirira kwa biotin chifukwa cha mphamvu
ATP, mu gawo 2 COO- idasamutsidwa
pa acetyl-CoA kupanga malonyl-CoA.
Acetyl CoA Carboxylase Enzyme Ntchito
amawona kuthamanga kwa zonse zotsatira
kaphatikizidwe zimachitika lc
citrate imayendetsa enzyme mu cytosol
acetyl CoA carboxylase. Malonyl CoA mu
kenako tikulephera kusamutsa okwera
mafuta acids kuchokera ku cytosol kupita ku matrix
mitochondria zoletsa ntchito
kunja acetyl CoA: carnitine acyltransferase,
potembenuza kukhathamiritsa kwa kukwera kwambiri
mafuta acids.
Acetyl-CoA Oxaloacetate →
HS-CoA Citrate
HSCOA ATP Citrate → Acetyl-CoA ADP Pi Oxaloacetate
Acetyl-CoA
mu cytoplasm amagwiritsa ntchito gawo loyambira
mu kapangidwe ka lcd, ndi oxaloacetate mkati
cytosol ikuchitika masinthidwe mkati
zotsatira zake zomwe pyruvate imapangidwa.
Cholesterol biosynthesis
Cholesterol biosynthesis imapezeka mu endoplasmic reticulum. Gwero la maatomu onse a kaboni mu molekyulu ndi acetyl-SCoA, omwe amachokera kuno kuchokera ku mitochondria mu citrate, monga momwe amapangira mafuta acids. Cholesterol biosynthesis imadya mamolekyulu 18 a ATP ndi mamolekyulu 13 a NADPH.
Kupangidwe kwa cholesterol kumachitika m'njira zoposa 30, zomwe zimatha kukhala m'magawo angapo.
1. kaphatikizidwe ka mevalonic acid.
Zotsatira ziwiri zoyambilira zimagwirizana ndi zomwe ketogenesis zimachita, koma pambuyo pa kapangidwe ka 3-hydroxy-3-methylglutaryl-ScoA, puloteni imalowa hydroxymethyl-glutaryl-ScoA reductase (HMG-SCOA reductase), ndikupanga mevalonic acid.
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