Bài giảng Hóa sinh 2: Phần 2 - Trường ĐH Võ Trường Toản

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Nối tiếp phần 1, phần 2 của tập bài giảng Hóa sinh 2 tiếp tục cung cấp cho sinh viên những nội dung tổng quan về: chuyển hóa hemoglobin; chuyển hóa acid nucleic; liên quan và điều hòa chuyển hóa; sự trao đổi nước và các chất điện giải; thăng bằng acid - base; hóa sinh thận và nước tiểu; hóa sinh gan; hóa sinh máu;... Mời các bạn cùng tham khảo chi tiết nội dung bài giảng!

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Nội dung Text: Bài giảng Hóa sinh 2: Phần 2 - Trường ĐH Võ Trường Toản

CHlJdNG 4 CHUYEN HOA HEMOGLOBIN MUC TIEU 1. Trinh bay va giai thich dtfdc tien trinh va cd chd cua qua trinh sinh tdng hdp hemoglobin. 2. Trinh bay va giai thich dtfdc tien trinh va cd che ciia qua trinh thoai hda hemoglobin. 3. Neu va giai thich dtfdc nhtfng benh ly gay ra do rd'i loan chuyen hda hemoglobin. 1. SINH TONG H0P HEMOGLOBIN 1.1. Sinh tdng hcfp hem Hem cd cau triic gdm nhan protoporphyrin III ket hdp vdi Fe"+. Stf tdng hdp hem xay ra trong hau het te bao ngoai trtf hong cau trtfdng thanh vi khong cd ty the. Khoang 85% stftdng hdp hem xay ra d te bao tien hong cau trong tuy xtfdng. 1.1.1. Tong hcfp nhan protoporphyrin III Hai nguyen lieu khdi dau cho qua trinh tdng hdp nhan porphyrin ttf do tao hem la succinyl CoA va glycin. Succinyl CoA la mot cha't trung gian ciia chu trinh acid citric, con glycin la mot acid amin . Qua trinh tdng hdp nhan protoporphyrin qua cac giai doan sau: 1.1.1.1. Tao acid 5 - amino levulinic (ALA) Stf tdng hdp ALA xay ra d ty the, ndi ma succinyl CoA dtfdc tao thanh trong cac phan tfng ciia chu trinh acid citric. Glycin dtfdc hoat hda bdi pyridoxal phosphat (vitamin B6) Succinyl CoA ket hdp vdi glycin, loai CoA tao thanh acid a - amino -P - ceto adipic. Chat nay nhanh chdng bi khtf carboxyl de tao thanh acid 5 -amino levulinic (ALA) vdi stf xiic tac ciia enzym ALA synthetase vdi coenzym la pyridoxal phosphat: COOH COOH COOH I I I CH9 CH9 CHo Succinyl CoA I I I CH 2 CH2 CH2 I _ . I ALA synthetase I CO-SCoA HSCoA CO pyridoxal phosphat fO + *" CH-NH2 T^n*" CH2-NH2 CH2-NH2 J^n "; UU2 Glycin i00u (COOjH Ac[d a.amlno levulinic (ALA) Acid a-amino p-cetoadipic 1.1.1.2. Tao porphobilinogen ALA dtfdc tao thanh se di chuyen den bao ttfdng. Tai day, hai phan ttf ALA ngtfng tu vdi nhau (loai 2 phan ttf H20) va dong vdng pyrol tao thanh porphobilinogen vdi stf xiic tac ciia enzym ALA dehydratase (porphobilinogen synthase), enzym nay bi tfc che bdi chi kim loai (Pb). 102
COOH COOH COOH I COOH CH CH2 COOH CK I CH2 CHP C H2 O C I ^2Ha° Ql_j /\LA dehydratase A / NH2-CH2 N NH2 - CH2 OH. N NH^CH^ ^N/VH 2 H Porphobilinogen 1.1.1.3. Tao uroporphyrinogen Bon phan ttf porphobilinogen ket hdp vdi nhau, loai 3NH3 tao thanh mot tetrapyrol mach thing va chat nay lai tidp tuc loai NH3 va dong vong, cac nhan pyrol ndi vdi nhau blng ciu ndi - CH2 cd the tao thanh uroporphyrinogen I (enzym xiic tac ia uroporphyrinogen synthetase) va uroporphyrinogen HI (enzym xuc tac la uroporphyrinogen cosynthetase). Hai chat nay chi khac nhau ve vi tri ciia 2nhdm the d nhan pyrol TV. Binh thtfdng, dong phan dtfdc tao thanh hau nhtf deu la uroporphyrinogen III. Khi cd rdi loan chuyen hda porphyrin mdi tao thanh uroporphyrinogen I •PA, -P A. 3NH3 H,N-CH H.N-CH, CH2/Vs^AcH2Ax^\cH2 N N H H \ ,p A\ /" N _ A A N uroporphyrinogenase IV ^NH hn( II IV )nh hn( II N N A p/ \ p'\ Uroporphyrinogen Uroporphyrinogen 103
1.1.1.4. Tao coproporphyrinogen III , , ~- Uroporphyrinogen III chuvdn thanh coproporphyrinogen III nhd stf khtf carboxyl cua tot ca cac gdc acetat (A) d mach nhanh dd chuydn thanh cac gdc metyl (M) vdi stf xiic tac cua enzym uroporphyrinogen decarboxylase. ,M IV >NH HN
" Sau khi dtfdc tong hdp xong, hem rdi ty thd ra bao ttfdng de kdt hdp vdi globin. Stf kdt hdp gitfa hem va globin dtfdc thtfc hien qua lien kdt pho'i tri gitfa Fe cua hem vdi nitd imidazol (histidin) ciia globin. Qua trinh tdng hdp hemoglobin xay ra chii ydu dcd quan tao mau nhtf tuy xtfdng va cac hong cau non. 2. THOAI HOA HEMOGLOBIN H6ng clu ngtfdi cd ddi song trung binh khodng 120 ngay, trong thdi gian nay Hb khong bi bien doi. Khi hong du chet, Hb se dtfdc giai phdng va bi thoai hda. Trong didu kien sinh If d ngtfdi trtfdng thanh binh thtfdng, cd ttf 1-2 x 108 hdng clu bi thoai hda trong 1gid.Trtf Fe va globin, nhffng san pham thoai hda ciia porphyrin khong dtfdc cd the stf dung trd lai. Stf thoai hda Hb xay ra chii yeu d nhffng te bao thuoc he tho'ng vdng noi mo nhtf gan, lach, tuy xtfdng.... Khi hemoglobin bi phan huy se giai phdng globin va hem: - Globin chuyen hda theo con dtfdng thoai hda ciia protein noi bao de tao acid amin, - Hem se thoai hda Ian ltfdt tao thanh sac td mat: 2.1. Tao biliverdin Dtfdi tac dong ciia enzym hem oxygenase, vdng porphyrin cua hem bi md gitfa nhan pyrol Iva II bang each oxy hda va loai Cdcau ndi methenyl a dtfdi dang carbon monoxid (CO), giai phdng sat dtfdi dang Fe3+ tao thanh biliverdin (sac td mat mau xanh). Fe tach ra ket hdp vdi mot protid van chuyen la transferin, dtfdc mau dtfa den tuy xtfdng de dung lai. M, V l%^{ Biliverdin Hinh 4.1. Sd do phan tfng tao sac to'mat biliverdin. 2.2. Tao bilirubin Biliverdin nhanh chdng bi khtf d cau no'i - CH= tai vi tri y( cong Hd Cy, Nkdt hdp vdi Hva cac no'i doi se di chuyen) tao thanh bilirubin (sac td mat cd mau vang xanh) vdi stf xiic tac 105
ciia enzym biliverdin reductase, co coenzym la NADPH cung cap hydro. Bilirubin nay khd tan trong^ntfdc, cho phan tfng mau diazo cham va gian tidp, goi la bilirubin ttf do hay gian tiep. Sau khi tao thanh d mo ngoai vi, nd dtfdc chuyen vao mau ket hdp vdi albumin, globulin ciia huyet thanh va theo mau den gan.Vi no la chat tan trong lipid nen co the tham qua mang te bao gan dd dang va tach khoi albumin, globulin. Bilirubin Hinh 4.2. Cau triic ciia sac td mat bilirubin. 2.2. Su* lien hr/p bilirubin d gan Tai gan, bilirubin ttf do lien hdp vdi 1hay 2 phan ttf acid glucuronic tao thanh dang lien hdp bilirubinmonoglucuronat (20%) va bilirubindiglucuronat (80%). Phan tfng xay ra gitfa 2 nhdm carboxyl (-COOH) ciia gd'c propionat (P) d mach nhanh ciia bilirubin vdi nhdm OH ban acetal ciia acid glucuronic. Acid glucuronic d dtfdi dang hoat hda uridin diphosphat glucuronat va phan tfng lien hdp dtfdc xiic tac bdi enzym glucuronyl transferase. Bilirubin lien hdp tan dtfdc trong ntfdc, cho phan tfng mau diazo nhanh va trtfc tiep, goi la bilirubin trtfc tiep. Bilirubin lien hdp dtfdc bai tie't vao mat theo mot cd che van chuyen chu dong rdi theo 6'ng dan mat dd vao ruot. Binh thtfdng, trong mat ngtfdi biliverdin cd mot ltfdng rat nho con bilirubin chiem khoang 15-20% trong ltfdng kho. OOC coo- Bilirubin diglucoronat Hinh 4.3. Cau triic ciia bilirubin lien hdp. 106
2.3. Su* biS'n ddi bilirubin d ruot druot, dtfdi tac dong ciia enzym p-glucuronidase, bilirubin lien hdp bi thiiy phan giai phdng bilirubin ttf do. Ddn dai trang, dtfdi tac dung ciia cac enzym ciia vi khua'n ydm khi bilirubin ttf do bi khtf oxy, bao hoa cac lien kdt doi di tao thanh urobilinogen va stercobilinogen' la nhffng hdp cha't khong mau. b ' ^ Tren 50% cac san pha'm khtf nay ciia bilirubin dtfdc tai hap thu qua tinh mach ciia- mot phan theo mau ve gan , dtfdc oxy hda trd lai tai tao bilirubin rdi lai theo mat dd vao ruot tao thanh mot chu trinh gan ruot, mot phln nhd theo mau vd than va dao thai ra ngoai theo ntfdc tieu. Phan con lai ciia urobilinogen va stercobilinogen d ruot khong dtfdc tai hap thu, se dtfdc dao thai ra ngoai theo phan. Trong phan va ntfdc tieu, urobilinogen va stercobilinogen bi oxy hda bdi oxy ciia khong khi tao thanh urobilin va stercobilin cd mau vang cam, tao mau cho phan va ntfdc tieu. Binh thtfdng ntfdc tieu chtfa rat it urobilinogen va urobilin (l-4mg/24gid), con stercobilinogen trong phan cd khoang 40-280mg/24gid. Khi bi tac mat, phan se mat mau do bilirubin lien hdp khong xuong ruot dtfdc, nen khong tao urobilinogen va stercobilinogen. - JTrtfdng hdp thidu men vi khulh ruot (udng nhidu khang sinh, tre sd sinh thidu enzym cua vi khuan ruot...) Bilirubin khong bi khtf druot, dtfdc
GAN Tb noi mac vong mo MAU ^Bilirubin Bilirubin ttf do Bilirubin NADPH. UDP- glucuronat Acid glucuronic Albumin Biliverdin in reductase ' transfersa ( J NADP+ Bilirubin lien hdp Biliverdin NADPH MAT \ f Hem oxynase ^ CO, Fe2+ RUOT acid glucuronic NADP+ Bilirubin Hemoglobin Hong cau V8H ) THAN — Urobilinogen—\ Urobilinogen AH y Stercobilinogen 2H Stercobilinogen 2H 2H uudc 2H PHAN TIEU Stercobilin Urobilin Urobilin Stercobilin Hinh 4.5. Sd dd ciia stf thoai hda hemoglobin. 3. ROI LOAN CHUYEN HOA HEMOGLOBIN 3.1. Rdi loan sinh tdng hdp hemoglobin 3 11 Roi loan sinh tdng ho*p hem S" hie'u hut cac enzym chinh trong qua trinh sinh tdng ho* porphyrin gay U. cac ne^ „ dong . chat cua porphyrin trong hong cau. cac dich c* thi va gan ;do .a nhffng benh thuoc nhom b?nh porphyrin ^.Vid,: ^ ^ ^ ^^ ^^ ^ ^ ri nl, do do khong tdng h„pV hem de' tao hdng cau lam cho benh nhan bi thieu mau tram trong. -Benh tf dong porphobilinogen trong gan gay roi loan than kinh. 3.1.2. Ro'i loan sinh td'ng hcfp globin ,*.,.• . u „„„i^;n Tren Mc US co khoang 300 loai gen tdng hdp nen cac chuc, globin cua hemoglobin.^ G5c loai nay chi khac nhau d1vi tri tren chudi polypeptid cua globin. Su hay do, nho nay khong .mty ddi dang ke' cau true va Cure n.ng cua phan * hemoglobin trff trU.ng ,p al amin valin thay cho glutamat avi tri thff 6cua chudi (3 cua globin gay benh thieu mau hon 2>Zmi Hem hay lysin thay cho giu.amat ovi tri thff 6cua chuoi pcua globin gay b?nh thieu mau hdng cau hinh bia. 108
3.2. Roi loan thoai hda hemoglobin Binh thtfdng, ndng do bilirubin toan phan trong mau vao khoang 0,2 -0,8 mg/lOOml, chii yeu ddang ttf do (85%) con dang lien hdp chi cd ddang vdt (15%). Khi bilirubin trong mau'vtfdt qua lmg/lOOmL se khuydch tan vao cac td chtfc dac biet la da va niem mac,vang da xua't hien khi nong dp bilirubin toan ph£n >2-2,5mg/100 ml huydt thanh. Stf tang ndng do bilirubin trong mau cd the do stf tao thanh bilirubin nhieu hdn stf dao thai dgan binh thtfdng; hay trtfdng hdp gan bi suy nen stfdao thai bilirubin giam. Sau day la mot sdbenh ly vang da do ro'i loan thoai hda hemoglobin: 3.2.1. Vang da trtfdc gan Xay ra do nhtfng nguyen nhan lam tan huyet hay tang stf pha huy hdng cau: - Benh do Hb bat thtfdng (HbS, thalassemia...) - Benh di truyen do thie'u enzym G6PD. - Benh miln dich (truyen nham nhdm mau, bat dong nhdm mau - Rhesus ....) -Benh mac phai (sd't ret, sot xuat huye't, nhilm trung, nmem doc dung moi htfu cd) Nhtfng trtfdng hdp nay se tao ra mot ltfdng ldn bilirubin ttf do, khong dtfdc dua phan tfng lien hdp d gan hetnen ndng do tang cao trong mdu (# 6-7mg%). (3 tre sd sinh, do he tho'ng lien hdp, cac thu the d mang te'bao gan chtfa hoan chinh nen cung lam tang bilirubin ttf do trong mau gay chtfng vang da sinh ly kha phd bien, thtfdng xay ra vao ngay thtf 2 hay thtf 3 sau khi sinh, dac biet d tre sinh non. Trong trtfdng hdp nay se khong cd bilirubin ttf do trong ntfdc tieu vi khong tan trong ntfdc nen khong qua dtfdc than. Ngoai ra, do ltfdng bilirubin tang nen urobilinogen va stercobilinogen se dtfdc dao thai nhieu ra phan va ntfdc tieu. Phan se cd mau vang slm. 3.2.2. Vang da tai gan Trong trtfdng hdp viem gan, td bao gan bi ton thtfdng lam giam kha nang lien hdp bilirubin, bilirubin ttf do trong mau tang va giam stercobilin trong phan. Ngoai ra, khi viem gan cac nhu mo gan bi phil nd chen ep cac vi qudn mat gay tac mat lam cho bilirubin lien hdp khong xuo'ng ruot dtfdc, tang cao trong mau va xuat hien trong ntfdc tieu (sac to'mat). Urobilinogen ctfng cd the tang trong ntfdc tieu vi ton thtfdng gan lam giam kha nang tai tao bilirubin ttf urobilinogen, chat nay bi tf dong d gan, tran vao mau va dao thai ra ngoai theo ntfdc tieu. 3.2.3. Vang da sau gan Trong trtfdng hdp dtfdng dan mat bi tac (do bi soi mat, u dau tuy tang...), bilirubin lien hdp khong xuo'ng ruot dtfdc, bi tf lai d gan, tran vao mau va tang len rat cao, chiem ty le >80% bilirubin toan phan. Bilirubin lien hdp tan dtfdc trong ntfdc nen qua dtfdc cau than va thai nhieu ra ntfdc tieu (cd sac to'mat trong ntfdc tieu). Urobilinogen cd the tang do tf trong gan, tran vao mau va xuat hien nhieu / ntfdc tieu. Bilirubin lien hdp khong xuo'ng ruot dtfdc nen se khong cd urobilinogen va stercobilinogen dao thai ra ntfdc tidu va phan -> phan cd mau trang xam nhtf dat set. TAI LIEU DOC THEM 1. Bo mon Hda sinh-Trtfdng Dai hoc Y ha Noi. Hda sinh, NXB Y hoc Ha Noi, 2001. 2. Bo mon Hda sinh - Dai hoc Y dtfdc TPHCM, Hda sinh y hoc NXB Y hoc TP HCM 2003. 3. Bo Y Te, Vu Khoa hoc va Dao tao, Hda sinh hoc, NXB Y hoc Ha Noi, 2005. 109
4 Victor L Davison, Donald b. Sittman, Biochemistry, 3th edition, Harwal Publishing, 1994. 5. Waiter X.Balcavage, Michael William King, Biochemistry (Examination &broad review) 1st edition, 1995. onnn 6 Peter NCampbell. Biochemistry Illustrated, 4th edition, Churchill hvmgston, 2000. 1. Robert K. Murray, Daryl K. Granner, Victor W. Rodwell, Harper's Illustrated Biochemistry 27th edition-Lange Medical Books/Mcgraw-Hill, 2006. CAUHOITtfLl/ONGGIA Chon tap hdp cau tra 161 dung 1. Nhtfng nguyen nhan lam tan huydt hay tang stf pha huy hdng clu gay vang da la: a. Benh do Hb bat thtfdng (HbS, Thalassemia...) b. Benh di truyen do thie'u enzym GePD. c. Benh mien dich d. Benh mac phai (sot ret, sot xuat huydt, nhiem trung..) 2. Phan tfng lien hdp bilirubin d gan: a tao thanh dang lien hdp bilirubinmonoglucuronat (80%) va bihrubindiglucuronat (20 *). b.'xay ra gitfa 2nhdm carboxyl (-COOH) cua gdc propionat (P) dmach nhanh cua bilirubin vdi nhdm OH ban acetal cua acid glucuronic. c. Acid glucuronic ddang hoat hda uridin diphosphat glucuronat. d. dtfdc xiic tac bdi enzym glucuronyl tranferase. 3. Bilirubin ttf do (gian tiep) a. khd tan trong ntfdc b. cho phan tfng diazo nhanh c. van chuydn trong mau ddang ket hdp vdi albumin, gobulin d. tham qua mang te bao gan de dang Chon cau tra lcfi ttfdng tfng a 4. Hay chon cac ydu td cd lien quan ddn cac benh ly sau day do roi loan chuyen hoa hemoglobin: 1. Vang da trtfdc gan a. Bilirubin ttf do trong mau tang 2. Vang da tai gan b. Bilirubin lien hdp trong mau tang 3. Vang da sau gan c. Cd sac td mat trong ntfdc tieu d. Cd nhieu urobilinogen va stercobilinogen dao thai ra ntfdc tidu va phan e. Cd it urobilinogen va stercobilinogen dao thai ra ntfdc tieu va phan f. Khong cd urobilinogen va stercobilinogen dao thai ra ntfdc tidu va phan 110
CAU HOI NGHIEN CtfU BAI HOC 1. Trinh bay va giai thich qua trinh thoai hda bilirubin d ruot. 2. Nguyen nhan va trieu chtfng ciia benh ly vang da trtfdc gan do rdi loan thoai hda hemoglobin 3. Neu cac hau qua do roi loan thoai hda hemoglobin trong trtfdng hdp bi tac mat. Ill
CHUCfNG 5 CHUYEN HOA ACID NUCLEIC MUC TIEU . 1. 'Vidt dtfdc sd dd stf thoai hoa base acid nucleic, base punn, base pynmidin. 2. Trinh bay dtfdc sd do tdng hdp nhan purin va pyrimidin. 3. Mo ta dtfdc qua trinh tdng hdp DNA, RNA. 4. Phan tich dtfdc cac rdi loan chuyen hda. Ta't ca cac te' bao cua cd thd sdng ddu co kha nang tdng hdp acid nucleic can thidt cho ta' bao do do knina yeu cau phai c6 acid nucleic trong thtfc an. Acid nucleic trong thtfc an khong co ynghia 2 lm.2 vdi cd thd. Acid ribonucleic cua td bao luon ddi mdi nhanh chdng, no tang trong te bao cung vdi sa tdng hdp protein. Stf ddi mdi AND trong cac mo thi cham hdn nhieu, stf dot md, xay ra trong cac te bao dang phat trien, te bao tai sinh. 1. THOAI HOA Acid nucleic "% Nuc|e0,jd ^^f Nucleosid ^ ^ Base nitd +Pentose (DNA, RNA) + phosphat Nuclease la phosphodiesterase co trong dich tuy. Nucleotidase la mot phospha.ase va nnrleosidae la mot phosphorylase, ca hai enzym co trong dich mot. ^W^oi stf dung trd lai cho qua trinh phosphoryl hda hay dtfdc thai ra trong ntfdc tieu ^ VjTe ttfItfc fn tham gia dang kd vao qua trinh tdng hdp acid nucleic cho cd thd. BTePurin va pyrimUUn dtfdc phdng thich trong qua trinh tieu hda caacid nucleic phan ldn dtfdc thoai hda va dao thai, mot phdn dtfdc stf dung lai de tong hdp acid nucleic. 1.1.Thoai hoa cac base purin Thnni hoa chinh cua base purin theo sd do sau: .,,.,> J i " vat cd vu thoai hda base vdi hai loai phan tfng chtf yeu la KM amin thay phan va oxTho" (htah 5.1). 0ngtfdi, linh trtfdng, chim va mot sd bo sat san pham thoai hoa cuo, L ctfabase purin 14 acU, uric va dtfdc dao thai ra ntfdc tidu. Ndng dp acid unc trong mau ngtfd, ^Z^llTLg/lOOml. Ltfdng acid uric trong ntfdc tidu 0,3-0,8g/24h. Ltfdng acid unc trong 2 Shay ddfthfo chddo an,' dL biet tang vdi chddo .n£u purin.gan than, th,t, cua). Trong benh gout, benh tang bach cau acid uric trong mau cd the tang den 7-8g/100ml. 112
AMP 5 .NUCLEOTIDASE NUCLEOSIDASE H20 02 HoO. 'NT Hypoxanthin ^ ^—_rYV XANTHIN OXIDASE *N' OH Acid Uric NH2 COO NH, NH, L-N II | HO-N^N Uricase 0=CV ^C^N/ O Allantoinase -crcxc. O M HH Acid Uric Allantoat Allantoin Allantoicase Urease j| 4NH< 2 H2N-C-NH, Hinh 5.1. Thoai hda cac base nhan purin. Urea O rnpt^so dong vat cd xtfdng sdng khac, acid uric bi thoai hda tidp tuc thanh allantoin nhd u at oxydase. O cac loai ca co xtfdng san pham cuo'i cung la allantoat. d loai ca cd sun va dong vat ltfdng ctf san pham cuo'i cung la ure. Nhirng dong vat bien khong cd xtfdng so'ng san pham cuoi cung la NH4 (hinh 5.1). 113
1.2. Thoai hoa cac base pyrimidin Stf thoai hda base pyrimidin xay ra chu yeu d gan theo sd do sau: NH; N NH Cytosin NH ex NH Thymin Uracyl HN \ HN N< cr NH' cAnH' Dihydrothymin Dihydrouracil M CH3 :0-NH-CH?CH2COOH NH2—CO NH2-CO-NH-CH2CH2COOH b_Ureidopropionic b_Ureidoisobutyric NH> CH3 NH2CH2CH2COOH NH2CH2CH2COOH b_Alanin Ure b_Aminoisobutyric Hinh 5.2. Thoai hoa base nhan pyrimidin. San pham thoai hda cudi cung cua pyrimidin la ure va p-alanin (ttf uracil) va P- aminoisobutyrat (ttf thymin) (hinh 5.2). 2. TONG HCfP 2.1. Tons hdp nucleotid .* • , ^u- - - *~ u~nu Trong cd the7 nucleotid dtfdc tong hdp tu~^ nhu cau nhat trien cua te bao va mo, dac biet khi .,.» u^ theo rnn pnai in td bao phan chia. Cd ,hai• con dtfdng ** „ hr^ nucieotia id.y con dtfdng tong hop moi, (2) con ^. ^.>, tong hdp nnrleotid la: (1) & dtfdng ^dn dung laV b^ang qua trinh phosphoribosyl hoa base hay nucleosid. 114
2.1.1. PRPP (5'-phosphoribosyI-l-Pyrophosphat) la cha't trung gian cd vai tro quan tron* tron* tong hdp nucleotid *° ° PRPP dtfdc tao thanh ttf ribose-5-phosphat va adenosin triphosphat (ATP). Ribose-5-phosphat + ATP -> PRPP + AMP NguSn ribose-5-phosphat dtfdc cung cap ttf qua trinh chuyin hoa glucose hay ttf qua trinh thoai hoa nucleosid. PRPP dtfdc suf dung cho ca qua trinh tong hdp mdi va qua trinh tan dung lai. Ndng do PRPP trong te bao luon dtfdc dieu hoa va thtfdng d mire thap, qua trinh tong hdp PRPP dtfdc xiic tac bdi PRPP synthetase va can Pi. Binh thudng ndng do Pi trong te bao d mtfc thap nen hoat dong PRPP synthetase thap, nhtfng khi Pi tang thi hoat dong enzym tang dang ke. Ngtfdc lai ADP tfc chd hoat dong PRPP synthetase. 2.1.2. Tong ho*p mdi nucleotid nhan purin NguSn cacbon va nita di tSng hap nhan purin. Nguon nay la glutamin, glycin, aspartat, cacbon dioxid, va cacbon ciia folat. Nhan purin dtfdc tdng hdp tren mot phan td PRPP (hinh 5.3) C02 (ttf he ho hap) Aspartat I / Glycin A/j/V-MethenyL W10_Formyl/^ ^V^NH tet'rahydrofolat tetrahydrofolat Amin cua glutamin Hinh 5.3. Nguon cacbon va nitd dung tdng hdp nhan purin. Tong hap inosin 5'-monophosphat (IMP). IMP dtfdc tdng hdp qua 11 btfdc va stf dung 6 lien kdt phosphat giau nang ltfdng (hinh 5.4). Day la qua trinh ton nhieu nang ltfdng. TSng hap AMP va GMP tic IMP. Ttf IMP qua qua trinh gan them nhdm amin cua aspartat cho AMP. Cung tir IMP qua qua trinh oxy hda va gan them nhdm amin cua glutamin cho GMP. Ve mat nang ltfdng thi GTP dtfdc suf dung cho qua trinh DVIP-»AMP va ATP dtfdc stf dung cho qua trinh IMP->GMP. Cd che nay giiip can bang ltfdng nucleotid adenin va guanin (hinh 5.5). 115
Glycin ,NHt H2C5 H2p 0=Q4 0=C4 ©"O-ChU ATP AM p ©—o— Glutamin Glutamat ©-0-CH scr ©-o-gH2 NH PRPP GLUTAMYL Mg PRPPSYNTHASE °-©-0—© AMIDOTRANSFERASE OH OH )H OH ATP ADP H OH OH OH 5_phospho Glycinamid ribosyl a_D_Ribose 5_phosphat PRPP (3_D_Ribosylamin 5_phosphat (IV) (I) (II) (III) A/5 M10 N ,N v. Methyl H4folat\ FORMYL TRANSFERASE O H4 folat , II H H _/£ N HC-N» HoO H2Cf7^CH o 3 4 *_ OH VII CARBOXYLASE CH X © Glutamat Glutamin H2CT7^CH » L II "4 II H2N N ©VW •N ATP Mg~ 2+ HN- Ct 9 o ^c: 9 o NH u ^— ATP Mg —w O NH u CO, VII SYNTHETASE R_5_© R_5_© VI SYNTHETASE R_5_© R_5_© Amioimidazoi carboxylat Amioimidazoi ribosyl 5-PhosPhat (VIII) rjbQsy| 5JDhosphat Formyl glycinamidin Formyl glycinamid ribosyl 5_phosphat ribosyl 5_phosphat -OOC + (VII) (VI) (V) IX HC-NH3 SYNTHETASE 6h, Aspartat O o At Formyl Fumarat II H4 folat H4 folat HoO ®^H,-^N N b 5 I Y> CH W. H2N^e5 N*CH ——^ > Hry- 0 / I N CH *N ADENYLO 3 FORMYL 0=CX^ 3 4 ' imp HC^v. SUCCINASE TRANSFERASE H NM N CYCLOHYDROLASE N I H R_5_© R_5_© R_5_© R_5_© Amioimidazoi succinyl Amioimidazoi carboxamid Formimidoimidazdl carboxamid Inosin carboxamid ribosyl 5_phosphat ribosyl 5_phosphat ribosyl 5_phosphat monophosphat (IMP) (IX) (X) (XI) (xii) Hinh 5.4. Qua trinh tdng hdp inosin trong qua trinh tdng hdp nhan purin. 116
Aspartat |_j ooc-c-c-coo- -ooc-c-c-coo- O HN /C N H2r^ H,o > H H OOC— C=C—COO~ NH. N N^ CH — I CH HO. GTP Mg2+ TP Mg H^M>W " N N" ""N ADENYLOSUCCINASE r ADENYLOSUCCINAT r' R_5_© SYNTHASE R_5-© R_5_© Inosin monophosphat Adenylosuccinat (IMP) Adenosin monophosphat (AMPS) (AMP) NAD^ •H20 o IMP DEHYDROGENASE NADH H+i O O Glutamin Glutamat HN-- CV-N. HN ,/C N ^lA|/ CH ATP TRANSAMIDINASE Tf H^N °\ N r CH R_5_© R_5_© Xanthosin monophosphat Guanosin monophosphat (XMP) (GMP) Hinh 5.5. Tdng hdpAMP va GMP ttf IMP. Dieu hda qua trinh tong hap mdi nucleotid bang ca che tic chenguoc (feedback). Hai enzym xiic tac ciia hai phan tfng dau tien trong qua trinh tdng hdp IMP la PRPP synthetase va PRPP^ amidotransferase bi tfc che ngtfdc bdi IMP, GMP va AMP (Mnh 5.6). Giai doan tong hdp adenylosuccinat ttf IMP bi tfc che bdi AMP va giai doan tong hdp XMP bi tfc chd bdi GMP (hinh 5.6). 117
Ribose_ 5-phosphat Q-< AMP- RIBOSE PHOSPHAT PYROPHOSPHOKINASE 0-< GMP- (PRPP SYNTHASE) 0-< IMP PRPP --AMP- 0- PRPP GLUTAMYL 0 ---GMP- AMIDOTRANSFERASE •-- IMP • 0- 5_Phosphoribosylamin t IMP ADENYLOSUCCINAT IMP DEHYDROGENASE SYNTHASE -AMP >•© Q-4. GMP- Adenylosuccinat XMP TRANSAMINASE ADENYLOSUCCINASE AMP GMP i Hinh 5.6. Bieu hoa tong hdp AMP va GMP. 2.1.3. Con dtfcmg "tan dung lai" nguon nucleosid hay base nittf
ADENIN PHOSPHORIBOSYL TRANSFERASE Adenin PRPP pp. N HYPOXANTIN.GUANIN N^ ^H PHOSPHORIBOSYL 'HOSPHORIBOS' TRANSFERASE Hypoxanthin iM PRPP PPi "i1 J S ••>-.> m JH HYPOXANTINJ3UANIN (PJ-O-HoC )-Q-H2C PHOSPHORIBOSYL TRANSFERASE Guanin Hinh 5.7. Con dtfdng tan dung lai base nitd de tdng hdp nucleotid. Gan la ndi tong hdp va cung cap chinh base nhan purin va nucleosid nhan purin cho qua trinh phosphoribosyl hda dcac to chtfc khong cd kha nang tong hdp mdi nucleotid. Vi du nhtf nao, hong cau va bach ciu da nhan sii- dung ngudn base purin de tao nucleotid purin chtf khong tong hdp nhan purin. 2.1.4. Tong hop mdi nhan pyrimidin Nguon cacbon va nita su: dung cho tong hap nhan pyrimidin. Nguon nay gdm glutamin, aspartat va cacbon dioxid. Khac vdi purin, nhan pyrirnidin khong dtfdc tdng hdp ttf PRPP ma sau khi tong hdp hoan chinh nhan pyrimindin mdi ke't hdp vdi PRPP tao nucleotid (hinh 5.8). Carbamyl N^ Aspartat phosphat j.__rlN_. Hinh 5.8. Nguon cacbon va nitd su' dung tdng hdp nhan pyrimidin. 119
Tong hap uridin 5'-monophosphat (UMP). Giai doan dau tien la tdng hdp carbamoyl phosphat. Carbamoyl phosphat dtfdc tdng hdp trong te bao chat ttf glutamin va cacbon dioxid, ngoai ra carbamoyl phosphat con dtfdc tdng hdp dty the te bao gan (chat trung gian cua qua trinh tdng hdp ure) (hinh 5.9). Tit UMP tong hap CTP va dTMP Ttf UMP den CTP qua hai giai doan: (1) chuyen UMP thanh UTP nhd phosphat kinase, (2) nhdm amino ciia glutamin ket hdp UTP cho CTP (hinh 5.9). De tdng hdp dTMP nhd enzym ribonucleotid reductase khu" UDP thanh dUDP, tiep tiieo enzym thimidylat synthase xiic tac chuyen nhdm methyl cua N5,N10 methyltetrahydrofolat de tao TMP (hinh 5.9). 120
C02 + Glutamin + ATP Carbamoylphosphat synthase II © o II Aspartat O—C\ transcar transcar ~Q— Q Dihydro q H3N3 4 cPH =>Y 2 bamoylase H2N CH2 orotase HN "CH^ 66h ©X*1 • ~S ,CH g\ * t CH i- © H3fi cod cfXN' COO- COO 11 Pi H20 ^ H Carbamoyl Aspartic Carbamoyl Dihydroorotic phosphat acid aspartic acid acid (DHOA) (CAP) (CAA) NAD+ Dihydroorotat dehydrogenase NADH C02 o PPi PRPP y©y hn Orotidylic acid Orotat decarboxylase O N COO| Phosphoribosyl fj TN COO" transferase IH R-5-© OMP Orotic acid (OA) ADP' NADPH H+ NADP+ dUDP Ribonucleotid reductase HoO o ADP' Pi dUMP Glutamin ATR Methyl H4 folat Thymidylat 0 CTP synthase synthase H2 folat R-5-©-©-© CTP TMP Hinh 5.9. Tong hdp nhan pyrimidin. Dieu hda sinh tong hap nucleotid pyrimidin Nucleotid pyrimidin tfc che ngtfdc enzym aspartat transcarbamoylase va dihydro orotase. 121