Cholesterol biosynthesis da ilimin halittar jikinta - Ciwon sukari
Ba tare da wata shakka ba, cholesterol shine mafi kyawun sananniyar maganin cutar farin jini ga jama'a; hakan sananne ne saboda babban hulda tsakanin cholesterol hawan jini da yawaitar cututtukan zuciya. Ba a kula da mahimmancin mahimmancin ƙwayar cholesterol a matsayin ɓangaren membranes tantanin halitta kuma a matsayin mai ƙaddara wa kwayoyin steroid da acid bile. Cholesterol ya zama dole ga dabbobi da yawa, gami da mutane, amma kasancewar sa a abincin dabbobi shine ba na tilas ba ne - kwayoyin jikinsu da kansu suna iya hada shi daga hanyoyin sauki.
Tsarin wannan kwalaben carbon-27 suna nuni ga hanya mai rikitarwa don tasirin halittarsa, amma dukkanin kwayoyin carbon dinsa ana samar dasu ne ta hanyar tsari guda daya - acetate. Kayayyakin mafi mahimmancin tsaka-tsakin yanayi daga acetate zuwa cholesterol, sune farkon abubuwan da yawa na lipids na halitta, kuma hanyoyin da ke tattare da tonon sililin sunadarai iri ɗaya ne a cikin hanyoyin hanyoyin rayuwa.
Za mu fara ne ta hanyar nazarin matakan farko na hanyoyin da ake kira cholesterol biosynthesis daga acetate, sannan mu tattauna batun jigilar cholesterol ta hanyar jini, shakar kwayoyin halitta, tsarin kwayar cholesterol na yau da kullun, da kuma ka'idoji a lokuta masu rikicewar ko ɗaukar sufuri. Sannan muna duban sauran abubuwanda suka fito daga cholesterol, kamar bile acid da hormones steroid. A ƙarshe, bayanin irin hanyoyin da ake amfani da su na halittar halittar halittu masu yawa - abubuwan da ke haifar da toshewar abubuwan haɗin keɓaɓɓu, waɗanda a cikinsu akwai matakan farko da ake amfani da su a cikin kwayar cholesterol, za su ba da kwatancin ƙawancewar rashin daidaituwa ta rashin ƙwaƙwalwar ungulu a biosynthesis.
Ana samar da cholesterol daga acetyl-CoA a matakai hudu
Cholesterol, kamar silsila mai kitse mai tsawo, an yi shi ne daga acetyl-CoA, amma tsarin haɗuwa gaba ɗaya ya bambanta. A cikin gwaje-gwajen farko, an saka alamar acetate tare da 14 C ko dai a methyl ko carbon carbon carbon zarra a cikin abincin dabbobi. Dangane da rarraba lakabin a cikin cholesterol da aka ware daga rukuni biyu na dabbobi (Fig. 21-32), an bayyana matakan enzymatic na choroerol biosynthesis.
Hoto 21-32. Tushen carbon atoms na cholesterol. An gano shi yayin gwaje-gwajen ta amfani da acetate na rediyoakti mai alama tare da carbon methyl (baƙi) ko carbon carbonl (ja). A cikin tsarin haɗin gwiwa, ana nuna zobba da haruffa A zuwa D.
Maganin yana faruwa a matakai hudu, kamar yadda aka nuna a cikin siffa. 21-33: (1) kwararar filaye uku na acetate don samar da tsaka-tsakin carbon-mevalonate guda shida, (2) sauyawar mevalonate zuwa ginin da ke kwance, (3) polymerization na kashi biyar na carbon carbon-squalene, (4) cyclization of squalene to form zobba huɗu na steroid nucleus, tare da jerin canje-canje (hadawan abu, ƙonawa ko ƙaura daga ƙungiyoyin methyl) tare da ƙirƙirar cholesterol.
Hoto 21-33. Cikakken hoto na cholesterol biosynthesis. An tattauna matakai huɗu na haɗawa cikin rubutun. Abubuwan fashewar Isoprene a cikin squalene suna alama ta layin ja da aka shuɗi.
Matsayi (1). Kira na mevalonate daga acetate. Mataki na farko na cholesterol biosynthesis yana haifar da ƙirƙirar samfurin matsakaici mevalonate (Siffa 21-34). Kwayoyin Acetyl CoA guda biyu sun yarda su bayar da acetoacetyl CoA, wanda ya yarda da kwayoyin acetyl CoA na uku don samar da fili na shida na carbon β-hydroxy-β-methylglutaryl-CoA (HM G -CoA). Waɗannan halayen biyu na farko ana ɗaukar su ne thiolase da NM G -CoA synthase, bi da bi. Cytosolic NM G-CoA synthase Wannan tafarki na rayuwa ya banbanta da mitochondrial isoenzyme, wanda ke daukar nauyin NM G -CoA yayin kirkirar jikin ketone (duba siffa 17-18).
Hoto 21-34. Samuwar mevalonate daga acetyl-CoA. An samo asalin C-1 da C-2 mevalonate daga acetyl-CoA a cikin ruwan hoda.
Halin na uku yana iyakance saurin dukkan ayyukan. A ciki, an rage NM G -CoA zuwa mevalonate, wanda kowane ɗayan kwayoyin NА D PH yana samar da electrons guda biyu. HMG-CoA reductase - haɗin membrane furotin na santsi na ER, yana aiki, kamar yadda zamu gani daga baya, a matsayin babban mahimmancin tsari na hanyoyin metabolic na samuwar cholesterol.
Matsayi (2). Canza mevalonate zuwa kashi biyu na iso Loose. A mataki na gaba na tasirin cholesterol, ana canza rukuni uku na phosphate daga kwayoyin ATP zuwa mevalonate (Fig. 21-35). Boundungiyar phosphate ta ɗaure zuwa rukunin hydroxyl a C-3 mevalonate a cikin tsaka-tsaki na 3-phospho-5-pyrophosphomevalonate ƙungiyar mai kyau ce ta barin, a mataki na gaba duka waɗannan phosphates da kuma ƙungiyar masu haɗarin carbonxyl, suna samar da haɗin gwiwa biyu a cikin samfurin carbon-∆ 3 -kadaiturkine pyrophosphate. Wannan shi ne farkon na biyu dake cikin isoprenes - manyan masu shiga cikin kwayar cholesterol. Isomerization na Δ 3 -isopentenylpyrophosphate yana ba da kashi na biyu na lantarki dimpleylallyl pyrophosphate. Sakamakon kira na isopentenyl pyrophosphate a cikin cytoplasm na sel tsiro yana faruwa ne bisa hanyar da aka bayyana anan. Koyaya, shuka chloroplasts da ƙwayoyin cuta da yawa suna amfani da hanyar mai zaman kanta daga mevalonate. Ba a samun wannan hanyar ta madadin dabbobi ba, saboda haka yana da kyau yayin ƙirƙirar sabbin ƙwayoyin rigakafi.
Hoto 21-35. Canza mevalonate cikin katangar isoprene ta kunna. Unitsungiyoyi shida waɗanda aka kunna suna haɗuwa don ƙirƙirar squalene (duba Hoto 21-36). Leavingungiyoyin da ke barin 3-phospho-5-pyrophosphomevalonate an fifita su da ruwan hoda. A cikin kusoshin murabba'i mai matsakaiciyar magana ce.
Matsayi (3). Dirƙiri shida na rabe-raben rabe rabuwa don ƙirƙirar squalene. Isopentenyl pyrophosphate da dimethylallyl pyrophosphate yanzu suna fuskantar ɗaukar kai-da-wutsiya, a cikin ɗayan nau'in pyrophosphate yana motsawa da nau'ikan sarkar carbon 10 - geranyl pyrophosphate (Siffa 21-36). (Pyrophosphate yana riƙe da kai.) Geranyl pyrophosphate yana ɗaukar ɗaukar biyun-zuwa-wutsiya tare da isopentenyl pyrophosphate, da kuma nau'ikan carbon-15 mai tsaka-tsakin yanayi farnesyl pyrophosphate. A ƙarshe, kwayoyin halitta guda biyu na farnesyl pyrophosphate suna haɗuwa “kai zuwa kai”, an cire rukunin phosphate biyu - an kafa su squalene.
Hoto 21-36. Tsarin squalene. Tsarin squalene wanda ke ɗauke da tarin zarra 30 yana faruwa yayin ɗaukar iskoki masu ƙarfi waɗanda keɓaɓɓu na carbon (carbon-carbon) guda biyar.
Sunaye gama gari don waɗannan tsaka-tsakin sun fito ne daga sunayen asalin inda daga farkon aka keɓe su. Geraniol, wani yanki ne na mai mai fure, yana da dandano geranium, kuma farnesol, wanda aka samo a launuka na Acacia farnesa, yana da fure mai ƙanshin kwari. Odoaukar tsire-tsire da yawa na halitta suna cikin abubuwan da aka gina daga ɓoyayyen abubuwan ɓoyayyen. Squalene, farkon ware daga hancin yanyan shark (nau'in squalus), ya kunshi kwayoyin zarra guda 30: atoms 24 a cikin babban sarkar da kuma zarra shida na karfe.
Matsayi (4). Canza squalene zuwa zobba huɗu na sitiriyo sitiriyo. A cikin ɓaure. 21-37 an bayyane a fili cewa sarkar squalene, da kuma sterols - cyclic. Dukkanin motocin suna da zoben da ke da hudu wadanda ke samar da sinadarin sitiriyo, kuma dukkansu giya ne da kungiyar hydroxyl a at C-3 atom, saboda haka sunan Ingilishi. A karkashin aiki squalene monooxygenase kwayar oxygen guda ɗaya daga O an ƙara zuwa ƙarshen sarkar squalene 2 kuma an samar da mayukan abinci. Wannan enzyme shine wani abu mai hade-mai aiki tare da oxidase (ƙara 21-1), NADPH yana rage wani iskar oxygen daga O 2 zuwa H2 O. Samfuran Samfura biyu squalene-2,3-epoxide An tsara shi ta hanyar abin da zai iya canzawa ya zama zai iya juyar da silsila mai hade da sikirin. A cikin sel dabbobi, wannan hawan keke yana haifar da samuwar lanosterol wanda ya ringsunshi halaye huɗu na halayyar sitiriyo. Sakamakon haka, ana canza lanosterol zuwa cholesterol ta hanyar jerin halayen kusan 20, wanda ya haɗa da ƙaurawar wasu rukunin baƙin ƙarfe da kuma cire wasu. Bayanin wannan kyakkyawar hanyar biosynthesis, ɗayan mafi wuya tsakanin sanannu, Conrad Bloch, Theodore Linen, John Cornfort da George Popiak ne a ƙarshen shekarun 1950.
Hoto 21-37. Closulli ringi ya zama layi ɗaya daga cikin matattarar steroid. Mataki na farko yana amfani da oxidase tare da aiki mai cakuda (monooxygenase), wanda babban kwas ɗin shine N AD PH. Samfurin shine mai ɗan iska mai ƙarfi, wanda a cikin mataki na gaba yana hawa cyclizes don samar da ƙwayar steroid. Sakamakon karshe na waɗannan halayen a cikin ƙwayoyin dabbobi shine cholesterol; a wasu kwayoyin halitta sterols kaɗan daban-daban daga garesu ana kafa su.
Cholesterol wani nau'in sitiri ne na sifofin sel, tsirrai, fungi da protists suna samar da wasu nau'ikan sterols iri iri.
Suna amfani da hanyar haɗin guda ɗaya zuwa squalene-2,3-epoxide, amma sannan hanyoyin suna rarrabewa kaɗan, kuma an kirkiro wasu sterols, kamar sigmasterol a cikin tsirrai da yawa da ergosterol a cikin fungi (Fig. 21-37).
Misali Kudaden 211 na Kuzarin kuzari na Tsarin Cocin Tsirrai
Menene farashin kuzarin (wanda aka bayyana azaman kwayoyin ATP) don haɗawar kwaya ɗaya ta squalene?
Magani. A cikin kira na squalene daga acetyl-CoA, ana amfani da ATP ne kawai a matakin lokacin da aka canza mevalonate zuwa wani abu mai gudana na isolorida squalene precursor. Ana buƙatar kwayoyin halitta guda shida na isolorida don gina ƙwayoyin squalene, kuma ana buƙatar kwayoyin halittar ATP guda uku don samar da kowace ƙwayar da aka kunna. Gaba ɗaya, ana amfani da kwayoyin ATP guda 18 a kan kwayar halitta ta squalene.
Abubuwa na cholesterol a jiki
A cikin layi, ana amfani da sinadarin cholesterol mai yawa a cikin hanta. Wasu daga cikin cholesterol da aka kera a wurin an hade su cikin membranes na hepatocytes, amma ana fitar dashi galibi daya daga cikin nau'ikan ukunsa: biliary (bile) cholesterol, bile acid ko cholesterol esters. Bile acid tsarfinsu yana da sinadarin hydrophilic na cholesterol, waɗanda suke haɗu a cikin hanta kuma suna ba da gudummawa ga narkewar lipids (duba Hoto 17-1). Esters na cholesterol kafa a cikin hanta ta hanyar aiki acyl-CoA-cholesterol-acyltransferase (ACAT). Wannan enzyme yana ɗaukar juyar da ragowar acid ɗin mai narkewa daga coenzyme A zuwa rukunin hydroxyl na cholesterol (Fig. 21-38), yana canza cholesterol zuwa wani nau'in hydrophobic. Cholesterol esters a cikin sirrin barbashi ana jigilar su zuwa wasu kyallen takarda ta amfani da cholesterol ko adana a cikin hanta.
Hoto 21-38. Kira na cholesterol esters. Ethevidence yana sanya cholesterol wani tsari mai ma'adinan hydrophobic don adanawa da sufuri.
Cholesterol ya zama dole ga dukkanin kyallen kwayoyin halittar dabba don haɓakar membranes, kuma wasu gabobin (alal misali, glandar adrenal da gland goruba) suna amfani da cholesterol a matsayin abubuwanda zasu iya zama farkon kwayoyin hormones (ana tattauna wannan a ƙasa). Cholesterol shima abu ne na abubuwanda ake sarrafawa na bitamin D (duba Hoto 10-20, v. 1).
Cholesterol da sauran lipids suna ɗauke da ƙwayoyin plasma lipoproteins
Cholesterol da cholesterol esters, kamar triacylglycerols da phospholipids, a zahiri basa cikin ruwa, kodayake, dole ne su motsa daga nama wanda aka haɗasu zuwa kyallen inda za'a adana su ko cinye su. Suna dauke da jini ta hanyar jini plasma lipoproteins - hadaddun sunadarai na ƙwaƙwalwar ƙwayoyin cuta (bazarba) tare da phospholipids, cholesterol, cholesterol esters da triacylglycerols suna cikin waɗannan hadaddun a cikin haɗuwa daban-daban.
Apolipoproteins (“apo” yana nufin furotin da ba shi da wadataccen furotin da kanta) haɗe tare da lipids don samar da gutsuttsuran ƙwayoyin lipoprotein da yawa - abubuwa masu tsinkaye tare da lipids na hydrophobic a tsakiya da kuma sarƙoƙin hydrogen na amino acid a farfajiya (Fig. 21-39, a). Tare da haɗuwa da yawa na abubuwan samar da ƙwayoyin lipids da sunadarai, ana ƙirƙirar barbashi na abubuwa daban-daban - daga chylomicrons zuwa manyan ƙwayoyin lipoproteins. Za'a iya raba waɗannan barbashi ta hanyar ƙwayar cuta (Table 21-1) kuma ana iya gani da gani ta amfani da ƙwaƙwalwar lantarki (Figure 21-39, b). Kowane juzu'i na lipoproteins yana aiwatar da takamaiman aiki, wanda aka ƙaddara ta wurin aikin haɗin gwiwa, abubuwan lipid da abun cikin apolipoprotein. Akalla apolipoproteins 10 daban-daban an samo su a cikin jini na jini na mutum (Table 21-2), wanda ya bambanta a cikin girman, halayen tare da takamaiman ƙwayoyin cuta, da kuma rarrabe halaye a cikin azuzuwan daban-daban na lipoproteins. Wadannan abubuwan gina jiki suna aiki azaman siginar abubuwa masu karkatar da sinadarin lipoproteins zuwa takamaiman kyallen takarda ko kunna enzymes wadanda suke aiki akan abubuwan lipoproteins.
Tebur 21-1. Hakkin dan adam na plasma lipoproteins
Abin da ke ciki (taro, kashi,%)
r = 513,000). Wani kashi na LDL yana dauke da kwayoyin kusan 1,500 kwayoyin cholesterol esters, a kusa da zuciyar akwai harsashi na kwayoyin 500 na cholesterol, 800 kwayoyin phospholipids da kwayoyin daya na apoB-100. b - azuzuwan huɗu na lipoproteins, wanda ake iya gani tare da microscope na lantarki (bayan bayyanar mara kyau). Hannun agogo, farawa daga siffa ta hagu na sama: chylomicrons - tare da diamita na 50 zuwa 200 nm, PL O NP - daga 28 zuwa 70 nm, HDL - daga 8 zuwa 11 nm, da LDL - daga 20 zuwa 55 nm. Ana ba da kaddarorin na lipoproteins a cikin tebur. 21-2.
Chylomicrons, ake magana a kai a cikin Sec. 17, matsar da abincin triacylglycerols daga hanji zuwa wasu kyallen takarda. Waɗannan sune mafi yawan lipoproteins, suna da mafi ƙarancin yawa kuma mafi girman abubuwan haɗin dangi na triacylglycerols (duba siffa 17-2). Chylomicrons an haɗe shi a cikin ER na sel wanda ke a cikin ƙananan hanji, sannan ya motsa ta cikin tsarin lymphatic kuma ya shiga cikin jini ta hanyar jijiyar subclavian ta hagu. Chylomicron apolipoproteins sun ƙunshi apoB-48 (na musamman don wannan aji na lipoproteins), apoE da apoC-II (Table 21-2). AroC-II yana kunna lipprotein lipase a cikin capillaries na adipose nama, zuciya, kasusuwa da lactating mammary gland, yana tabbatar da yaduwar kitse mai kyauta a cikin wadannan kyallen. Don haka, chylomicrons suna canza abinci mai kitse zuwa kyallen takarda, inda za'a cinye su ko adana su a matsayin mai (Fig. 21-40). Shafin Chylomicron (galibi an kubutar dashi daga triacylglycerols, amma har yanzu yana dauke da cholesterol, apoE da apoB-48) ana jigilar su ta hanyar jini zuwa hanta. A cikin hanta, masu karɓar rataye suna ɗaure zuwa apoE da ke cikin ragowar chylomicron kuma suna sulhunta shansu ta hanyar endocytosis. A cikin hepatocytes, waɗannan sharan sun saki cholesterol da suke ɗauke dasu kuma an lalata su cikin lysosomes.
Tebur 21-2. Plaan Adam ɗin na lilapropoin apolipoproteins
Aiki (idan an sani)
Yana kunna L CAT, yana ma'amala da mai jigilar ABC
Yana hana L CAT
Yana kunna L CAT, jigilar cholesterol / sharewa
Yana ɗaure zuwa mai karɓar LDL
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Zai fara share VLDL da sharan chylomicron
Lokacin da abinci ya ƙunshi mafi ƙoshin mai wanda ba shi da za a iya amfani da shi yanzu a matsayin mai, sai su juye zuwa triacylglycerols a cikin hanta, wanda ke samar da juzu'ai tare da takamaiman ƙwayoyin cuta lowpo yawa na lipoproteins (VLDL). Hakanan ana iya canza carbohydrates mai yawa a cikin hanta kuma za'a iya canza su zuwa triacylglycerols kuma a fitar dashi azaman VLDL (Fig. 21-40, a).Baya ga triacylglycerols, ragowar VLDL ya ƙunshi adadin adadin cholesterol da cholesterol esters, kazalika apoB-100, apoC-1, apoC-II, apoC-III da apoE (Table 21-2). Wadannan lipoproteins kuma ana jigilar su ta jini daga hanta zuwa tsoka da tsopose nama, inda, bayan an kunna lipoprotein lipase ta apo-C II, ana sakin mai mai kyauta daga triacylglycerols na juzu'in VLDL. Adipocytes suna kama kitse mai kitse, sake juya su cikin triacylglycerols, waɗanda aka adana a cikin waɗannan ƙwayoyin a cikin nau'in lipid inclusions (saukad da), myocytes, akasin haka, nan da nan oxidize mai acid don samar da makamashi. Yawancin sharan VLDL an cire su daga wurare dabam dabam ta hanyar hepatocytes. Samun su, mai kama da shaye shaye na chylomicrons, ana yin sulhu dashi ta hanyar masu karɓa kuma ya dogara da kasancewar apoE a cikin ragowar VLDL (a ƙara. 21-2, an bayyana alaƙar da ke tsakanin apoE da cutar ta Alzheimer).
Hoto 21-40. Lipoproteins da jigilar lipid, da - lipids ana ɗaukar su ta hanyar jini a cikin nau'i na lipoproteins, wanda aka haɗu cikin ɓangarori da yawa tare da ayyuka daban-daban da abubuwan daban-daban na sunadarai da lipids (shafin 21-1, 21-2) kuma yayi dace da yawa na waɗannan gutsutsuren. Ana tattara abubuwan samar da abinci a cikin chylomicrons, yawancin abubuwan triacylglycerols da ke ciki ana fitar dasu ta hanyar lipoprotein cikin adipose da ƙwayar tsoka a cikin capillaries. Shafin Chylomicron (wanda ya ƙunshi yawancin furotin da cholesterol) hepatocytes ne suka kama su. Ana samar da lipids na yau da kullun da cholesterol daga hanta zuwa adipose da ƙashin tsoka a cikin hanyar VLDL. Addamar da lipids daga VLDL (tare da asarar wasu apolipoproteins) sannu a hankali suna canza VLDLP zuwa LDL, wanda ke ba da ƙwayar cholesterol zuwa ƙwayoyin cuta na extrahepatic ko mayar da shi cikin hanta. Hankalin yana ɗaukar ragowar VLDL, LDL da ragowar chylomicrons ta endocytosis mai karɓa. Cutar yawan ƙwayoyin cuta a cikin ƙwayoyin cuta na extrahepatic ana jigilar su zuwa hanta a cikin hanyar LDL. A cikin hanta, wani ɓangare na cholesterol ya juya ya zama salts na bile. b - samfuran jini na jini wadanda aka ɗauka bayan yunwa (hagu) da kuma bayan cin abinci tare da mai mai yawa (dama). Chylomicrons wanda aka kirkira ta hanyar cin abinci mai mai mai ba shi ya ba wa plasma kwatankwacin madara ga madara.
Tare da asarar triacylglycerols, ana canza wani yanki na VLDL zuwa ragowar VLDL, wanda kuma ake kira matsakaici mai yawa na lipoproteins (VLDL), ƙarin cire triacylglycerols daga VLDL yana ba low lipoproteins (LDL) (tab. 21-1). Rashin LDL, wanda yake da arziki sosai a cikin cholesterol da cholesterol esters, sannan kuma ya ƙunshi apoB-100, yana canja wurin cholesterol zuwa ƙwayoyin cuta na extrahepatic waɗanda ke ɗaukar takamaiman masu karɓa na gane apoB-100 akan membrans na plasma. Waɗannan masu karɓar ra'ayoyin suna daidaita yanayin tasirin cholesterol da estlesterol (kamar yadda aka bayyana a ƙasa).
Karin 21-2.ApoE alleles ƙayyade abin da ya faru na cutar Alzheimer
A cikin 'yan Adam, akwai bambance-bambancen halaye guda uku (alleles uku) na hanyar gabatarwar apolipoprotein E. Daga cikin apoE alleles, APOEZ allele shine ya zama ruwan dare a cikin mutane (kusan 78%), APOE4 da APOE2 alleles sune 15 da 7%, bi da bi. APOE4 allele musamman halayyar mutane ne da ke fama da cutar ta Alzheimer, kuma wannan alaƙar tana ba da damar faɗi abubuwan da ke faruwa game da cutar tare da yuwuwar cutar. Mutanen da suka gaji APOE4 suna da haɗarin cutar haɓaka cutar Alzheimer. Mutane homozygous na APOE4 sune sau 16 mafi kusantar bunkasa cutar, matsakaicin shekarun waɗanda suka kamu da rashin lafiya kusan shekaru 70 ne. Ga mutanen da suka gaji kofi biyu na AROEZ, akasin haka, matsakaicin shekarun cutar Alzheimer ya wuce 90.
Har yanzu ba'a san tushen kwayoyin don haɗuwa tsakanin apoE4 da cutar Alzheimer ba. Bugu da ƙari, har yanzu ba a san yadda apoE4 zai iya tasiri ga ci gaban igiyar amyloid ba, waɗanda a bayyane suke ainihin sanadin cutar ta Alzheimer (duba siffa 4-31, aya 1). Abubuwan da aka ɗauka suna ba da hankali ga yiwuwar apoE a cikin inganta tsarin cytoskeleton na neurons. Sunadaran apoE2 da apoEZ sun daure da wasu sunadarai da suka danganci microtubules na neurons, yayin da apoE4 ba a ɗaure ba. Wannan na iya hanzarta mutuwar ƙwaƙwalwa. Duk abin da wannan tsari zai iya zama ya kasance, waɗannan abubuwan lura suna ba da bege don fadada fahimtarmu game da ayyukan nazarin halittu na apolipoproteins.
Nau'in nau'in lipoproteins - yawaitar lipoproteins (HDL), wannan rukunin an samar dashi ne a hanta da karamin hanji a hanun kananan furotin da ke dauke da sinadarai wadanda suke dauke da sinadarin kwalakwala kadan kuma babu cikakkiyar isasshen cholesterol (Fig. 21-40). Ctionarfin HDL ya ƙunshi apoA-I, apoC-I, apoC-II da wasu apolipoproteins (Table 21-2), kazalika lecithin-cholesterol-acyltransferase (LC AT), wanda ke ɗaukar nauyin cholesterol esters daga lecithin (phosphatidylcholine) da kuma cholesterol (Fig. 21-41). L CAT a farfajiya ta sabon barbashi na HDL yana canza chylomicron cholesterol da phosphatidylcholine da ragowar VLDL zuwa cholesterol esters, waɗanda suka fara samar da nucleus, suna canza sabon tsarin disgiyar HDL zuwa barbashi na HDL mai girma. Wannan arzikin mai dauke da sinadarin cholesterol din sai a koma hanta, a inda ake “barkewar cholesterol”, wasu daga cikin wannan kwalastin ana canza su cikin gishiri.
Hoto 21-41. Halin da aka kama da lecithin-cholesterol-acyltransferase (L CAT). Wannan enzyme yana nan akan saman barbashin HDL kuma an kunna shi ta hanyar apoA-1 (ƙunshi juzu'in HDL). Cholesterol esters suna tarawa a cikin sabon ƙwayoyin HDL da aka kirkira, tare da juya su zuwa HDL masu girma.
Ana iya daukar HDL a cikin hanta ta hanyar endocytosis na mai karɓa, amma aƙalla wasu daga cikin ƙwayoyin HDL ana ba da su ga wasu ƙwayoyin ta wasu hanyoyin. Abubuwan HDL na iya ɗaure zuwa SR - BI mai karɓar ƙwayar cuta akan ƙwayar plasma na sel hanta da kuma a cikin ƙwayar steroidogenic kamar glandar adrenal. Wadannan masu karɓar ba su sulhunta da endocytosis ba, amma sashi da zaɓi na canja wurin cholesterol da wasu ƙananan leɓo daga cikin ƙunshin HDL cikin tantanin halitta. Fraarfin HDL ɗin '' wanda ya lalace 'sannan ya sake shiga cikin jini, inda ya haɗa da sabon ɓangarorin lipids daga ƙwayoyin chylomicrons da ragowar VLDL. Har ila yau, HDL guda ɗaya na iya kama cholesterol da aka adana a cikin ƙwayoyin cuta na extrahepatic kuma canza shi zuwa hanta ta juyawa da safarar cholesterol (Siffa 21-40). A ɗayan bambance bambancen jigilar jigilar kayayyaki, hulɗar da sakamakon HDL tare da masu karɓar SR-BI a cikin ƙwayoyin cholesterol masu haɓaka abubuwa masu ƙarfi na cholesterol daga farfajiyar tantanin halitta zuwa cikin barbashi na HDL, wanda sannan canja wurin cholesterol zuwa hanta. A cikin wani canji na jigilar kayayyaki a cikin ƙwayar cholesterol mai yawan gaske, bayan ɓarnatar da HDL, apoA-I tana hulɗa da mai ɗaukar jigilar mai, furotin ABC. ApoA-I (kuma mai yiwuwa HDL) yana karɓar endocytosis, sannan kuma an sake ɓoye shi, an ɗora shi da cholesterol, wanda ke hawa zuwa hanta.
Protein ABC1 wani bangare ne na babban dangin dillalai da magunguna da yawa, wadannan masu jigilar jigilar wasu lokuta ana kiransu jigilar masu ABC, tunda duk suna ɗauke da katako masu ɗaukar nauyin ATP (ATP - cassettes cassettes), suna kuma da yanki biyu na gado tare da helices shida na tunawa (duba babi. . 11, aya ta 1). Wadannan sunadarai suna canza wurin ion da yawa, amino acid, bitamin, hormones na steroid da kuma salts na bile ta hanyar membran plasma. Wani wakilin wannan dangin mai ɗauka shi ne furotin na CFTR, wanda, tare da cystic fibrosis, ya lalace (duba ƙara. 11-3, aya 1).
Kwayoyin cholesterol suna shiga cikin sel ta hanyar endocytosis na mai karba-karba
Kowane ƙwayar LDL a cikin jini yana ƙunshe da apoB-100, wanda keɓaɓɓun sunadarai masu karɓa na daskararru -Masu karɓa LDL a kan membrane na sel wadanda suke buƙatar kama cholesterol. Hanyar LDL ga mai karɓar LDL tana farawa da endocytosis, saboda shine LDL da mai karɓar sa ya shiga cikin sel a cikin mahaɗin (Fig. 21-42). Osarshen ƙarshen yana haɗuwa tare da lysosome, wanda ya ƙunshi enzymes wanda ke inganta ƙwayoyin cholesterol, yana saki cholesterol da acid mai a cikin cytosol. ApoB-100 daga LDL kuma yana rushewa don samar da amino acid wanda aka tono cikin cytosol, amma mai karɓa na LDL yana guje wa lalata kuma ya sake komawa zuwa farfaɗiyar tantanin halitta don sake shiga cikin abubuwan LDL. ApoB-100 kuma yana nan a cikin VLDL, amma yanki mai ɗaukar nauyin ba shi da ikon ɗaure wa mai karɓa na LDL; sauyawar VLDLP zuwa LDL yana sanya yanki mai riƙe mai riƙewa zuwa apoB-100 mai sauƙi. Michael Brown da Joseph Goldstein sun yi nazarin wannan tafarkin na cholesterol na hanyar safarar jini da kuma abubuwan da ke shigowa dashi.
Michael Brown da Joseph Goldstein
Hoto 21-42. Kama cholesterol ta hanyar endocytosis na mai karɓa-karɓa.
Cholesterol, wanda yake shiga sel ta wannan hanyar, ana iya haɗa shi cikin membranes ko kuma ya sake kasancewa a cikin ACAT (Fig. 21-38) don adanawa a cikin ƙwayoyin cytosol na ciki. Lokacin da ake samun isasshen cholesterol a cikin kashi na LDL na jini, ana hana tara yawan tasirin cholesterol ta hanyar rage adadin kwayar sa.
Mai karɓar LDL kuma yana ɗaure wa apoE kuma yana taka muhimmiyar rawa a cikin ci gaba da ragowar chylomicrons da ragowar VLDL ta hanta. Koyaya, idan masu karɓar LDL basu samu ba (kamar, misali, a cikin ƙwayar motsi tare da ƙwayar mai karɓa ta LDL), ragowar VLDL da chylomicrons har yanzu hanta suna ɗauke da su, kodayake LDL bai karɓa ba. Wannan yana nuna kasancewar tsarin ajiyar taimako don endocytosis mai shiga tsakani na VLDL da ragowar chylomicron. Ofaya daga cikin masu karɓar ajiyar kaya shine furotin LRP (furotin mai karɓa na lipoprotein), wanda ke da alaƙa da masu karɓa na lipoprotein, wanda ya ɗaura nauyin apoE da kuma wasu adadin ligands.
Yawancin matakan cholesterol biosynthesis tsari
Kwayar cholesterol tsari ce mai wahala mai kuzari sosai, saboda haka a bayyane yake cewa jiki yana da fa'ida don samun tsari na daidaita tasirin cholesterol biosynthesis, wanda yake cike adadinsa ban da abin da yake zuwa da abinci. A cikin dabbobi masu shayarwa, an tsara abubuwan sarrafa cholesterol ta hanyar maida hankali ne cikin jiki
cholesterol da hormones glucagon da insulin. Matsayin juyawa na HMG - CoA zuwa mevalonate (Fig. 21-34) yana iyakance saurin a cikin hanyar haɓaka hanyar kirkiro cholesterol (babban mahimmin tsari). HMG - Coa reductase yana daukar nauyin sa. Ina'idar amsawa game da canje-canje a matakan cholesterol yana yin sulhu tsakani ta hanyar ingantacciyar tsarin kayyade fassarar ƙwayar halittar HMG - CoA reductase. Wannan kwayar, tare da wasu kwayoyin halittar sama da 20 wadanda ke haɓaka enzymes waɗanda ke haɗuwa da ɗaukar kwayar cholesterol da kitse mai ƙoshin abinci, ana gudanar da su ta hanyar karamin dangin sunadaran da ake kira sunadarai waɗanda ke hulɗa tare da tsarin sarrafawa na abubuwan gina jiki (SREBP; . Bayan kira, ana gabatar da wadannan sunadarai cikin endoplasmic reticulum. Iyakar abin da yankin SREBP amino-tashar mai narkewa kawai yake azaman mai kunna rikodin amfani da hanyoyin da aka bayyana a Ch. 28 (aya 3). Koyaya, wannan yanki ba shi da damar shiga tsakiya kuma ba zai iya shiga cikin kunna kwayoyin ba muddin ya kasance a cikin ƙwayoyin SREBP. Don kunna fassarar kwayar HMG - CoA reductase da sauran kwayoyin, an raba yankin transcriptionally mai aiki tare da ragowar SREBP ta hanyar kariya ta proteolytic. Lokacin da cholesterol ya yi yawa, sunadaran SREBP basa aiki, an tsaresu akan ER a hadaddun tare da wani sinadarin da ake kira SCAP (SREBP - furotin mai aiki mai aiki) (Fig. 21-43). SCAP ce ke ɗaukar cholesterol da kuma wasu nau'ikan sterols, suna aiki a matsayin firikwensin motar sitiri. Lokacin da matakan sterol suka yi yawa, ƙungiyar ta SCAP - SREBP wataƙila tana ma'amala da wani furotin, wanda yake adana duka hadaddun a cikin ER. Lokacin da matakan sterols a cikin tantanin halitta suka sauka, canjin yanayi a cikin SCAP yana haifar da asarar ayyukan riƙewa, kuma ƙungiyar ta SCAP - SREBP ta ƙaura daga cikin vesicles zuwa ginin Golgi. A cikin hadaddun Golgi, an kare sunadaran SREBP sau biyu ta hanyar kariya daban daban, kashi na biyu wanda yake sakin yanki amino-tashar cikin cytosol. Wannan yanki yana motsawa zuwa tsakiya kuma yana kunna fassarar kwayoyin halitta. Yankin gina jiki na furotin SREBP na amino-tashar yana da ɗan gajeren rabin rayuwa kuma an lalata shi da sauri ta hanyar kariya (duba siffa 27-48, t. 3). Lokacin da matakan sterol ya isa daidai, sakin kariya na wuraren furotin na SR EBP tare da amino terminus yana sake toshewa, kuma lalata garkuwar proteasome na yanki mai aiki yana haifar da saurin rufe asalin kwayoyin.
Hoto 21-43. Kunnawa na SR EBP. SREB P sunadarai suna hulɗa tare da abubuwan sarrafawa ta hanyar launin toka (launin kore), nan da nan bayan kira, an gabatar da su a cikin ER, suna samar da hadaddun tare da S CAP (launi ja) (N da C yana nuna ƙarshen amino da carboxyl ƙarshen sunadarai.) A cikin iyakar S-CAP, SRE BP sunadarai ba su da aiki. Lokacin da matakin sterol din ya ragu, SR EBP-S CAP hadaddun ya yi ƙaura zuwa hadadden ginin Golgi, kuma furotin SR EBP an raba su ta biyu daban-daban. Filin tashar amino acid da aka 'yanta SR EBP yanki yana ƙaura zuwa ga tsakiya, inda yake kunna fassarar ƙwayoyin halittar jini.
Hakanan ana amfani da sinadaran Cholesterol ta wasu hanyoyin da yawa (Fig. 21-44). Ikon ciki na matsakaici ne ta hanyar canjin canjin NM G-CoA reductase. Wannan enzyme yana wanzu a cikin phosphorylated (m) da kuma dishosphorylated (aiki) siffofin. Glucagon yana motsa phosphorylation (inactivation) na enzyme, kuma insulin yana inganta dephosphorylation, yana kunna enzyme kuma yana fifita ƙirar cholesterol. Babban hadaddun ƙwayoyin cholesterol yana kunna ASAT, wanda ke ƙara haɓakar tasirin cholesterol don ajiya. A ƙarshe, babban matakan cholesterol na celluline yana hana jigilar kwayar halitta wanda ke kewaye da mai karɓa na LDL, rage samar da wannan mai karɓa kuma, sabili da haka, haɓaka cholesterol daga jini.
Hoto 21-44. Rea'idar matakan cholesterol yana samar da daidaito tsakanin kira da ɗaukar cholesterol daga abinci. Glucagon yana sauƙaƙe phosphorylation (inactivation) na NM G -CoA reductase, insulin yana inganta dephosphorylation (kunnawa). X - wanda ba a bayyana ƙwayar cholesterol metabolites waɗanda ke motsa proteolysis na NM G -CoA reductase.
Kwayoyin da ba su daidaita ba suna iya haifar da mummunan cuta a cikin mutane. Lokacin da jimlar kwayar cholesterol da cholesterol da aka samu daga abinci ya wuce adadin da ake buƙata don haɗuwar membrane, haɗuwar salts na salula da steroids, tarin abubuwa na cholesterol a cikin tasoshin jini (atherosclerotic plaques) na iya bayyana, yana haifar da toshewar su (atherosclerotic). A cikin kasashe masu arzikin masana'antu, gazawar zuciya ce saboda toshewar jijiyoyin jini wanda shine babban dalilin mace-mace. Haɓaka atherosclerosis yana da alaƙa da hauhawar jini cholesterol kuma musamman tare da ƙwaƙwalwar ƙwayar cuta ta LDL wanda ke jurewa; matakan HDL na jini, akasin haka, zai iya inganta yanayin tasoshin jini.
Tare da hypercholesterolemia na asali (lahani na ƙwayar cuta), matakin cholesterol na jini yana da girma sosai - atherosclerosis mai ƙarfi yana tasowa a cikin waɗannan mutanen da suka riga sun yara. Saboda rashi mai karɓar LDL, isasshen mai karɓa-karɓa-karɓa na LDL cholesterol yana faruwa. Sakamakon haka, ba'a cire cholesterol daga cikin jini ba, yana tarawa kuma yana ba da gudummawa ga ƙirƙirar filayen atherosclerotic. Hadin cholesterol yana ci gaba, duk da yawan kwayar cholesterol a cikin jini, tunda kwalar kwayar kwayar halitta baya iya shiga cikin tantanin halitta don tsara kwayar ta intracellular (Fig. 21-44).Don lura da marasa lafiya da keɓaɓɓen hypercholesterolemia da sauran cututtukan da ke da alaƙa da ƙwaƙwalwar ƙwayar ƙwayar jini, ana amfani da azuzuwan statin. Wasu daga cikinsu ana samun su ne daga asalin halitta, yayin da wasu kuma masana'antun magunguna ke haɗa su. Statins sun yi kama da mevalonate (ƙara 21-3) kuma masu hanawa na NMS-CoA reductase.
Addendum 21-3. MIJINA. Tsarin lipid da halittar mutummutumai
Cutar sankara ta zuciya (CHD) ita ce babban dalilin mace-mace a cikin kasashe masu tasowa. Lalacewar jijiyoyin zuciya wanda ke dauke jini zuwa zuciya yana faruwa ne sakamakon samuwar kitse mai suna atherosclerotic plaques; wadannan filayen suna dauke da sinadarin cholesterol, sunadaran fibrillar, alli, allin platelet, da gutsutsuren sel. A cikin karni na XX. An yi muhawara mai zurfi game da dangantakar tsakanin toshewar jijiya (atherosclerosis) da cholesterol jini. Wadannan tattaunawar da bincike mai zurfi a cikin wannan jagorar sun haifar da haifar da ingantattun magunguna waɗanda ke rage cholesterol.
A cikin shekarar 1913, N.N. Anichkov, sanannen masanin kimiyyar Rasha kuma kwararre a fagen gwaji, ya wallafa wani aiki da ya nuna cewa zomaye suna ciyar da abinci mai wadataccen sinadarin cholesterol suna lalata lalacewar tasoshin jini wanda yayi kama da tatsuniyar atherosclerotic a cikin jiragen tsofaffi. Anichkov ya gudanar da bincikensa tsawon shekaru da dama kuma ya buga sakamakon a sanannun mujallolin ƙasashen yamma. Abin takaici, bayanansa ba su zama tushen abin ƙira don ci gaban atherosclerosis a cikin mutane ba, tunda a wancan lokacin hasashen yana mamayar cewa wannan cutar asalin cuta ce ta tsufa kuma ba za a iya hana ta ba. Kodayake, a hankali a hankali aka fara samun alaƙar dangantaka tsakanin kwalayen ƙwayar cuta (serum cholesterol) da haɓakar atherosclerosis (hypohesis), da kuma cikin shekarun 1960. wasu masu binciken sun bayyana a fili cewa za a iya magance wannan cuta ta magunguna. Koyaya, ra'ayi mai akasin haka ya kasance har zuwa lokacin bugawa a cikin 1984 na sakamakon bincike mai zurfi game da rawar cholesterol wanda Cibiyar Kula da Lafiya ta Amurka ke gudanarwa (Gwajin Tsarin rigakafin Farko na Farko). An nuna raguwar ƙididdiga a yawan ƙwayar myocardial infarction da bugun jini tare da raguwar ƙwayar cholesterol. A cikin wannan binciken, anyi amfani da cholesterol, resin musayar anion wanda yake ɗaure acid bile, don amfani da ƙananan cholesterol. Sakamakon ya haifar da bincike don neman sababbin, magungunan warkewa mafi ƙarfi. Dole ne in faɗi cewa a cikin duniyar kimiyya, shakku game da ingancin maganin lipid ɗin gaba ɗaya ya ɓace kawai tare da bayyanar gumakan a ƙarshen 1980 - farkon 1990s.
Akira Endo ta gano statin farko a Sankyo a Tokyo. Endo ya buga aikinsa a 1976, kodayake ya magance matsalar ƙwayar cutar cholesterol shekaru da yawa. A shekara ta 1971, ya ba da shawarar cewa ana iya kasancewa a cikin kwayoyi masu hana kwayoyi kwayoyi a cikin masu samar da namomin kaza wadanda aka yi nazari a lokacin. Shekaru da yawa na aiki mai ƙarfi, ya bincika al'adun gargajiya sama da 6,000 na namomin kaza daban-daban, har sai da ya sami sakamako mai kyau. Sakamakon abin da ya haifar ana kiranta compactin. Wannan abun ya rage cholesterol a cikin karnuka da birai. Wadannan karatuttukan sun kama hankalin Michael Brown da Joseph Goldstein na Jami'ar Texas Southwest yammacin School Medical School. Brown da Goldstein, tare da Endo, sun fara nazarin hadin gwiwa kuma sun tabbatar da bayanan sa. Manyan nasarorin da aka samu a gwajin farko na asibiti sun haɗa da kamfanonin harhada magunguna a cikin haɓakar waɗannan sababbin magunguna. A Merck, ƙungiyar da Alfred Alberts da Roy Wagelos suka jagoranta sun ƙaddamar da sabon binciken al'adun namomin kaza kuma, sakamakon nazarin jimlar al'adu 18, sun gano wani magani mai aiki. Sabuwar abu ana kiranta lovastatin. Koyaya, a lokaci guda, an yi imanin cewa, aiwatar da babban adadin kuzari ga karnuka na haifar da ci gaba da cutar kansa da kuma bincika sababbin gumakan a 1980s. an dakatar da shi. Koyaya, a wannan lokacin, amfanin amfani da statins don kula da marasa lafiya da familial hypercholesterolemia ya rigaya ya bayyana. Bayan shawarwari da yawa tare da masana na duniya da Hukumar Abinci da Magunguna (FDA, Amurka), Merck ya fara bunkasa lovastatin. Karatuttuka masu zurfi a cikin shekaru 20 masu zuwa ba su bayyana tasirin carcinogenic na lovastatin da sabon ƙarni na magungunan da suka bayyana bayan shi ba.
Hoto 1. Statins suna hana masu rage NM G-CoA reductase. Kwatanta tsarin mevalonate da samfuran magunguna guda huɗu (mutum-mutumi) waɗanda ke hana aikin NM G -CoA reductase.
Statins hana aikin HMG - CoA - reductase, yin kwaikwayon tsarin mevalonate, don haka ya toshe ayyukan cholesterol. A cikin marasa lafiya tare da hypercholesterolemia wanda ya haifar da lahani a cikin kwafin guda ɗaya na abubuwan karɓa na LDL, lokacin ɗaukar lovastatin, matakan cholesterol an rage su da 30%. Magungunan yana da inganci sosai idan aka haɗu da resins na musamman waɗanda ke ɗaure bile acid kuma suna hana shanyewar hanjinsu daga hanjin.
A halin yanzu, akasari ana amfani da su sau da yawa don rage ƙwayoyin jini na jini. Lokacin shan kowane magani, tambayar ta tashi game da tasirin sakamako masu illa da ba a yarda dasu ba. Koyaya, dangane da almara, yawancin sakamako masu illa, akasin haka, suna da kyau. Wadannan kwayoyi na iya tayar da jijiyoyin jini, suna gyara filayen atherosclerotic tuni (don kar su rabu da bangon jijiyoyin jini kuma kar su tsoma baki tare da kwararawar jini ba), da hana tarawar platelet, da kuma raunana hanyoyin kumburi a jikin bangon jijiyoyin jini. A cikin marasa lafiya da ke ɗauke da siffofi a karon farko, ana bayyanar da waɗannan tasirin tun kafin matakan cholesterol su fara raguwa, kuma mai yiwuwa ana danganta su da hanawa da haɗuwa da rashin haɗin kai na isoprenoid. Tabbas, ba kowane sakamako na statins yana da amfani ba. A cikin wasu marasa lafiya (yawanci a tsakanin waɗanda ke ɗaukar statins a haɗe tare da wasu kwayoyi waɗanda ke rage cholesterol), raunin ƙwayar tsoka da rauni na tsoka na iya faruwa, kuma wani lokacin a cikin tsari mai ƙarfi. Hakanan ana yin rijistar wasu sakamako masu illa da yawa na jikin mutum, wanda, alamu, da kyar ake faruwa. A cikin mafi yawan masu haƙuri, ɗaukar mutum-mutumi na iya hana ci gaban cututtukan zuciya. Kamar kowane magani, likitan yakamata a yi amfani dashi kamar yadda likitanka ya bada shawarar.
Tare da rashi gado na HDL cholesterol, matakan cholesterol suna da ƙanƙantar yawa, tare da cutar Tangier, ƙwaƙwalwar ƙwaƙwalwa ba a tantance shi ba. Dukkanin cututtukan ƙwayoyin cuta suna faruwa ne daga maye gurbi a cikin ƙwayoyin ABC1. Rashin kwalagin cholesterol na HDL ba zai iya kama cholesterol daga sel masu karancin ABC1 ba, kuma sel da ke cikin cholesterol an cire su cikin jini cikin sauri kuma suna rugujewa. Dukansu rashin gado na HDL da cutar Tangier suna da wuya sosai kaɗan (ƙarancin iyalai 100 da ke da cutar Tangier sanannu ne a duk duniya), amma waɗannan cututtukan suna nuna matsayin furotin ABC1 wajen daidaita matakan plasma na HDL. Tunda ƙananan matakan HDL plasma suna da dangantaka da hauhawar lalacewa da jijiyoyin jini, furotin ABC1 na iya zama manufa mai amfani ga magungunan da aka tsara don daidaita matakan HDL. ■
Ana samar da kwayoyin hodar iblis ta hanyar rarraba sashin layi na cholesterol da hadawan abu da iskar shaka.
Wani mutum yana karɓar duk kwayoyin halittun steroid din daga cholesterol (Fig. 21-45). Kungiyoyi biyu na kwayoyin horarwa na mahaifa an hade su a cikin adrtal bawo: ma'adinai corticoids,wanda ke daidaita shawo kan abubuwan ion inorganic (Na +, C l - da HC O) 3 -) a cikin kodan, da glucocorticoids, wanda ke taimakawa wajen daidaita gluconeogenesis da rage amsawar kumburi. Ana samar da kwayoyin halittar jima'i a cikin sel na maza da mata kuma a cikin mahaifa. Daga cikinsu progesterone wanda ke tsara tsarin haihuwar mace, androgens (misali testosterone) da estrogens (estradiol), wanda ke shafar haɓakar halayen jima'i na maza da mata, bi da bi. Hotunan steroid suna da tasiri a cikin raguwa sosai kuma sabili da haka an haɗu da su a cikin kaɗan kaɗan. Idan aka kwatanta da salts na bile, kadan ana amfani da kwalalin don samar da kwayoyin halittun steroid.
Hoto 21-45. Wasu kwayoyin steroid an kirkiro su daga cholesterol. Tsarin wasu daga cikin wadannan mahadi ana nuna su a cikin fig. 10-19, aya ta 1.
Tsarin kwayoyin hoorin steroid na bukatar a cire yawancin ko dukkan abubuwan zarra a cikin “sarkar gefen” na C-17 D-zobe na cholesterol. Cire sarkar sashi na faruwa a cikin mitochondria na kyallen takarda na steroidogenic. Tsarin cirewa ya ƙunshi hydroxylation na zarra biyu na zarra na carbon sarkar sashi (C-20 da C-22), sannan ɓoye ɗaurin a tsakani (Fig. 21-46). Kirkirar kwayoyin halittu daban-daban suma sun hada da gabatar da iskar oxygen. Duk abubuwan da ake amfani da su da kuma iskar shakar iskar shaka yayin tasirin stesy biohesntis ana daukar su ne ta hanyar hadawar abubuwa da suka hada da aiki (kara. 21-1) wadanda ke amfani da NА D PH, O 2 da kuma cyitochrome mitochondrial P-450.
Hoto 21-46. Cleavage na sarkar na gefe a cikin aikin hodar iblis. A cikin wannan tsarin oxidase tare da aiki mai cakuda wanda ke lalata carbon atoms, cytochrome P-450 yana aiki azaman mai ɗaukar lantarki. Hakanan wadanda ke cikin aikin sune sunadarai masu jigilar lantarki, adrenodoxin da adrenodoxin reductase. Wannan tsarin tsagaita sarkar gefe an samo shi a cikin mitochondria na adrenal cortex, inda samar da aiki mai mahimmanci na steroids ya faru. Pregnenolone tsari ne ga dukkan sauran kwayoyin steroid (Fig. 21-45).
Tsarin cholesterol biosynthesis yana cikin wasu hanyoyin hanyoyin rayuwa.
Baya ga aikinta a matsayin matsakaici na kwayar halitta na cholesterol biosynthesis, isopentenyl pyrophosphate tana aiki ne a matsayin kaddara mai aiki a cikin tarin kwayoyi masu tarin yawa na kwayoyin halittu masu aiki iri daban-daban (siffa 21-47). Waɗannan sun haɗa da bitamin A, E da K, alamu na shuka kamar carotene da sarkar chlorophyll phytol, roba na halitta, mai mahimmanci mai yawa (alal misali, ƙaƙƙarfan tushe na man lemun tsami, eucalyptus, musk), ƙwayoyin kwari na kwaro wanda ke daidaita metamorphosis, dolichols, wanda zama mai ɗaukar ruwa mai narkewa a cikin hadaddun haɗin polysaccharides, ubiquinone da plastoquinone - masu ɗaukar lantarki a cikin mitochondria da chloroplasts. Duk waɗannan kwayoyin sunadarai ne game da tsari. Sama da 20,000 daban-daban isoprenoids an samo su a cikin yanayin, kuma ana bayar da rahoton daruruwan sababbi kowace shekara.
Hoto 21-47. A hoto na gaba daya na biosynthesis na isoprenoids. Tsarin yawancin samfuran ƙarshen ƙarshen da aka gabatar anan ana ba su a cikin baaba. 10 (aya 1).
Hanyar haihuwa (covalent abin da aka makala na wani isoprenoid, duba siffa 27-35) wani tsari ne na gama gari wanda kekalar kariya ta hanayar ciki ta cikin sel membranes (duba siffa 11-14). A wasu sunadarai, ƙarancin lipid yana wakiltar ƙungiyar farnesyl carbon-15, a cikin wasu rukuni ne na geranyl 20-carbon. Wadannan nau'ikan lipids guda biyu suna haɗe da enzymes daban-daban. Yana yiwuwa maganganun da aka yi a kai tsaye sunadaran sunadarai ne ga membranes daban-daban dangane da abin da yake tattare da lipid din. Tsarin furotin shine wata muhimmiyar rawar takawa ga abubuwan keɓewa - mahalarta hanyar ƙwayar cutar cholesterol.
Takaitawa daga Sashe na 21.4 Biosynthesis na cholesterol, Steroids, da Isoprenoids
Formed An kirkiro cholesterol daga acetyl-CoA a cikin hadaddun matakan jerin abubuwa ta hanyar tsaka-tsaki kamar β-hydroxy-β-methylglutaryl-CoA, mevalonate, isoleteen dimethylallyl pyrophosphate da isopentenyl pyrophosphate. Ensarfin kwandon rabe-raben abubuwa yana ba da squa cyan cyclic squalene, wanda cyclizes zai iya samar da tsarin ringin mai kariya da sarkar gefen steroid.
Maganin cholesterol yana ƙarƙashin kulawar hormonal kuma, ƙari, ana hana shi ta hanyar haɓaka ƙwayoyin intracellular, wanda ke faruwa ta hanyar canzawa da sauƙaƙewa.
Kwarogin cholesterol da cholesterol esters da jini suna ɗaukar jini kamar plasma lipoproteins. Fraarfin ɓarke na VLDL yana canja wurin cholesterol, cholesterol esters da triacylglycerols daga hanta zuwa wasu kyallen takarda, inda maganin triacylglycerols ya share ta hanyar lipoprotein lipase kuma VLDL ya canza zuwa LDL. Dungiyoyin LDL da aka wadatar cikin cholesterol da cholesterol esters suna kai tsaye ta hanyar masu karɓa ta hanyar endocytosis, yayin da masu karɓar ƙwayoyin ƙwayoyin cuta na plasma membrane suna gane shi. HDL cire cholesterol daga jini, canja shi zuwa hanta. Yanayin abinci mai gina jiki ko lahani a cikin ƙwayoyin cuta na cholesterol metabolism na iya haifar da atherosclerosis da infarction na myocardial.
Hormon hormones na steroid (glucocorticoids, mineralocorticoids da hormones na jima'i) an samo su daga cholesterol ta hanyar canza sarkar gefen kuma gabatar da atom din oxygen a cikin tsarin steroid na zoben. Yawancin sauran mahadi na isoprenoid ana samarwa ne daga mevalonate ta hanyar iskewar jini na isoachenyl pyrophosphate da dimethylallyl pyrophosphate tare da cholesterol.
Ren Tsarin wasu sunadarai suna ba su jagora zuwa wuraren da ke jikin membranes kuma yana da mahimmanci ga aikin halittar su.
Tambaya 48. guaukaka metabolism na mai yawan kitse (β-oxidation da biosynthesis). Kira na malonyl CoA. Acetyl CoA carboxylase, ƙayyadaddun ayyukansa. Transport of acyl Co-a cikin membrane na ciki na mitochondria.
Babban
adadin phenylalanine yana cinyewa
a cikin hanyoyi 2:
kunna
a cikin squirrels,
ya juya
a cikin tyrosine.
Juyawa
phenylalanine zuwa tyrosine da farko
Dole a cire wuce haddi
phenylalanine, tunda babban taro
Yana da guba ga sel. Ilimi
cutar tyrosine bata da matsala da gaske
tunda rashin wannan amino acid
a sel kwatsam baya faruwa.
Babban
metabolism na phenylalanine yana farawa
tare da hydroxylation (Fig. 9-29), a cikin
sakamakon cutar sankarau.
Wani irin aiki ne yake ɗaukar hankalin shi
monooxy-nase - phenylalanine hydra (zsilase,
wanda yayi aiki a matsayin coferment
tetrahydrobiopterin (N4BP).
Ayyukan enzyme shima ya dogara
gaban Fe2.
A
hanta an hanata hanzarta tattara mutane
glycogen (duba sashe na 7). Koyaya hannun jari
glycogen a cikin hanta yana tsautsayi
18-24 na azumi. Babban tushe
glucose kamar yadda hannun jari ya ƙare
glycogen ya zama gluconeogenesis,
wanda ya fara hanzarta ta
Hoto
11-29. Manyan canje-canje na rayuwa
makamashi lokacin da yake canza sha
jihar postabsorbent. CT
- jikin ketone, FA - mai kitse.
4-6 h
bayan abincin da ya gabata. Maimaitawa
Ana amfani da glycerol don yin amfani da glucose,
amino acid da lactate. A sama sosai
saurin taro na glucagon
kitse mai kitse ya rage saboda
phosphorylation da inactivation
acetyl CoA carboxylase da kuma ƙima
p-oxidation yana ƙaruwa. Koyaya,
karuwar samar da kitse ga hanta
acid wanda ake jigilar su
daga fatarar fat. An kafa Acetyl-CoA
a cikin hadawan abu na iskar shaka, ana amfani dashi
a hanta don kwayar jikin ketone.
A
adipose nama tare da kara maida hankali
glucagon ya rage yawan saurin saiti
TAG da lipolysis suna motsa su. Starfafawa
lipolysis - sakamakon kunnawa
hormone lipase mai saurin motsa jiki
adipocytes a ƙarƙashin rinjayar glucagon.
Acids Acid ya zama mahimmanci
tushen kuzari a hanta, tsokoki da
nama tsotse.
Don haka
don haka, a cikin lokacin postabsorption
an kiyaye yawan glucose na jini
a matakin 80-100 mg / dl, da kuma yawan mai
acid da jikin ketone suna ƙaruwa.
Sukari
ciwon sukari cuta ce da ke faruwa
saboda cikakken ko dangi
karancin insulin.
A.
Babban siffofin asibiti na sukari
ciwon sukari
A cewar
Kungiyar Duniya
rashin lafiya na masu cutar sankara
classified bisa ga bambance-bambance
dalilan kwayoyin halitta da asibiti
manyan sifofi guda biyu: ciwon sukari
Nau'in I - insulin-dependence (IDDM), da ciwon suga
Nau'in Na II - mai zaman kansa insulin (NIDDM).
Tsarin doka
kira na zhk
kira na lcd - acetyl CoA carboxylase.
Wannan enzyme ana sarrafa shi da yawa
hanyoyi.
Kunnawa / Ragewa
enzyme subunit hadaddun. A
nau'i na rashin aiki na acetyl CoA carboxylase
wakiltar hadaddun gidaje,
kowane ɗayan ya ƙunshi ƙananan ƙananan 4.
Enzyme activates citrate. Yana karfafawa
haɗuwa da hadaddun abubuwa, sakamakon haka
wanda aikin enzyme yana ƙaruwa
. Inhibitor-palmitoyl-CoA. Yana kira
hadadden rarrabuwar kawuna da raguwa
aikin enzyme.
Phosphorylation / Mai saukarwa
acetyl CoA carboxylase. A
postabsorption jihar ko a ciki
aikin jiki yana glucagonized
adrenaline ta hanyar adenylate cyclase
ana kunna tsarin ne ta hanyar prokinase A da
karfafa phosphorylation na subunits
acetyl CoA carboxylase. Phosphorylated
enzyme ba shi da aiki da kuma yawan mai
acid yana tsayawa.
Ba a yarda ba
lokacin insulin na aiki phosphatase,
kuma acetyl-CoA carboxylase yana shiga
jihar katsewa Sannan
a ƙarƙashin rinjayar citrate yana faruwa
polymerization na protomers na enzyme, kuma
sai ya zama mai aiki. Baya ga kunnawa
enzyme citrate yayi wani
aiki a cikin kira na LCD. Ba a sani ba
lokaci a cikin mitochondria na hanta sel
ya tara citrate, a ciki
an rage ragowar acyl zuwa
cytosol.
Tsarin doka
rates-oxidation matakan.
Β-oxidation-metabolic way,
da alaƙa da aikin CPE da na gaba ɗaya
hanyoyin catabolism. Saboda haka saurin sa
kayyade ta hanyar buƙatun tantanin halitta
makamashi i.e. ta hanyar martanin ATP / ADP da NADH / NAD, gwargwadon karɓuwar amsawar CPE da
hanyar gama gari ta hanyar cinyewa. Sauri
β-oxidation a cikin kyallen takarda ya dogara da kasancewa
canzawa, i.e.
a kan yawan kitse
acid na shiga cikin mitochondria.
Ciki Acid Aciki
cikin jini yakan hau kan kunnawa
lipolysis a cikin nama mai narkewa yayin azumi
a ƙarƙashin rinjayar glucagon da lokacin jiki
yi aiki a ƙarƙashin rinjayar adrenaline. A cikin waɗannan
kitse mai kitse ya zama
asalin tushen makamashi
don tsokoki da hanta, a sakamakon
β-oxidations an yi shi ta hanyar NADH da acetyl-CoA inhibiting
pyruvate dehydrogenase hadaddun.
Canza tsari na pyruvate
daga glucose zuwa acetyl-CoA yana raguwa.
Matsakaici metabolites tara
glycolysis kuma, musamman, glucose-6-phosphate.
Glucose-6-phosphate yana hana hexokinase
sabili da haka ya hana
yin amfani da glucose a cikin tsari
kwalliya. Saboda haka, m
amfani da lcd a matsayin babban tushe
makamashi a cikin ƙwayar tsoka da hanta
ceton glucose don ƙwayar jijiya da
ƙwayoyin jini.
Β-oxidation din kudi shima
ya dogara da aikin enzyme
carnitine acyltransferases I
A cikin hanta, wannan enzyme an hana shi.
malonyl CoA, abu ne wanda aka kirkira
tare da biosynthesis na lcd. A lokacin m
glycolysis yana aiki a cikin hanta kuma
samuwar acetyl-CoA yana ƙaruwa
daga pyruvate. Da farko kira
Canjin lcd na acetyl-CoA zuwa malonyl-CoA.
Malonyl-CoA yana hana id-oxidation na lcd,
wanda za a iya amfani da shi don yin kira
mai.
Ilimi
malonyl-CoA daga tsarin sarrafawa na acetyl-CoA
dauki a cikin biosynthesis lcd. Na farko dauki
kira lcd hira da acetyl-CoA zuwa
malonyl CoA. Maganin enzyme
wannan dauki (acetyl Coa carboxylase),
kasance a cikin aji na ligases. Ya ƙunshi
covalently daure biotin. A farkon
co2 covalent dauki matakai
ya danganta ga biotin saboda kuzari
ATP, a mataki na 2 COO - canjawa wuri
a kan acetyl-CoA don ƙirƙirar malonyl-CoA.
Acetyl CoA Carboxylase Ayyukan enzyme
kayyade saurin dukkan m
kira lc
citrate yana kunna enzyme a cikin cytosol
acetyl CoA carboxylase. Malonyl CoA in
bi da bi na hana canja wuri na mafi girma
m acid daga cytosol zuwa matrix
mitochondria hana ayyukan
acetyl CoA na waje: carnitine acyltransferase,
saboda haka kashe hadawan abu da iskar shaka
mai kitse.
Acetyl-CoA Oxaloacetate →
HS-CoA Citrate
HSCOA ATP Citrate → Acetyl-CoA ADP Pi Oxaloacetate
Acetyl-CoA
a cikin cytoplasm yana aiki azaman farawa
a cikin don haɗin lcd, da oxaloacetate in
cytosol yana fuskantar canje-canje a ciki
sakamakon abin da pyruvate ke kafa.
Cholesterol biosynthesis
Cholesterol biosynthesis yana faruwa a cikin endoplasmic reticulum. Tushen dukkanin kwayoyin carbon a cikin kwayar halitta shine acetyl-SCoA, wanda ya zo daga nan daga mitochondria a matsayin wani bangare na citrate, kamar yadda yake cikin tsarin acid din mai. Kwayoyin halitta na cholesterol sun cinye kwayoyin 18 na ATP da kwayoyin NADPH 13.
Samuwar cholesterol yana faruwa a cikin halayen fiye da 30, waɗanda za'a iya haɗasu cikin matakai da yawa.
1. Maganin mevalonic acid.
Abubuwan haɗuwa guda biyu na farko sun haɗuwa da halayen ketogenesis, amma bayan haɗin 3-hydroxy-3-methylglutaryl-ScoA, enzyme ya shiga hydroxymethyl-glutaryl-ScoA reductase (HMG-SCOA reductase), samarda mevalonic acid.
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