Cholesterol biosynthesis na ndu ya - Diabetes
Obi abụọ adịghị ya, cholesterol bụ ihe kachasị amara n'etiti ọha mmadụ; ọ bụ ihe ama ama n'ihi mmekọrịta dị n'etiti cholesterol ọbara mgbali elu na ugboro ugboro nke ọrịa obi mmadụ. Enweela nlebara anya dị mkpa maka ọrụ cholesterol dị ka akụrụngwa nke mkpụrụ ndụ yana dịka ihe butere homonụ steroid na acid bile. Cholesterol dị mkpa maka ọtụtụ ụmụ anụmanụ, gụnyere mmadụ, mana ọnụnọ ya na nri anụmanụ bụ nhọrọ - mkpụrụ ndụ n'ahụ onwe ha nwere ike ịhazi ya site na usoro dị mfe.
Ihe mejuputara uzo carbon-27 a n’eme ka uzo di ike ma obu biosynthesis ya, ma atumatu ya nile sitere n’otu uzo acetate. Isoprene mgbochi - ihe kachasị dị mkpa site na acetate na cholesterol, ha bụ ihe na-ebute ụzọ nke ọtụtụ mkpụrụ eke eke eke si arụ ọrụ, na usoro ndị ejiri sọlfọ na-akpụ akpụ na polymerized bụ otu ụzọ n'ụzọ metabolic niile.
Anyị na-amalite site n’inyocha ụzọ ndị dị na ụzọ nke cholesterol biosynthesis si na acetate, wee tụlezie njem nke cholesterol site n'ọbara ọbara, ịmịkọrọ ya site na mkpụrụ ndụ, usoro iwu cholesterol nkịtị, yana usoro iwu nke nnabata ma ọ bụ njem. Mgbe ahụ anyị na-elele ihe ndị ọzọ sitere na cholesterol, dị ka bile acid na homonụ steroid. Na ngwụcha, nkọwa nke ụzọ biosynthetic maka ịtọ ọtụtụ ogige - usoro nke sọlfọiki, ebe enwere ọkwa mbu na cholesterol synthesis, ga-egosiputa oke pụrụ iche nke nnweko isoprenoid na biosynthesis.
A na-emepụta cholesterol site na acetyl-CoA na ọkwa anọ
Cholesterol, dị ka ụyọkọ abụba ogologo, ka a na-eme site na acetyl-CoA, mana usoro mgbakọ dị iche kpamkpam. Na nyocha nke mbụ, acetate akpọrọ nwere 14 C ma na methyl ma ọ bụ carbon carbonl atọm na-agbakwunye na nri anụmanụ. Dabere na nkesa akara a na cholesterol dịpụrụ iche site na ìgwè anụmanụ abụọ (Fig 21-32), a kọwara ọkwa nke enzymatic nke cholesterol biosynthesis.
Fig. 21–32. Isi mmalite nke carbon atọm nke cholesterol. Achọpụtara n'oge nnwale na-eji carbon redio acetate akara carbon methyl (ojii) ma ọ bụ carbonxyl (ọbara ọbara). N'usoro owuwu, a na-egosi mkpụrụedepụ A ruo D.
Ngwakọta ahụ na-ewere ọnọdụ na usoro anọ, dị ka egosiri na fig. 21–33: (1) ihe ndozi nke nkpuru ato acetate iji meputa uzo carbon nke mevalonate, (2) ngbanwe nke mevalonate na mgbochi iso iso ihe, (3) polymerization nke ero ise nke carbon di iche iche mejuputa akpukpo ahiri karine 30, (4) cyclization nke squalene ka ogha yiri mgbaaka anọ nke steroid nucleus, na-esochi usoro mgbanwe (oxidation, mwepu ma ọ bụ mpụga nke ìgwè methyl) na izụ cholesterol.
Fig. 21–33. Foto di elu nke cholesterol biosynthesis. A tụlere akụkụ anọ nke njikọta ederede. Akara edo edo nke Iso Loose na squalene bu akara edoghi achajiri achaa.
Ogbo (1). Ihe mevalonate sitere na acetate. Oge mbu cholesterol biosynthesis na - eduga n’inwepụta ihe dị na etiti mevalonate (Fig 21-34). Mkpụrụ ndụ acetyl CoA abụọ ahụ na-eme ka ha nwee ike inye acetoacetyl CoA, nke na-echekwa mkpụrụ ndụ acetyl CoA nke atọ mejupụta kọlụm carbon isii. β-hydroxy-β-methylglutaryl-CoA (HM G -CoA). Abụọ na mmeghachi omume mbụ a thiolase na NM G -CoA synthase, n'otu n'otu. Cytosolic NM G-CoA synthase Metabolzọ metabolic a dị iche na mitochondrial isoenzyme, nke na-ejikọ njikọ nke NM G -CoA n'oge e guzobere ahụ ketone (lee fig 17-18).
Fig. 21–34. Nhazi nke mevalonate sitere na acetyl-CoA. A na-egosipụta isi iyi nke C-1 na C-2 mevalonate sitere na acetyl-CoA na pink.
Mmeghachi nke ato na-egbochi ọsọ nke usoro ahụ dum. N'ime ya, a na-ebelata NM G -CoA na mevalonate, maka nke nke ọ bụla n'ime NА D PH abụọ na-enye elektrọn abụọ. HMG-CoA reductase - ngwakọta membrane protein nke ire ụtọ ER, ọ na - arụ ọrụ, dịka anyị ga - ahụ ka emesịa, dịka isi ihe na - achịkwa usoro metabolic nke usoro cholesterol.
Ogbo (2). Ntughari mevalonate abuo abuo iso Loose rụọ ọrụ. Na ọkwa ọzọ nke cholesterol njikọ, a na - ebugharị ìgwè phosphate atọ sitere na mkpụrụ ndụ ATP gaa mevalonate (Fig 21-35). Phosphate jikọtara ya na hydroxyl dị na C-3 mevalonate na etiti 3-phospho-5-pyrophosphomevalonate bụ ezigbo ndị na-ahapụ, na usoro nke abụọ nke phosphates ndị a na ngbanye ụgbọelu carbon na-esote, na-akpụkọ nkekọ abụọ na ngwaahịa carbon carbon ∆ 3 -dịpụrụ adịpụ pyrophosphate. Nke a bụ nke mbụ n’ime mmadụ abụọ nọpụrụ iche - ya bụ ndị bụ isi na cholesterol synthesis. Isomerization nke Δ 3 -isopentenylpyrophosphate na-enye nkeonwe isolete dimethylallyl pyrophosphate. Ngwakọta nke isopentenyl pyrophosphate na cytoplasm nke mkpụrụ ndụ na-apụta dị ka ụzọ akọwara ebe a. Agbanyeghị, osisi chloroplasts na ọtụtụ nje na-eji okporo ụzọ emeghị ihe mevalonate. Achọpụtaghị ụzọ ọzọ a na anụmanụ, yabụ ọ na-adọrọ adọrọ mgbe ị na-emepụta ọgwụ mgbochi ọhụrụ.
Fig. 21-35. Ntughari mevalonate n'ime mgbochi nke iso Loose Akụkụ isii rụọ ọrụ na-agwakọta iji mejupụta squalene (lee eserese 21-36). Otu 3-phospho-5-pyrophosphomevalonate na-apụ apụ na pink. Na ogwe osisi etiti bụ etiti na-eche echiche.
Ogbo (3). Condension nke isii isii na - arụ ọrụ na –eme ka squalene. Isopentenyl pyrophosphate na dimethylallyl pyrophosphate na-enwezi mkpo isi na ọdụ, nke otu pyrophosphate na-akpali ma na-enwe ụdị silin 10 - geranyl pyrophosphate (Fig 21-36). (Pyrophosphate na-etinye aka na isi.) Geranyl pyrophosphate na-eso ikuku-iso-ụdị ọdụdụ ahụ, yana ụdị carbon 15 na-etiti. farnesyl pyrophosphate. Na mmechi, ụmụ irighiri mmiri abụọ nke farnesyl pyrophosphate gwakọtara “isi n’isi”, a na-ewepụ otu foshatụ abụọ - guzobere squalene.
Fig. 21–36. Ojiji nke squalene. Ọdịdị squalane nke nwere atom carbon 30 na-eme mgbe a na-eme ka mkpụrụ ndụ na-esochi (carbon-carbon) rụọ ọrụ ugboro abụọ.
Aha ndị a na - akpọkarị maka etiti ndị a sitere na aha ndị sitere na mbụ ha nọ na mbụ ha. Geraniol, ihe sitere na mmanụ rose, nwere uto geranium, farnesol, nke a chọtara na agba acacia farnesa, nwere lily nke isi iyi ndagwurugwu. Ọtụtụ ísì ihe ọkụkụ sitere n'okike so n'ihe ndị mepụtara site na nkankaị na-adịghị ahụkebe. Squalene, nke dịpụrụ adịpụ site na imeju shark (ụdị squalus), mejupụtara atọm carbon: 30 atoms n'ime isi yinye na atọm nke atọ n'ime igwe.
Ogbo (4). Gbanwe squalene ka ọ bụrụ mgbaaka anọ nke steroid nucleus. Na fig. 21-37 a na-ahụ nke ọma na shịrịị silsila squirane, na sterols - cyclic. Igwe sterol niile nwere mgbanaka nwere agba anọ mejupụtara steroid nucleus, ha niile bụ ndị a alcoụrụma nwere otu hydroxyl na atọm nke C-3, yabụ, Bekee kpọrọ sterol. N'okpuru omume squalene monooxygenase otu oxygen atom sitere na O na etinye ya na njedebe nke agbụ squalene 2 ewe mepụta epoxide. Enzyme a bụ oxidase agwakọta ọzọ (gbakwunye 21-1), NADPH na-ebelata ikuku oxygen ọzọ site na O 2 ka H2 O. Abụọ Mkpokọta Ngwakọta squalene-2,3-epoxide haziri nke oma na mmeghachi omume kwesiri ntukwasi obi nwere ike igbanwe onu ogugu uda n'ime ulo. N'ime mkpụrụ ndụ anụmanụ, cyclization a na-eduga n'ịbe lanosterol nke nwere njiri mara anọ nke steroid nucleus. N'ihi ya, a na-agbanwe lanosterol ka ọ bụrụ cholesterol site na usoro ihe dị ka mmeghachi omume 20, nke gụnyere Mbugharị nke ụfọdụ igwe igwe na iwepụ ndị ọzọ. Nkọwa nke ụzọ a dị ịtụnanya nke biosynthesis, otu n'ime ihe kachasị sie ike n'etiti ndị a maara, bụ Conrad Bloch, Theodore Linen, John Cornfort na George Popiak na ngwụcha 1950s.
Fig. 21–37. Imechi akwa na-agbanye n’ahịrị squalene ka ọ bụrụ steroid gbawara agbado. A na-ewere oxidase nke nwere ọrụ dị n'otu (monooxygenase), nke onye na-ahụ maka ya bụ N AD PH. Ngwaahịa ahụ bụ epoxide, nke na-esote ọkwa nke cyclizes iji mepụta steroid isi. Ngwaahịa ikpeazụ nke mmeghachi omume ndị a na mkpụrụ ndụ anụmanụ bụ cholesterol; n'ime ihe ndị ọzọ, sterols dịtụ iche na ya.
Cholesterol bụ njiri mara stere nke anụmanụ, ahịhịa, fungi na protist na - emepụta sterol ndị ọzọ yiri.
Ha na-eji otu usoro njikọ ahụ gaa squalene-2,3-epoxide, mana mgbe ahụ ụzọ ndị ahụ na-agbada ntakịrị, na etolite sterol ndị ọzọ, dị ka sigmasterol n'ọtụtụ osisi na ergosterol na usoro dịkwa ka usoro (Fig. 21-37).
Ihe Nlereanya 21-1 Akwụ ụgwọ ike maka Squalene Synthesis
Kedu ihe akwụ ụgwọ ike egosiri (akọwapụtara dị ka mkpụrụ ndụ nke ATP) maka njikọ nke otu molikal squalene?
Ngwọta. Na nchịkọta squalene sitere na acetyl-CoA, a na-etinye ATP naanị na ogbo mgbe a gbanwere mevalonate ka ọ bụrụ onye nrụpụta iso Loose squalene precursor. A chọrọ ụmụ irighiri elektrọn isii maka iji wuo moalsal squalene, ma a chọrọ moali atọ ATP ka imepụta otu n’ime molekul na-arụ ọrụ. Na ngụkọta, mkpụrụ 18 ATP na-etinyere njikọ nke otu molikal squalene.
Ihe ndi cholesterol na aru
Na vertebrates, cholesterol buru ibu na-arụ ọrụ n'ime imeju. Offọdụ n'ime cholesterol a gwakọtara ọnụ ebe enwere na mkpokọta nke hepatocytes, mana a na-ebubata ya n'otu n'ime ụzọ atọ ya: biliary (bile) cholesterol, bile acid ma ọ bụ cholesterol esters. Bile acids nnu ha bụ ọgwụ hydrophilic nke cholesterol, nke a na-ekekọta na imeju ma na-atụnye na mgbaze nke egbugbere ọnụ (lee fig 17-1). Esters nke cholesterol hiwere imeju site na ime ya acyl-CoA-cholesterol-acyltransferase (ACAT). Enzyme a na - ebute nnyefe nke ihe fọdụrụ na acid si na coenzyme A na hydro choll cholesterol (Fig 21-38), na - atụgharị cholesterol ka ọ bụrụ ụdị hydrophobic ọzọ. A na-ebugharị esters cholesterol na mkpụrụ ndụ ihe dị na lipoprotein na anụ ahụ ndị ọzọ na-eji kọlesterol ma ọ bụ echekwa n'ime imeju.
Fig. 21–38. Nlekọta nke cholesterol esters. Ntinye ihe choputara na - eme cholesterol dika ihe ndi ozo nke hydrophobic maka ichekwa na ibu.
Cholesterol dị mkpa maka anụ ahụ niile na - eto eto na - eto eto maka njikọ nke membranes, yana ụfọdụ akụkụ ahụ (dịka ọmụmaatụ, gland adrenal na glands) na - eji cholesterol dịka ihe eji eme ka homonụ steroid (a ga - atụle nke a n'okpuru). Cholesterol bụkwa ihe mbido na vitamin D (lee ọgụgụ 10-20, v. 1).
Cholesterol na lipids ndị ọzọ na-ebu plasma lipoproteins
Cholesterol na cholesterol esters, dị ka triacylglycerols na phospholipids, bụ ihe a na-enweghị ike ịbanye na mmiri, agbanyeghị, ha ga-esikwa na anụ ahụ a gwakọtara ya na anụ ahụ ebe ha ga-echekwa ma ọ bụ rie. Ọbara ọbara na-eburu ha n’ụdị nke ọbara plasma lipoproteins - mgbagwoju anya nke macromolecular nke protein ndi n’enye ya (apolipoproteins) ya na phospholipids, cholesterol, cholesterol esters na triacylglycerols dị na ogige ndị a n'ọtụtụ dịgasị iche iche.
Apolipoproteins (“apo” na-ezo aka na protein protein n’onwe ya) jikọtara ya na lipids iji mepụta ọtụtụ irighiri ihe nke lipoprotein - akụkụ okirikiri nwere hydrophobic lipids n’etiti ya na hydrophilic amino acid chain n’elu (Fig. 21-39, a). Site na nchịkọta dị iche iche nke lipids na protein, a na-etolite oghere dị iche iche - site na chylomicrons ruo nfuli dị elu nke protein. Enwere ike ikewapụ ụmụ irighiri ihe ndị a site na iji nyocha igwe (Table 21-1) ma jiri anya ha hụ ya site na iji microscopy electron (Fig. 21-39, b). Mkpụrụ nke lipoproteins ọ bụla na-arụ ọrụ a kapịrị ọnụ, nke a na-ekpebisi ike site na njikọta ya, ihe mejupụtara ahụ na ọdịnaya apolipoprotein. Ọ dịkarịa ala 10 dị iche iche a na-ahụ apolipoproteins na plasma ọbara mmadụ (Isiokwu 21-2), nke dịgasị iche na nha, mmeghachi omume na ọgwụ mgbochi akọwapụtara, yana nkesa njiri mara klas dị iche iche nke lipoproteins. Ihe mejupụtara protein ndị a na-arụ ọrụ dị ka ihe na-eme ka ọ bụrụ ihe na - eduga lipoproteins na akwara ndị a kapịrị ọnụ ma ọ bụ enzymes na - eme na lipoproteins.
Isiokwu 21-1. Plasma lipoproteins mmadụ
Ngwakọta (akụkụ buru ibu,%)
r = 513,000). Otu ihe nke LDL nwere ihe dị ihe dị ka 1,500 ụmụ irighiri cholesterol esters, gburugburu isi ahụ bụ shei nke ụmụ irighiri 500 nke cholesterol, 800 ụmụ irighiri phospholipids na otu molikị nke apoB-100. b - klas anọ nke lipoproteins, nke a na-ahụ anya na ihe elektrọniki elele (mgbe ngosipụta nke adịghị mma). Elekere elekere, malite na ogidi aka ekpe dị elu: chylomicrons - nke nwere nha 50 ruo 200 nm, PL O NP - site na 28 ruo 70 nm, HDL - site na 8 ruo 11 nm, na LDL - site na 20 ruo 55 nm. Enyere ngwongwo nke lipoproteins na tebụl. 21-2.
Chylomicrons, zoro aka na Sec. 17, megharia nri triacylglycerols site na eriri afọ gaa na akwara ndị ọzọ. Ndị a bụ ọdụdụ kachasị nke ukwuu, ha nwere njupụta dịkarịsịrị ala yana ọdịnaya nwere oke nke triacylglycerols (lee fig 17-2). A na - ekekọta Chylomicrons n'ime ER nke sel epithelial na - ejikọ obere eriri afọ, ma gafere na sistemụ lymphatic wee banye n'ọbara site na akwara subclavian ekpe. Chylomicron apolipoproteins nwere apoB-48 (pụrụ iche maka klas nke lipoproteins), apoE na apoC-II (Isiokwu 21-2). AroC-II na - eme ka lipoprotein lipase dị n'ụdị edozi nke anụ ahụ adipose, obi, akwara na akwara mammary, na - agbapụta mmiri nke abụba n'efu. Ya mere, chylomicrons na-ebufe abụba abụba nri na anụ ahụ, ebe a ga-eri ha ma ọ bụ chekwaa ya dị ka mmanụ (Fig 21-40). Ihe ndị fọdụrụ Chylomicron (nke kachasị nwere onwe ha na triacylglycerols, mana ha ka nwere kọlesterol, apoE na apoB-48) na-ebuga n'ọbara n'ọbara. N'ime imeju, ndị na-anabata ihe na-ejikọ apoE dị na nsị chylomicron ma na-eme ka mmata ha site na endocytosis. Na hepatocytes, ahihia ndị a na-ahapụ kọlestrọl dị n'ime ha ma bibie ya na lysosomes.
Isiokwu 21-2. Human plasma lipoprotein apolipoproteins
Ọrụ (ọ bụrụ na amara ya)
Rụọ ọrụ L CAT, na ABC na-emekọrịta ihe
Na-egbochi L CAT
Na-arụ ọrụ L CAT, cholesterol igafe / nwepu ya
Na-ekekọta onye na-anabata LDL
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Na-amalite iwepu VLDL na chylomicron residues
Mgbe nri nwere ihe ndị nwere abụba karịa ka enwere ike iji ya ugbu a dị ka mmanụ, ha na-agbanwe n'ime triacylglycerols na imeju, bụ nke nwere akụkụ dị nta na apolipoproteins a kapịrị ọnụ. lipoproteins dị obere (VLDL) dị ala. Enwere ike ịtụgharị sọks riri oke umeju na imeju na triacylglycerols ma bupu ya dika VLDL (Fig. 21-40, a).Na mgbakwunye na triacylglycerols, irighiri VLDL nwere ụfọdụ cholesterol na cholesterol esters, yana apoB-100, apoC-1, apoC-II, apoC III na apoE (Isiokwu 21-2). A na-eburukwa lipoproteins ndị a site na ọbara site na imeju na akwara na anụ ahụ na-adị n’ire, ebe, mgbe a gbasasịrị lipoprotein lipase site na apo-C II, a na-ahapụ abụba abụba na triacylglycerols nke mkpokọta VLDL. Adipocytes na-ejide abụba na-enweghị ihe ọ bụla, gbanye ha n'ime triacylglycerols, nke a na-echekwa na mkpụrụ ndụ ndị a n'ụdị lipid inclusions (ọdịda), myocytes, na ntụle, ozugbo oxidize ọdụdụ abụba iji mepụta ike. Ewepu otutu ahihia VLDL site na hepatocytes. Ntinye ha, nke yiri nnabata chylomicrons, na-anabata onye na-anabata ya ma dabere na ọnụnọ nke apoE na nsị VLDL (gbakwunye. 21-2, a kọwara mmekọrịta dị n'etiti apoE na ọrịa Alzheimer).
Fig. 21-40. Ọkpụkpụ lipoproteins na akpịrị, na - a na - ebuga ọbara ọcha n'ụdị lipoproteins, nke a na - ejikọkọta n'ọtụtụ ụzọ yana ọrụ dị iche iche na ihe dị iche iche nke protein na lipids (Isiokwu 21-1, 21-2) ma kwekọọ na njupụta nke ụmụ irighiri ihe ndị a. A na-agbakọta lipids nri n'ime chylomicrons, ọtụtụ n'ime triacylglycerols dị n'ime ha bụ ndị a na-ahapụ site na lipoprotein lipase n'ime adipose na akwara anụ ahụ na capillaries. A na-enweta ahihia Chylomicron (nke nwere ihe kachasị protein na kọlesterol) site na hepatocytes. A na - enyefe lipids na cholesterol site na imeju na adipose na anụ ahụ anụ ahụ n'ụdị VLDL. Nwepu nke egbugbere ọnụ sitere na VLDL (yana ọnwụ nke ụfọdụ apolipoproteins) ji nwayọọ nwayọọ gbanwee VLDLP ka ọ bụrụ LDL, nke na-enye kọlesterol ka ọ nweekwa extrahepatic anụ ma ọ bụ weghachi ya na imeju. Imeju na-ejide ndọtị nke VLDL, LDL na ihe ndị fọdụrụnụ na chylomicrons site na endocytosis nke usoro mgbasa ozi. A na-ebugharị kọlesterol na anụ ahụ extrahepatic n'ime imeju n'ụdị LDL. N'ime imeju, akụkụ nke cholesterol na-agbanwe ghọọ salts salts. b - ihe nlele plasma nke ọbara nke a na-ewere mgbe agụụ gụchara (n'aka ekpe) yana mgbe ha risịrị nri nwere nnukwu abụba (n'aka nri). Chylomicrons guzobere site na iri nri ndị nwere abụba na-enye plasma ahụ dịka mmiri ara.
Site na mfu nke triacylglycerols, a na-atụgharị otu akụkụ nke VLDL ka nsị nke VLDL, nke a na-akpọkwa nkwụghachi ụgwọ lipoproteins (VLDL), mwepụ ọzọ nke triacylglycerols sitere na VLDL na-enye. lipoproteins dị ala (LDL) (tab. 21-1). Iberibe LDL, nke bara ụba na cholesterol na cholesterol esters, ma nweekwa apoB-100, na-ebufe cholesterol na anụ ahụ extrahepatic nke na-ebu ụfọdụ ndị na-anabata ndị na-anabata apoB-100 na membrans nke plasma. Ndị a na-anabata ya na-ebugharị mbido cholesterol na cholesterol esters (dịka akọwapụtara n'okpuru).
Mgbakwunye 21-2.ApoE alleles na-ekpebi ihe kpatara ọrịa Alzheimer
N'ime ọnụ ọgụgụ mmadụ, enwere ụdị amaara atọ (alleles) nke mkpụrụ ndụ ịrịọ apolipoprotein E. N'ime apoE alleles, APOEZ allele bụ ihe kachasị na mmadụ (ihe dịka 78%), APOE4 na APOE2 alleles bụ 15 na 7%, otu. APOE4 allele bụ njirimara ndị mmadụ nwere ọrịa Alzheimer, mmekọrịta a na-enyekwa ohere ịkọ ụdị ọrịa ahụ nwere nnukwu ike. Ndi mmadu ketara eketa APOE4 nwere nsogbu di elu nke ibute oria ndi Alzheimer. Ndị mmadụ a na - akpọ homozygous maka APOE4 ugboro iri na isii o yikarịrị ka ha butere ọrịa a, afọ ndụ ndị na - arịa ọrịa ihe dị ka afọ 70. Maka ndị na-eketa mkpụrụ abụọ nke AROEZ, na ntụle, nkezi afọ nke ọrịa Alzheimer karịrị afọ 90.
Usoro ihe omimi nke njikọta n'etiti apoE4 na ọrịa Alzheimer ka amabeghị. Na mgbakwunye, a ka edobeghị anya otú apoE4 nwere ike isi metụta uto nke ụdọ amyloid, nke doro anya bụ ihe kpatara ọrịa Alzheimer (lee fig. 4-31, v. 1). Echiche na-elekwasị anya n'ọrụ ga-ekwe omume nke apoE iji mee ka nhazi nke cytoskeleton nke neurons dị. Ihe nchebe apoE2 na apoEZ na-ejikọ ọtụtụ protein na-emetụta microtubules nke neurons, ebe apoE4 anaghị ejikọ. Nke a nwere ike mee ngwangwa ọnwụ nke neurons. Ihe ọ bụla usoro a nwere ike ịbụ, nchọpụta ndị a na-enye olileanya maka ịgbasawanye nghọta anyị banyere ọrụ ndu apolipoproteins.
Fourthdị nke anọ nke lipoproteins - akwa npoproteins dị elu (HDL), a na- emejupụtara akụkụ a na imeju na obere eriri afọ n'ụdị obere protein nwere protein nke nwere obere kọlesterol na kpamkpam nke cholesterol (Fig. 21-40). Mpekere nke HDL nwere apoA-I, apoC-I, apoC-II na apolipoproteins ndị ọzọ (Isiokwu 21-2), yana lecithin-cholesterol-acyltransferase (LC AT), nke na - eme ka cholesterol esters si lecithin (phosphatidylcholine) na cholesterol (fig 21-41). L CAT n’elu mmiri nke etolitela HDL ọhụrụ ahụ gbanwere chylomicron cholesterol na phosphatidylcholine na VLDL nsị na kọlesterol esters, nke na-amalite etolite akwara, na-agbanwe usoro mkpirisi HDL ahụ mebere ọhụrụ ka ọ bụrụ ihe nkwalitere HDL tozuru oke. Mgbe ahụ kọọrọ protein a bara ụba nke cholesterol a laghachiri umeji, ebe 'choputara' cholesterol, ụfọdụ n'ime kọlestrọl a ka ọ bụrụ nnu nnu.
Fig. 21-41. Mmeghachi omume a sitere na lecithin-cholesterol-acyltransferase (L CAT). Enzyme a dị na elu nke HDL ma rụọ ọrụ site na apoA-1 (ihe mejupụtara usoro HDL). Cholesterol esters na-agbakọta n'ime ahụ HDL nke emepụtara ọhụrụ, na-atụgharị ha ka ọ bụrụ HDL tozuru oke.
Enwere ike ịnabata HDL n'ime imeju site na endocytosis ihe nnabata, ma ọ dịkarịa ala, a na-ebunye ụfọdụ HDL cholesterol na ntanetị ndị ọzọ site na usoro ndị ọzọ. Ngwakọta nke HDL nwere ike kegide SR - BI na-edozi protein na akpụkpọ ahụ plasma nke sel akwara na anụ ahụ steroidogenic dị ka gland adrenal. Ndị na-anabata ihe ndị a anaghị atụgharị endocytosis, kama na-elele cholesterol na lipids ndị ọzọ nke HDL irighiri ihe n'ime mkpụrụ ndụ. Nkpirisi HDL nke “gbariri agbacha” wee banye ọzọ n'ọbara, ebe ọ gụnyere akụkụ ọhụrụ nke lipids sitere na mmiri chylomicrons na VLDL. Otu HDL ahụ nwekwara ike weghara cholesterol echekwara na anụ ahụ extrahepatic ma bufee ya na imeju site na laa azu cholesterol (Fig 21-40). Na otu n'ime mgbanwe mgbanwe nke mgbanwe, njikọta nke HDL na-esite na ndị na-anabata SR-BI na mkpụrụ ndụ cholesterol na - ebute oke cholesterol site na sel ahụ banye na HDL, nke na - ebugharị cholesterol n'ime imeju. N’ime mgbanwe njem mbu ọzọ n’ime sel cholesterol bara ụba, mgbe oghachachara nke HDL, apoA-I na onyere uchu na-aru oru, protein ABC. ApoA-I (yana nke a na-akpọ HDL) site na endocytosis, na-echekwa ọzọ, buru ibu nke kọlesterol, nke na-ebuga na imeju.
Protein ABC1 bụ akụkụ nke nnukwu ezinụlọ nke na - ebu ọtụtụ ọgwụ, ndị na - ebu ndị a na - akpọkarị ndị na - ebugharị ABC, ebe ọ bụ na ha niile nwere cassettes ATP (ATP - cassettes), ha nwekwara ngalaba ncheta abụọ nwere helices isii na - echeta (lee isi. 11, v. 1). Ihe nchebe ndị a na - enyefe ọtụtụ ion, amino acid, vitamin, homonụ steroid na nnu bile site na membran plasma. Onye nnọchi anya nke ezinụlọ a na - ebu ihe bụ CFTR protein, nke, ya na cystic fibrosis, mebiri (lee tinye 11-3, v. 1).
Cholesterol esters na-abanye na sel site na endocytosis ihe nnabata
Mkpụrụ ọgwụ LDL ọ bụla dị n'ọbara nwere apoB-100, nke protein dị mkpa na - anabata ya dị elu -Ndị na-anabata LDL na akpụkpọ ahụ nke dị mkpa iji jide cholesterol. Ijikọ LDL na LDL na-anabata ihe na-amalite endocytosis, n'ihi nke LDL na onye na-anabata ya na-abanye na sel n'ime endosome (Fig 21-42). Njedebe ahụ na-ejikọ lysosome, nke nwere enzymes nke hydrolyze cholesterol esters, na-ewepụta cholesterol na ọdụdụ abụba n'ime cytosol. ApoB-100 sitere na LDL na-akụrisị wee mepụta amino acid nke zoro ezo n'ime cytosol, mana LDL na-anabata ihe na-egbochi mbibi ma laghachi na sel ahụ iji sonye ọzọ na mbido LDL. ApoB-100 dịkwa na VLDL, mana ngalaba nnabata ya anaghị enwe ike ijikọ ihe nnabata nke LDL; ntụgharị nke VLDLP na LDL na-eme ka ngalaba nnabata banye apoB-100 nweta. Michael Brown na Joseph Goldstein amụọla ụzọ a na - ebu ụzọ na -elekọta ọnya cholesterol ọbara na endocytosis nke na-anabata ya na mkpụrụ ndụ mgbaru ọsọ.
Michael Brown na Joseph Goldstein
Fig. 21-42. Nchịkwa nke cholesterol site na endocytosis nke na-anabata ihe.
Cholesterol, nke na-abanye sel dị otu a, enwere ike itinye ya na membranes ma ọ bụ tinyeghachi ya na ACAT (Fig 21-38) maka nchekwa na cytosol n'ime ụmụ irighiri mmiri. Mgbe cholesterol zuru ezu dị na mkpụrụedemede ọbara LDL, a na-egbochi mkpokọta cholesterol dị ukwuu site na mbenata ọnụego nke njikọ ya.
Ihe nnabata nke LDL mechikwara apoE ma rụọ ọrụ dị mkpa na nkwalite chylomicrons na mkpoku VLDL site na imeju. Agbanyeghị, ọ bụrụ na ndị na-anabata LDL adịghị (dịka ọmụmaatụ, n'ụdị òké nwere ihe na-anabata ihe nnabata nke LDL), ọnya VLDL na chylomicron ka na-amịrị imeju, ọ bụ ezie na LDL anaghị anabata ya. Nke a na-egosi na ọnụnọ nke usoro ndozi enyemaka maka endocytosis nke nnabata nke VLDL na chylomicron. Otu n'ime ndị na-anabata ihe bụ protein LRP (protein na-emetụta lipoprotein), nke metụtara nnabata lipoprotein, nke na-ejikọ apoE na ọtụtụ ligands ndị ọzọ.
Otutu usoro cholesterol biosynthesis iwu
Ngwakọta cholesterol bụ usoro siri ike ma sie ike, ya mere o doro anya na anụ ahụ bara uru ịnwe usoro maka ịhazi cholesterol biosynthesis, nke na-emezigharị ego ya na mgbakwunye na nri. N'ime anụmanụ, na-achịkwa mmeju nke cholesterol site na itinye uche nke intracellular
cholesterol na homonụ glucagon na insulin. Uzo ntụgharị nke HMG - CoA mevalonate (Fig 21-34) na-egbochi ọsọ na metabolic n'ụzọ nke cholesterol guzobere (isi ihe na-achịkwa iwu). Mmeghachi omume a bụ nke sitere n'aka HMG - CoA reductase. Iwu na nzaghachi na mgbanwe nke cholesterol na-agbasa site na usoro iwu transpreal nke mara mma maka HG - HC - CoA reductase. A na-achịkwa mkpụrụ ndụ ihe nketa a, ya na ihe karịrị mkpụrụ ndụ iri abụọ ndị ọzọ na - abanye na nnabata na cholesterol na abụba na - enweghị afọ ojuju, na - achịkwa obere ezinụlọ nke a na - akpọ protein nke na - emekọrịta na njikwa ihe nchịkwa nke protein protein (SREBP, ihe nchịkwa nchịkwa nke na - egbochi protein). . Mgbe njikọta gasịrị, a na-ewebata protein ndị a n'ime endoplasmic reticulum. Naanị ngalaba ngalaba SREBP amino-soluble na-arụ ọrụ dị ka onye na-agagharị agagharị na-eji usoro akọwara na Ch. 28 (v 3). Agbanyeghị, ngalaba a enweghị ohere irighiri akwara ma ọ nweghị ike isonye na rụọ ọrụ nke mkpụrụ ndụ ma ọ bụrụhaala na ọ ka dị na mkpụrụ ndụ SREBP. Iji mee ka ntụgharị nke mkpụrụ ndụ HMG - CoA reductase na mkpụrụ ndụ ihe nketa ndị ọzọ, ngalaba transcriptionally na-arụ ọrụ na-ekewapụ akụkụ SREBP ndị ọzọ site na nchebe cleov. Mgbe cholesterol dị elu, protein SREBP anaghị arụ ọrụ, na-edozi ya na ER n'ime ebe nchekwa nwere protein ọzọ akpọrọ SCAP (SREBP - protein a na-eme ka arụ ọrụ rụọ ọrụ) (Fig 21-43). Ọ bụ SCAP na - ejikọ cholesterol na ọtụtụ sterol ndị ọzọ, na - arụ ọrụ dị ka onye na-ahụ maka sterol. Mgbe ọkwa sterol dị elu, ogige SCAP - SREBP nwere ike ịbụ na ya na protein ọzọ na-emekọrịta ihe. Mgbe ọkwa sterol nke dị na sel dara, mgbanwe mgbanwe na SCAP na - eduga n'ịhapụ ọrụ njigide, yana SCAP - SREBP complex na - akwaga n'ime vesicles gaa na Golgi ogige. Na ogige Golgi, SREBP na-edozi protein dị iche iche ugboro abụọ site na nchebe abụọ dị iche iche, nke abụọ na-ahapụ ịhapụ ngalaba amino-terminal na cytosol. Ngalaba a na-agagharị na nucleus ma na-eme ka nnabata nke mkpụrụ ndụ ndị mepụtara pụta. Mpaghara protein SREBP amino-terminal nwere obere ndụ-ndụ ma bụrụkwa nke na-emebi ala ngwa ngwa (lee fig 27-48, t. 3). Mgbe ọkwa sterol bilitere nke ọma, mwepụta nke protealytic nke ngalaba protein EBP nwere amino terminus na-egbochikwa ọzọ, mbibi nke nchekwa ngalaba nke arụ ọrụ dị ugbu a na-eduga na ngwa ngwa mkpụrụ ndụ ndị a chọrọ.
Fig. 21-43. Ọrụ nke SR EBP. Ihe nchebe SREB P na-eme ihe na sterol na-achịkwa (agba akwụkwọ ndụ akwụkwọ ndụ), ozugbo njikọta, webatara na ER, na-etolite S SAP (agba na-acha ọbara ọbara). (N na C na-egosi amị na carboxyl njedebe nke protein ahụ.) N'ime ókèala S-CAP, protein SRE BP anaghị arụ ọrụ. Mgbe ọkwa sterol ahụ belatara, SR EBP-S CAP dakọtara na-akwaga na ogige Golgi, nchebe SR EBP na-edozi abụọ dị iche iche n'otu oge. Mpaghara amino acid a tọhapụrụ SR EBP ngalaba protein na-akwaga na akwara, ebe ọ na-eme ka mkpụrụ ndụ ihe nchịkwa na-achịkwa achịkwa achịkwa.
A na-achịkwa usoro cholesterol site na ọtụtụ usoro ndị ọzọ (Fig. 21-44). Njikwa Hormonal na-agbagha site na mgbanwe covalent nke NM G-CoA reductase. Enzyme a dị n'ụdị phosphorylated (adịghị arụ ọrụ) na dephosphorylated (arụ ọrụ). Glucagon na - akpali phosphorylation (inactivation) nke enzyme, insulin na - akwalite dephosphorylation, na - eme ka enzyme ahụ ma nwee mmasị na njikọta cholesterol. Nnukwu ọnya cholesterol na - eme ka ASAT, nke na - eme ka ịbawanye ụba nke cholesterol maka itinye ego. Na mmechi, cholesterol dị elu nke na-egbochi ịdepụta mkpụrụ ndụ nke na-egbochi ihe nnabata LDL, na -ebelata mmepụta nke onye nnabata ihe a, yabụ, ịbalite cholesterol n'ọbara.
Fig. 21-44. Iwu nke cholesterol na-enye nguzozi n'etiti njikọta na nnabata cholesterol na nri. Glucagon na - eme ka phosphorylation (inactivation) nke NM G -CoA reductase, insulin na - akwalite dephosphorylation (ịgbalite). X - ihe cholesterol cholesterol metabolites na - akọpụtaghị nke na - akpali proteinolysis nke NM G -CoA reductase.
Cholesterol a na - achịkwaghị achịkwa nwere ike ibute ọrịa siri ike na mmadụ. Mgbe ngụkọta nke cholesterol na cholesterol a na-enweta site na nri gafere ego achọrọ maka mkpokọta membrane, njikọta nke bile salts na steroid, nchịkọta ihe cholesterol n'ime arịa ọbara (atherosclerotic plaques) nwere ike pụta, na-eduga na mgbochi ha (atherosclerotic plaques), na-eduga na mkpọchi ha (atherosclerotic). Na mba ndị mepere emepe, ọ bụ nkụda obi n'ihi mgbochi nke akwara ọbara bụ ihe kacha akpata ọnwụ. Mmepe nke atherosclerosis na-emetụta oke ọkwa cholesterol ọbara na ọkachasị na cholesterol na-anabata site na mpekere nke LDL; oke ọbara HDL, na ntụle, na-emetụta steeti nke arịa ọbara.
Site na hypercholesterolemia (akụrụngwa nke mkpụrụ ndụ ihe nketa), ọkwa nke cholesterol ọbara dị elu nke ukwuu - atherosclerosis siri ike na-etolite n'ime ndị a ugbua na nwata. N'ihi nnabata LDL nwere nkwarụ, nnabata ihe na-adịghị mma nke cholesterol nke LDL na-ewere ọnọdụ. N'ihi ya, a dịghị ewepu cholesterol n'ọbara ọbara, ọ na-agbakọ ma na-eme ka e nwee ike ịmalite ihie ụlọ nke atherosclerotic. Ngwakọta nke cholesterol na-aga n'ihu na-aga n'ihu, n'agbanyeghị oke cholesterol n'ime ọbara ahụ, ebe ọ bụ na cholesterol extracellular enweghị ike ịbanye na sel iji mezie njikọ intracellular (Fig. 21 -44).Maka ọgwụgwọ nke ndị ọrịa nwere hypercholesterolemia na ọrịa ndị ọzọ metụtara ọrịa cholesterol dị elu, a na-eji klaasị statin eme ihe. A na-enweta ụfọdụ n'ime ha site na isi mmalite, ebe ndị ọzọ na-emepụta ọgwụ. Statins yiri mevalonate (gbakwunye 21-3) ma bụrụ ndị na-egbochi asọmpi NMS-CoA.
Tinye 21-3. Ọgwụ. Ihe ogwugwo nke egbugbere onu ya na okike nke statins
Ọrịa obi na akwara obi (CHD) bụ isi ihe na-akpata ọnwụ na mba ndị mepere emepe. Mbelata akwara ndị na - ebute akwara obi na - ebute ọbara na mkpụrụobi na - apụta site na izụpụta abụba ndị ana - akpọ atherosclerotic plaques; plasta ndị a nwere kọlestrọl, protein protin, calcium, platelet, na iberibe sel. Na narị afọ nke XX. E nwere arụmụka siri ike gbasara mmekọrịta dị n'etiti ihe mgbochi akwara (atherosclerosis) na cholesterol ọbara. Mkparịta ụka ndị a na nyocha siri ike na akụkụ a emeela ka e nwee ọgwụ ndị dị irè na-agbada cholesterol.
Na 1913, N.N. Anichkov, onye ama ama na sayensi Russia ma bụrụ ọkachamara n’ọrịa gbasara nnwale, bipụtara ọrụ ebe o gosipụtara na oke bekee ji nri nwere oke cholesterol mepụta mbibi nke arịa ọbara nke yiri paịlịclerotic arịa n’ime arịa nke ndị agadi. Anichkov duziri nyocha ya ruo ọtụtụ iri afọ ma bipụta nsonaazụ ya na akwụkwọ akụkọ ndị Western a maara nke ọma. O bu ihe nwute, ihe omuma ya abughi nke ndabere maka ihe nlere maka atherosclerosis n’aru mmadu, ebe obu na n’oge ahu hypothesis na agbasokariri na oria a bu ihe ebuputa site n’okpo nkari na enweghi ike igbochi. Agbanyeghị, ihe akaebe ji nwayọọ nwayọọ na-amalite mmekọrịta dị n'etiti cholesterol na mmepe nke atherosclerosis (hypid hypothesis), na 1960s. ụfọdụ ndị nyocha ekwuola hoo haa na enwere ike ịgwọ ọrịa a na ọgwụ. Ka osi di, echiche di iche di adi rue mgbe edeputara ya na 1984 ihe omumu nke ihe omumu banyere oru cholesterol nke US Institute of Health (Coronary Primal Trial Trial) mere. Egosiputara mbelata ihe di egwu na oge nke myocardial infarction na strok na mbelata cholesterol. N'ime ihe omumu a, ejiri cholesterol, ihe ntughari nke anion na-ejiko bile acid, ejiri mee ka cholesterol belata. Nsonaazụ kpaliri ịchọ ọgwụ ọhụrụ, dị ike karịa. Ekwesịrị m ikwu na n'ụwa sayensị, obi abụọ banyere abamuru nke egbugbere ọnụ egbugbere ọnụ kpamkpam kpamkpam na mmalite nke statins na njedebe 1980s - mmalite 1990s.
Akira Endo chọtara statin mbụ na Sankyo na Tokyo. Endo bipụtara akwụkwọ ya na 1976, n'agbanyeghị na ọ lebara nsogbu cholesterol metabolism ọtụtụ afọ. N’afọ 1971, ọ tụrụ aro na cholesterol synthesis inhibitors nwekwara ike ịdị n’arụpụta ndị na - emepụta ọgwụ ọgwụ nje n’oge ahụ. Ruo ọtụtụ afọ nke ọrụ siri ike, ọ nyochara ihe karịrị ọdịbendị 6,000 nke olu dị iche iche, ruo mgbe ọ bịara rụpụta ihe dị mma. A na-akpọ kọlụm a na-akpọ compactin. Ihe a mebere cholesterol na nkịta na enwe. Ọmụmụ ihe ndị a dọtara uche nke Michael Brown na Joseph Goldstein nke Mahadum Texas Southwwest Medical School. Brown na Goldstein, ya na Endo, bidoro ọmụmụ ihe na nkwonkwo ma gosipụta data ya. Nnukwu ihe ịga nke ọma nke ule mbụ nke ụlọ ọgwụ metụtara ụlọ ọrụ na-emepụta ọgwụ na mmepe nke ọgwụ ọhụrụ ndị a. Na Merck, otu otu Alfred Alberts na Roy Wagelos duziri nyocha ọhụrụ nke ọdịbendị olu ha, maka nyochara ngụkọta nke ọdịnala iri na asatọ, chọpụtara ọgwụ ọzọ dị arụ ọrụ. A na-akpọ ihe ọhụụ. Agbanyeghị, n'otu oge ahụ, ekwenyere n'ọtụtụ ebe na nchịkwa nke nnukwu onyunyo nke nkịta na-ebute mmepe nke ọrịa kansa na nchọta akụrụngwa ọhụrụ na 1980s. a kwụsịtụrụ. Agbanyeghị, n'oge ahụ, uru nke iji ihe eji ele ihe anya dị iche iche iji gwọọ ndị ọrịa nwere hypercholesterolemia. Mgbe ọtụtụ ndị ọkachamara na mba ụwa na Nri na Nchịkwa nri na ọgwụ ọjọọ (FDA, USA), nyochachara ọtụtụ oge, Merck malitere ịmalite lovastatin. Nnyocha sara mbara n'ime iri afọ abụọ na-esote ekpugheghị ihe ọ bụla carcinogenic mmetụta nke lovastatin na ọgbọ ọhụrụ nke ọgwụ pụtara mgbe ọ nwụsịrị.
Fig. 1. Statins bụ ndị na - egbochi NM G-CoA reductase. Tụnyere ihe owuwu nke mevalonate na ngwaahịa ọgwụ anọ (statins) na-egbochi ọrụ NM G -CoA reductase.
Ọnọdụ gbochie ọrụ nke HMG - CoA - reductase, na-eyi ihe owuwu nke mevalonate, ma si otú a gbochie njikọta cholesterol. N'ime ndị ọrịa nwere hypercholesterolemia kpatara nkwarụ na otu okike nke usoro nnabata LDL, mgbe ị na-ewere lovastatin, cholesterol na-ebelata 30%. Ọgwụ a na-akachasị uru ma na-etinye ọnụ na mmiri pụrụ iche na-ejikọ bile acid ma gbochie mmiri iwepu ya na eriri afọ.
Ugbu a, statins na-ejikarị belata plasma cholesterol ọbara. Mgbe ị na-a medicationụ ọgwụ ọ bụla, ajụjụ a na-ebilite banyere mmetụta ọjọọ ọ na-adịghị mma. Kaosinadị, n'ihe banyere statins, ọtụtụ mmetụta dị iche iche, n'ụzọ dị iche, dị mma. Ọgwụ ndị a nwere ike ịkwalite ọbara ọgbụgba, dozie oghere mbido atherosclerotic (ka ha ghara isi n'akụkụ mgbidi arịa ọbara ghara igbochi ọbara ọgbụgba), na-egbochi nchịkọta platelet, ma na - emekwa ka usoro mkpali ghara ịdị na mgbidi nke arịa ọbara. N'ime ndị ọrịa na-ewere statins na nke mbụ, a na-egosipụta mmetụta ndị a ọbụna tupu ọkwa ọkwa cholesterol amalite iju, yana ikekwe na-esonye na mgbochi nke njikọ isoprenoid. N'ezie, ọ bụghị n'akụkụ niile nke statins na-aba uru. N'ime ụfọdụ ndị ọrịa (ọ na-abụkarị n'etiti ndị na-ewere statins yana ọgwụ ndị ọzọ na-ebelata cholesterol), mgbu akwara na ike ọgwụgwụ nwere ike ime, ma oge ụfọdụ n'ụdị ike. E debara aha ọtụtụ ihe ndị ọzọ metụtara statins, nke, ọ bụ ihe ọma, ọ na-anaghị adịkebe. N'ọtụtụ ndị ọrịa, ịkpụ akpụ nwere ike igbochi mmepe nke ọrịa obi. Dịka ọgwụ ọ bụla, a ga-eji statins dị ka dọkịta gị si chọọ.
Ebe enweghi cholesterol HDL cholest chorol, cholesterol di ala nke ukwuu, ya na oria Tangier, cholesterol achoghi nke oma cholesterol. Ọrịa abụọ ahụ sitere na mmụba na protein ABC1. Iberibe cholesterol HDL enweghị ike ijide cholesterol site na mkpụrụ ndụ ndị ABC1 na-erughị ala, a na-ewepụ mkpụrụ ndụ cholesterol ọbara ngwa ngwa n'ọbara ma mebie ya. Abụọ enweghị ihe nketa nke HDL na ọrịa Tangier dị ụkọ (erughị ezinụlọ 100 nwere ọrịa Tangier bụ ndị a maara n'ụwa niile), mana ọrịa ndị a na-egosipụta ọrụ nke protein ABC1 n'ịhazi ọkwa ọkwa plasma nke HDL. Ebe ọ bụ na ọkwa plasma HDL dị ala na-emekọ ihe ọnụ na nnukwu mbibi akwara obi, protein ABC1 nwere ike bụrụ ebumnuche bara uru maka ọgwụ ndị emepụtara iji hazie ọkwa HDL. ■
A na-etolite homonụ steroid site na nkewa cholesterol na oxidation ya n'akụkụ.
Mmadu na-enweta homonụ steroid ya niile na cholesterol (Fig 21-45). A na-agwakọta klas homonụ steroid abụọ na eriri akpa adrenal: mineralcorticoids,nke na-edozi nnabata nke ion inorganic (Na +, C l - na HC O) 3 -) n'ime akụrụ, na glucocorticoids, nke na-enyere aka ịhazi gluconeogenesis ma belata mmeghachi omume mbufụt. A na-emepụta homonụ mmekọahụ na mkpụrụ ndụ nke ụmụ nwoke na ụmụ nwanyị na Plasenta. N'ime ha progesterone na-edozi usoro ọmụmụ nwa, androgens (dịka ọmụmaatụ testosterone) na estrogens (estradiol), nke na-emetụta mmepe nke njiri mara mmekọahụ na ụmụ nwoke na ụmụ nwanyị n'otu n'otu. Homonụ steroid nwere mmetụta na oke ala yana ya mere etinyere ha obere obere obere. E jiri ya tụnyere salts salts, a na-eri obere kọlestrọl maka mmepụta homonụ steroid.
Fig. 21-45. Arefọdụ homonụ steroid sitere na cholesterol. E gosiputara uzo nke ufodu mmanu ndi a na fig. 10-19, v. 1.
Ngwakọta nke homonụ steroid chọrọ iwepu otutu ma ọ bụ ha dum carbon atom na “olu n'ụdị” nke C-17 D-ring nke cholesterol. Mwepu yinye akụkụ na-eme na mitochondria nke anụ ahụ steroidogenic. Usoro mwepu ahụ mejupụtara hydroxylation abụọ nke carbon carbon abụọ nke eriri akụkụ (C-20 na C-22), mgbe ahụ nkpuchi nkekọ dị n'etiti ha (Fig 21-46). Mepụta homonụ dị iche iche gụnyekwara iwebata ikuku oxygen. Ihe mmeghari mmiri na mmeghachi mmezi ahu na steroid biosynthesis na-ejiko ya site na oxidases na-aru oru (tinye. 21-1) nke na-eji NА D PH, O 2 na mitochondrial cytochrome P-450.
Fig. 21-46. Cleavage nke akụkụ yinye na njikọ nke homonụ steroid. N'ime sistemụ oxidase a nwere ọrụ agwakọta nke na-egbochi carbon atọm n'akụkụ, cytochrome P-450 na-arụ ọrụ dị ka onye na-ebu electron. Ndi tinyekwara aka na usoro a bụ protein na-ebugharị elektrọn, adrenodoxin na adrenodoxin reductase. A hụrụ usoro nkewa nke akụkụ a na mitochondria nke adrenal cortex, ebe mmepụta steroid dị ike na-ewere ọnọdụ. Pregnenolone bụ ihe dị mkpa maka homonụ steroid ndị ọzọ niile (Fig 21-45).
Cholesterol biosynthesis intermediates na-etinye aka n'ọtụtụ ụzọ metabolic ndị ọzọ.
Na mgbakwunye na ọrụ ya dị ka etiti nke cholesterol biosynthesis, isopentenyl pyrophosphate na-arụ ọrụ dị ka ihe ntụgharị aka na njikọta nke nnukwu biomolecules nke na-arụ ọrụ dị iche iche maka ndu (Fig. 21-47). Ihe ndị a gụnyere vitamin A, E na K, ahịhịa mkpụrụ osisi dị ka carotene na chlorophyll phytol, roba eke, ọtụtụ mmanụ dị mkpa (dịka ọmụmaatụ, isi ala nke mmanụ lemon, mmiri na-eucalyptus, musk), homonụ nke ụmụ ahụhụ na-achịkwa metamorphosis, dolichols, nke na-eje ozi dị ka ndị na-eme ka mmiri na-egbu egbu na nchịkọta nke polysaccharides, ubiquinone na plastoquinone - ndị na-ebu electron na mitochondria na chloroplasts. Mole ndị a niile bụ isoprenoids n’usoro. Achọpụtala ihe dị iche iche karịrị 20,000 na ekike, na-akọ narị narị ndị ọhụrụ na afọ ọ bụla.
Fig. 21-47. Foto n'ozuzu nke biosynthesis nke isoprenoids. Enyere usoro nke ọtụtụ ngwaahịa ngwaahịa a na-ekwu ebe a ka enyere na isiakwụkwọ. 10 (v. 1).
Mgbapụta (njikọta njikọta nke ihe na - adọ adọ, lee fig. 27-35) bụ ihe eji eme ka ihe ndi mmadu na - edozi ihe ntinye na elu aru nke akwara mammalian (lee fig 11-14). N'ụfọdụ protein, a na-anọchite anya egbugbere ọnụ agbụ ahụ mejupụtara site na farnesyl carbon 15, na ndị ọzọ, ọ bụ ìgwè geranyl 20 carbon. Lidị lipids abụọ a na-ejikọ enzymes dị iche iche. O kwere omume na imeghachi omume na - egbochi ihe na - akpata protein dị iche iche na - adabere na nsochi nwere njikọ. Rilmepụta protein bụ ọrụ ọzọ dị mkpa maka ndị na - ekewapụta ele Loose - ndị sonyere usoro cholesterol metabolic way.
Nchikota Nkebi nke 21.4 Biosynthesis nke cholesterol, Steroid, na Isoprenoids
A na-etolite cholesterol site na acetyl-CoA na usoro mmeghachi omume dị mgbagwoju anya site na ntanetị dịka β-hydroxy-β-methylglutaryl-CoA, mevalonate, iso Looseen dimethylallyl pyrophosphate na isopentenyl pyrophosphate. Ihe odide nke bibe iche na –eme ka ihe ndi na –emeghi ka cyclic squalene puta ihe, nke ndi cyclizes meputara usoro eji abanye ya ma dobe ya.
■ Nlekọta cholesterol dị n'okpuru nlekọta homonụ na, na mgbakwunye, enwere mgbochi site na ịba ụba nke choralerol intracellular, nke na-eme site na mgbanwe mgbanwe na nhazi nke transtọva.
The A na-ebu mmiri cholesterol na kọlestrọl dị ka plasma lipoproteins. Mbelata VLDL na-ebufe cholesterol, cholesterol esters na triacylglycerols site na imeju gaa na akwara ndị ọzọ, ebe triacylglycerols na-ehichapụ lipoprotein lipase na VLDL na-agbanwe ka LDL. Iberibe LDL mejupụtara na cholesterol na cholesterol esters na-anabata n'ụzọ na-apụtaghị ìhè site na ndị na-anabata ya site na endocytosis, ebe a na-anabata nnabata B-100 apolipoprotein na LDL. HDL wepu cholesterol n'ime ọbara, bufee ya na imeju. Ọnọdụ nri ma ọ bụ ntụpọ mkpụrụ ndụ ihe nketa na metabolism cholesterol nwere ike ibute atherosclerosis na infarction myocardial.
Are a na-etolite homonụ steroid (glucocorticoids, mineralocorticoids na homonụ mmekọahụ) site na kọlestrọl site na-agbanwe ụdọ n'akụkụ yana iwebata atoms oxygen n'ime sistemụ steroid nke mgbanaka ahụ. E mepụtara ọtụtụ ogige ndị ọzọ na - anọpụ iche site na mevalonate site na mgbochi nke isopentenyl pyrophosphate na dimethylallyl pyrophosphate yana kọlestrọl.
■ Ime ka protein ụfọdụ na-edunye ha ka ha kee mkpokoro sel ma bụrụkwa ihe dị mkpa maka ọrụ ha.
Ajụjụ 48. Iwu nke metabolism nke abụba abụba (β-oxidation na biosynthesis). Ngwa nke malonyl CoA. Acetyl CoA carboxylase, iwu nke ọrụ ya. Ibu nke acyl Co-a nke membrane nke mitochondria.
Isi
a na-eri ego nke phenylalanine
na ụzọ abụọ:
gbanye
na squirrels,
atụgharịa
na tyrosine.
Na-atụgharị
phenylalanine ka tyrosine bụ isi
dị mkpa iji wepu ngafe
phenylalanine, ebe ọ bụ na nnukwu ịta
Ọ na-egbu nsị na mkpụrụ ndụ. Agụmakwụkwọ
tyrosine enweghị ihe ọ bụla
ebe enweghi amino acid a
niime ụlọnga ihe anaghị eme.
Isi
metabolism nke phenylalanine na-amalite
ya hydroxylation (Fig 9-29), n’ime
na - ebute ịba ọcha n'anya.
Otu ọkachamara mere ka mmeghachi omume a na-emetụta
monooxy-nase - phenylalanine hydra (zsilase,
nke a n’eme ka ndi n’enye ihe
tetrahydrobiopterin (N4BP).
Enzyme ọrụ na-adaberekwa
ọnụnọ nke Fe2.
Na
imeju ya na-agba ume ngwa ngwa
glycogen (lee mpaghara 7). Agbanyeghị
glycogen na imeju agbariwo
18-24 awa nke ibu ọnụ. Isi mmalite
glucose dị ka ebuka na-agwụ
glycogen na - aghọ gluconeogenesis,
nke na-amalite ngwa ngwa site na
Fig.
11-29. Nnukwu mgbanwe metabolic
ike mgbe ị na-agbanwe ihe absorbent
postabsorbent steeti. CT
- ozu ketone, FA - abụba bara ụba.
4-6 ikp
mgbe nri ikpeazụ. Na-ekwupụta
A na-eji glycerol eme ihe maka glucose njikọ,
amino acid na lactate. N’elu elu
glucuagon ịta nchịkọta ọnụego
abụba nke ọdụdụ belatara n'ihi
phosphorylation na inactivation
acetyl CoA carboxylase na ọnụego
p-oxidation na-abawanye. Kaosinadị,
abụba na-eweta oke umeju
acid na-ebugharị
sitere na deba abụba. Acetyl-CoA guzobere
a na a useda mmanu nke abuba
na imeju maka njikọ nke ahụ ketone.
Na
adipose anụ ahụ na ịba ụba ịta
glucagon belatara onu ahia onodu
A kpaliri TAG na lipolysis. Mkpali
lipolysis - nsonaazụ nsonaazụ
lipase na-emetụta ihe hormone
adipocytes n'okpuru nduzi nke glucagon.
Acids Acry Abụrụ Mkpa
ike sitere na imeju, akwara na
anụ ahụ adị.
Yabụ
n'ihi ya, n'oge postabsorption
a na-eme ka ịbawanye ọcha na ọbara
na ọkwa 80-100 mg / dl, na ọkwa nke abụba
acid na aru ketone na-abawanye.
Ọka
ọrịa shuga bụ ọrịa na-eme
n'ihi oke ma ọ bụ onye ikwu
erughi insulin.
A.
Isi ụlọ ọgwụ dị n'ụdị shuga
ọrịa shuga
Dabere na
Nzukọ ụwa
ahụike na-arịa ọrịa shuga
nkewa di iche-iche
mkpụrụ ndụ ihe nketa na-adakarị
isi abuo abuo: oria shuga
Idị nke I - insulin-dependance (IDDM), yana ọrịa shuga
IIdị II - insulin nọọrọ onwe ya (NIDDM).
Iwu
Usoro enzyme nke zhk
njikọ nke lcd - acetyl CoA carboxylase.
Enzyme a na - achịkwa ọtụtụ
ụzọ.
Ntughari / kewapu
Enzyme subunit ogige. Na
acdị acetyl CoA carboxylase adịghị arụ ọrụ
na-anọchi anya ogige dị iche iche,
nke ọ bụla n’ime ha mejupụtara 4 ndepụta okwu.
Onye na-eme ka enzyme ahụ bụ citrate. Ọ na-akpali
ngwakọta nke ogige dị iche iche, n'ihi ya
ya mere ihe enzyme na-abawanye
. Inhibitor-palmitoyl-CoA. Ọ na-akpọ
mkpesa di nkpa na ibelata
enzyme ọrụ.
Phosphorylation / Dephosphorylation
acetyl CoA carboxylase. Na
postabsorption steeti ma ọ bụ na
ọrụ anụ ahụ glucagonized
adrenaline site na adenylate cyclase
sistemụ na-arụ ọrụ site na prokinase A na
na-akpali phosphorylation subunit
acetyl CoA carboxylase. Phosphorylated
enzyme adịghị arụ ọrụ yana njikọ nke abụba
acid akwụsị.
Anaghị anabata
oge insulin na-eme ka phosphatase rụọ ọrụ,
na acetyl-CoA carboxylase na-abanye
steeti ike. Mgbe ah
n'okpuru mmetụta nke citrate emee
polymerization nke protomers nke enzyme, na
ọ na-arụ ọrụ. Na mgbakwunye na mmegharị
enzyme, citrate na-arụ ihe ọzọ
ịrụ ọrụ na njikọ nke LCD. Anaghị anabata
oge na mitochondria nke sel akwara
na-agbakọta citrate, nke
a na-ebugharị mmiri acyl gaa
cytosol.
Iwu
β-oxidation udu.
Β-oxidation-metabolic way,
jikọtara ọnụ na ọrụ CPE na izugbe
ụzọ nke catabolism. Ya mere ọsọ ya
na-ahazi ụkpụrụ ụlọnga
ike i.e. site na oke nke ATP / ADP na NADH / NAD, yana mmeghachi omume CPE na
n'okporo ụzọ nkịtị nke catabolism. Ọsọ
β-ox iji es mee id mee id iji id mee id mee id iji id mee id mee ihe n’eme ka oghara
mkpụrụ, i.e.
n'ọnu abuba
acid na-abanye na mitochondria.
Ngwakọta nke Acid Free
n'ọbara na-ebili n’elu ọrụ
lipolysis na adipose anụ ahụ n’oge ibu ọnụ
n'okpuru nduzi nke glucagon na n'oge anụ ahụ
na-arụ ọrụ n'okpuru nduzi nke adrenaline. N'ime ndị a
abuba abuba ibu
ike kachasị
n'ihi na akwara na imeju, dị ka a N'ihi
A na-emepụta id-oxidations site na NADH na acetyl-CoA inhibiting
ogige pyruvate dehydrogenase.
Mgbanwe nke uzo pyruvate
site na glucose na acetyl-CoA na-eji nwayọ nwayọ.
Metabolites ndị na-agba etiti na-agbakọta
glycolysis na, ọkachasị, glucose-6-phosphate.
Glucose-6-phosphate na-egbochi hexokinase
ya mere na-egbochi
ihe glucose n’usoro
glycolysis. N'ihi ya, ihe kasịnụ
eji lcd dika isi ihe
ume na akwara anụ ahụ na umeji
na-azọpụta glucose maka akwara anụ ahụ na
mkpụrụ ndụ ọbara uhie.
Β-oxidation kwa
dabere na ọrụ enzyme
carnitine acyltransferases nke m.
N'ime imeju, a na-egbochi enzyme a.
malonyl CoA, ihe mejupụtara
ya na biosynthesis nke lcd. N'oge nnabata
glycolysis na-arụ ọrụ na imeju na
guzobe acetyl-CoA na-abawanye
site na pyruvate. Ihe mbu mere
Ntughari lcd nke acetyl-CoA gaa malonyl-CoA.
Malonyl-CoA gbochiri β-oxidation nke lcd,
nke eji eme ya
abụba.
Agụmakwụkwọ
malonyl-CoA sitere na nhazi-iwu acetyl-CoA
mmeghachi omume na biosynthesis lcd. Mmeghachi omume mbụ
njikọ lcd nke acetyl-CoA ka
malonyl CoA. Enzyme catalytic
mmeghachi omume a (acetyl Coa carboxylase),
so na klaasị ligases. O nwere
na - ejikọ biotin. Na mbu
co2 covalent mmeghachi omume
na - egbochi biotin n'ihi ume
ATP, na ogbo 2 COO- bufere ya
na acetyl-CoA iji mepụta malonyl-CoA.
Acetyl CoA Carboxylase Enzyme Arụ Ọrụ
na-ekpebi ọsọ nke ndị niile na - eso ya
njikọ mmeghachi omume lc
citrate na-eme ka enzyme dị na cytosol
acetyl CoA carboxylase. Malonyl CoA in
n'aka nke ya na-egbochi mbufe nke elu
abuba sitere na cytosol rue matriks
mitochondria igbochi ọrụ
acetyl CoA: carnitine acyltransferase,
si otú a na-agbanyụ ya mmiri oyi
abuba abuba.
Acetyl-CoA Oxaloacetate →
Hit-CoA Citrate
HSCOA ATP Citrate → Acetyl-CoA ADP Pi Oxaloacetate
Acetyl-CoA
na cytoplasm na-arụ ọrụ dị ka mkpụrụ amalite
maka njikọ nke lcd, na oxaloacetate na
cytosol na-enyocha mgbanwe na
nsonaazụ nke pyruvate guzobere.
Cholesterol biosynthesis
Cholesterol biosynthesis na - eme na endoplasmic reticulum. Ihe na - eme ka amịlị carbon niile dị na molekul bụ acetyl-SCoA, nke na - esite na mitochondria bụ akụkụ nke citrate, dị ka njikọ nke ọdụdụ abụba. Cholesterol biosynthesis na-eri irighiri ihe 18 ATP na ụmụ irighiri ihe 13 NADPH.
Guzo cholesterol na - aputa ihe karia mmeghachi omume 30, nke enwere ike ịhazi ya n'ọtụtụ nkebi.
1. Ngwakọta nke mevalonic acid.
Mmeghachi izizi abụọ mbụ dabara na mmeghachi omume ketogenesis, mana mgbe njikọta nke 3-hydroxy-3-methylglutaryl-ScoA, enzyme na-abanye hydroxymethyl-glutaryl-ScoA reductase (HMG-SCOA reductase), na-akpụ acid mevalonic.
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