3. Shikimate Pathway and mevalonate pathway_OCR.pdf

Shikimate Pathway and Mevalonate Pathway 1 Shikimate Pathway - Alternative route to aromatic compounds (polyketide pathway) - Aromatic AA: Phenylalanine, Tyrosine, Tryptophan - Pathway in M/O and plant: Human from diet - Cinnamic acids, coumarins, lignans, flavonoids 2 ''占Shikimic acid Jll ——...

Shikimate Pathway and Mevalonate Pathway 1 Shikimate Pathway - Alternative route to aromatic compounds (polyketide pathway) - Aromatic AA: Phenylalanine, Tyrosine, Tryptophan - Pathway in M/O and plant: Human from diet - Cinnamic acids, coumarins, lignans, flavonoids 2 ''占Shikimic acid Jll —— - Isolated from llicium sp. （ 붓순나 Japanese ‘shikimi’） - raw material for synthesis of Tamiflu - fruits of star anise （ 팔각） （ Illicium verum: Illiciaceae） 3 Shikimic Acid Molecular formula Molar mass Melti ng point CAS number C7H10O5 174.15 g mol-1 185–187 °C 138-59-0 4 HO 杉7 O 1 6 5 OH Tamiflu ShikimicAcid 4 OH 3 O 18일 한의학계에 따르면 광동한방 병원은 신종플루 감염을 염려하는 환자들에게 면역력을 높이는 면역 대보탕과 면역대보단을 처방하고 있다. H 이는 신종플루 치료제인 타미플루 의 주성분인 시킴산(shikimic acid) 이 팔각회향(八角茴香)이라는 한 약재에 다량 함유됐다는 점에 착안, 팔각회향을 해독 효과가 있는 황련 등과 섞어 제조한 것이다. GLYCOLYSIS OH 1 OH 1 .OH HO (')H CYCLE OH P()、 X 스、 % 、느、＜ PO OH PENTOSE PHOSPHA TE JDH OH OH (')H glucose 6-P D-glucose PHOTOSYNTHESIS 리ythrose 4-P OHC、,OH .CO^H r- CO2H PO NH2 glycine NH2 glyceraldehyde 3-P L-pheny I alanine CO 서 CO2H H(),C、,OH HS-YC02H 2H -〕 NH2 NH2 L-serine L-cysteine L-1ymsinc0bH OH 、 SHIKIMIC ACID NH2 NH L-tryptophan -T phosphoenolpymvate NH2 、 、다 NH2 () 니 ( HCX^OP CO2H L-valine HO PO 3-phospho응lyceric acid 파、 CO2H H()2C O OP O OH NH2 L-alanine pyruvic acid DEOXYXYLULOSE 5-P HO 、으、厂 CO서 CoAS HO2C I NH2 L-leucine ACETYL-CoA OH MEVALONIC ACID KREBS CYCLE CO2H NH2 L-isoleucine /S L-aspartic acid CO2H H2N NH2 L-methionine CChH NH2 L-lysine HO2C^^CO2H HO2C—、fco 서— o oxaloacetic acid O 2-oxoglutaric acid NH x H,N N H CO2H NH2 L-arginine HO2C CC사I NH2 L-glulamic acid 日2自저으2H NH2 L-orni thine 7 Shikimate Pathway phosphoenolpyruvate COOH 人 PO 스H COOH COOH PO C6C3 OH HO > O OH erythrose 4-phosphate 6OH 0H HO shikimic acid phenylpyruvic acid Lignan, podophyllum, apoptosis 8 o 丁 0 여y jO 」厂 PAL coon'너 NHj cooir <'(x>ir phenylalanine cinnamic add Shikimate pathway 广스、'0,, 서우 COSCoA /針 、 XCOOH HjG COSCoA 4-coumamyl-CoA />coumaric ucid m 끼 onykCoA Acetate pathway general phenylpropanoid pathway 11‘\少>" _ CHS CIIS/CIIR "드아。- 즈 g trihydmxychaloi chaicone resveratrol stilbene 스/ $甘 망 letrahydroxychalcmw 、 乂스 chaicone DFR CHI 方計。 H liquiritigenin o aurones 애 F3’ll naringenin flavanone eriodictyol flavanones l IFS 인_J므느브 isoflavone R II daidzem । R=OH;(；cniw；in 4 IO M l di hydrokaempfbn기 FS2 OC’H, ITH 1,0 Tir FJ’S'li OH R OH O 尺 H. 11VoH: dihydmquawtin R=OH. FC=OFI: dihydromyrecciin < 3-OH-flavanones (di hydro flavonols) R H, R- H: kaempferol\ R H, Rr-OH: quercetin \jl°、•셔 R OH. R'=OH: myrccciin \ & UFGT OH O DFR ihlobaphenes 궉r Glc-O flavonol glycosides flavonols R flavones LCR 2*-hydroxy Isoflavanone DMID medicarpin isoflavonoids 0 v^^-OH flavan-3-ols 〔〕〔 OH OH OCH, * v y* 广 OH J f1avan-3,4,-diols (Iciicoanthocyanidins) LDOX ▼ "XO으.“, OH 3-01 l-anthocyanidins OH condensed tannins (proanthocyanidins) OMT . IJFGT O'li, OCH, C>-Gk CKCHc-O-Rhii anthocyanins 9 Shikimate Pathway nucleophilic attack on to protonated double bond of PEP CO 사4 CO 사4 CO7H "CO2H EPSP synthase shikimic acid shikimic acid 3-P 1,4-eliminati이i of phosphoric acid CO,H L-Phe L-Tyr 서 -HOP 1,2-eliniinciti이i of phosphoric acid CO2H -HOP prephenic acid Y CO,H CO2H OH chorismic acid EPSP 10 Shikimate Pathway ti'cinsanuniitioH： keto acid decarboxylation、 ciromatizatioH and loss of leaving group decarboxytatioti, aronuitication and loss of leaving ^roup oxidation retained on clecarboxxlatioii and aromatization: no discrete ketone mtermediate ◎ formed additional oxidation step (of alcohol to ketone) means OH ts ret cm led on decctrboxvlamm cmd aromatization: no discrete ketone intermediate is formed 4-hydroxyphenyJpyruvic acid Melanin biosynthesis O2 tetrahydro­ biopterin O2 tetrahydro­ biopterin CATECHOLAMINES iK)radrenaline, adrenaline L-DOPA nucleophilic attack on to enone MELANINS 12 Lignans and Lignin building block ■ A strengthening material for plant cell wall ■ From 4-hydroxycinnamyl alcohol, coniferyl alcohol, sinapyl alcohol ■ C6C3 13 Lignans 14 α-peltatin: R =OH, R =R =H β-peltatin: R =OH, R =H, R =CH3 1 2 1 2 3 gomisin: -O-CH2-O- 3 furoguaiacin enterolactone (+)-pinoresinol: R1=OH, R2=OCH3 (+)-sesamin:-O-CH2-O- 15 Arctii Fructus （ 우방자） Arctium lappa Compositae 계 Lignin : Arctiin （주）, arctigenin. 0 너3co厂、＞ Ri-0 人니 厂、 ►CH；j 0-------- O HOCH3O HOH2C ,丁? 우 O H3CO 으 Rl R? arctiin Glc CH3 arctigenin H CH3 OCHO CH3O ☆ HO OCH3 CH2OH O 3 H3CO 今 G OCH3 lappaol A OH OO CH2OH u OCH3 lappaol F OH CO2H Photo tde.'.ss 18 Aspirin Since the time of ancient Greeks willow bark was used to reduce fever and pain ■ Isolated from Salix sp. （ Willow bark, 버드나 므〕거즈 무 껍질） n ■ In the 1800’s salicylic acid was isolated fro m Spiraea sp. （ meadow sweet, 조팝나무） ■ End of 1800’s acetyl salicylic acid was synthesized at Bayer ■ Aspirin is an antiinflammatory, antipyretic, and analgesic ■ Aspirin suppresses platelet aggregation: Prevention of heart attack ■ 19 Aspirin Biosynthesis Cinnamic acid 20 Dicoumarol and Warfarin （ 혈전치료） ■ Dicoumarol ■ ■ ■ ■ Melilotus officinalis （ Sweet clover, 자주개나리） causes fatal haemorrhages （ 출혈） interferes with the effects of vitamin K in blood coagulation OH OH dicoumarol Warfarin ■ ■ blood anticoagulant in the treatme nt of thrombosis （ life threatening blood clots） initially developed as a rodenticide （ 살서 제: 쥐약） 21 Coumarin Biosynthesis trans-cis isomerization 、즈 OH cinnamic acid lactone formation COnH 2-coumarie acid coumarin 、으^*CO2H COH 4-coumaric acid 2 4-di hydroxy­ umbel life rone cinnamic acid scopolin scopoletin aesculetin 22 Flavonoids and Stilbenes CoAS 4-hydroxycinnamoyl-CoA Claisen resveratrol (a stilbene) Flavonoids and Stilbenes O2 2-oxoglularatc R O2 2-oxoglutaralc OH O R = H, dihydrokaempferol R=OH, dihydroquercetin (dihydroflavon 이 s) R = Hj naringenin R = OH, eriodictyol (flavcinones) O그 2-oxogkitarale 'OH R = H, kaempferol R = OH, quercetin (flavbnols) NADPH i， 느、、 R = H, apigenin R = OH, kite이in (flavones) OH OH R = H, leucopelargonidin R = OH, leucocyanidin (tlavandiols; leucoanthocyanidins) NADPH OH afzalechin R = OH, (+)-catechin (catechins) I R = H, pelargonidin R = OH, cyanidin (anthocyanidins) 24 Tea ■ Camellia sinensis (Thea sinensis) (Theaceae) ■ Green tea: steaming and drying; catechi n, epicatechin, epicatechin gallate, epigall ocatechin, epigallocatechin gallate ■ Black tea: fermentation (enzymic oxidati on of the polyphenols); theaflavins and t hearubigins 26 Tea Y 스 Y ''LJL 1 OH 스 HO 、厂'으广O 、丄、』、 n 니 HO OH 、厂*스~즈O、厂 4 OH OH catechin OH OH ''OH OH epicatechin 4 epigallocatechin epigallocatechin gallate 27 Catechin 류 장/간 대사 Methyl-ECG sulfite |33| ECG sulftte glucuronide pl) ECG glucur어tide (3비 EGCGwICM 리 5] 1 MethykEGC |I8| M베tyl-ECG |32| Epicatechin gaMatc (ECG) |1| EpigaBocatcchin gallate (EGOO)H) EGC wl&ie |2| EC Glucuronide |H| EC sulfate |1«] MelhyUEC«uU«te 12gl M하hyl-EC [28| Epicatechin (EQ EGC glucuronide |l 갸 EGC sulfate glwmwklc |3] Epigallocotechin (EGC) Mcihyl.3위PP=I sulfate [3이 Mtlhyl-3-HPP-2*«l glucuronide |21| ◎A 三ojic' 3,4,"diHPP-2‘Ol wlfaie |7| Mctliyl-3,4,-diHPP-2-ol |35| W.4',Wrihydroxypheny|卜 广valcrolactone (M4) |햐 3.4广diHPP>2서 [fi| M4 sulfttc |22] M4dinil&tel3 기 34fpp-2*«118| Methjrl-34diHPP.2+l glucumnide |19| Meihyi-3,4,>diHPP.：MI wlbtc |20| 3,4,"diHPP.2■이 glucuronide |34| 人 HM’dihydroxyphctiyl}’ valeric acid |12| $4mcd»xyl어 3.4*dihydn>xyphcny I 卜 dihydroxyphenyl)hydmxyphenylHvalcrk valeric acid sulftie valeric acid sulfate |I3| _ acidwlfat 리 24| glucumnide |4허 5*(3,,‘4'-<iihydmxyplrenyl)’ir» valemhctone |23| 1 Bihydroxy-nKtboxylTrihydmxybenzenepentanoic acidbcnzencpcntanoic acid _ wlfiue fl 히 sulfate (2히 _ 3-Hydmxypbenyl Ktlic Kid sulfate |41| |=rf Mcthyl-M6, |38| 5«(3\5'"djhydmxyphenyl>T* valerolKtone (M6*) |2JJ 、、 M6 glucuronide [I 이 Fcnilic uid sul&te |2이 Mcihyl-M6’sulfte 이 II| M61 glucuronide [l이 M«hyl-M6' glucuronide |39| A方 나lydmxy4meth<wyl’ phenylacetic acid sul&le |M| Mctby!'M6$ulftlc|ll} Hydmxyphenyl propionic Acid |42| 그 AT Blue : catechin In 아vo metabolites found in large intestine Red : catechin /n vivo metabolites found in livar Mc《hyl>M6 ]3히 Purple : catechin fn vivo metabolites found in both large intestine an<f liver 28 । Meihyl-M6 glucumftidc |19]| Silybins OH HO O OH OH OCH3 OH O L、、CH20H Silybin A(1) OMe 'CH20H CH2OH Isosilybin A (3) Isosilybin B (4) 29 Silybins Biosynthesis OH one-electron oxidation one-electron oxidation OH HO — rl OMe "C OH coniferyl alcohol taxifol in radical coupling OMe HO OH Hiicle이)hilic attack of OH OMe 0n f() quinonemethide (o stereochemistries possible) silybin (diastereoisomeric pair) 30 Isoflavonoids - oxidation to free radical ],2-aryl migration R = H, liquintigenin R = OH, naringenin |(tlavonom] R = H, daidzein R = OH, genistein (isoflavonoid) Curcumin 강황, 울금 —伊 (Turmeric Extract in 95% ethanol for 24 h, filter and dry ■ Polyphenol ■ Bright Turmeric Turmeric Turmeric Curcumin (Neutral) (Acidic) (Alkaline) orange- yellow color pigment of turmeric (Curcuma longa L.) ■ First isolated in 1815 32 Biosynthesis of curcumin OH CS3 H Shlkimlc Acid OH Cinrarric Acid：e) p-Caumaric Acid (5) 어 p-Coumarayf-CoA ⑶ .. CCOMT OH p-Coum aroyl W>Sh kima:c (11) Malony^oA'-.： polyketioe : Syn：hase(s) OH f】H Caffeoyl M>SWWe (13} C,affs 外 kCflA i：12j FerjIoyKoA (10i MalonyhCoA Malonyl-CoA ■. • u, Po|y<e(ioe Polykelide Syrlhas 마 s) ! Syrthasgs) * Hydroxylase Bisdemethoxycurcurrin 아 Y 'OH Y OH .OMe H*d 째 Demethoxycurcumin Curcumin 33 * Tautomerism of curcumin ► ► ► Under acidic and neut ral conditions, the bisketo form Enolate form is found above pH 8 Exist as a ketoenol rather than bis-keto structure 34 Biological activity of curcumin 主------■ ■ ■ ■ ■ ■ ■ ■ 강황, 울금 Inhibition of carcinogenesis - prevent cancer in the breast, colon, skin, stomach, liver, lung, duodenum Inhibition of cyclooxygenase (COX) transcription Effect on detoxification enzyme expression mechanism Antioxidant activity - scavenging of a variety of reactive oxygen species(ROS) Anti-inflammatory effects Anti-cancer effects - Induction of apoptosis in cancer cells Anti-microbial effects 35 Anti-parasitic effects 누Mevalonate Pathway Terpenoids and steroids 36 斗「SCoA CO2H 、乂 SCoA O acetyl-CoA 、、으 malonvl-CoA - Mevalonate pathway SCoA 3x Y O acetyl-CoA 스 mevalonic acid OH isoprene unit 必 『흐『OP HQ 人스OP 그 O OH deoxyxylulose phosphate DOXP OH OH methylerythritol 리으이 C5 - MEP(DOXP) pathway MEP crx XTX Crv .CO2H CO2H ——s L-Phe .CO2H shikimic acid 서 L-Phe 2H C6C2N ind 이 e.C2N NH2 L-Orn L-Lys NH2 37 Terpenoids - C5 isoprene units - mevalonic acid (mevalonate pathway) - methylerythritol phosphate (MEP pathway, DOXP pathway) - Head-to-tail, tail-to-tail - (C5)n - >35,000: largest group of natural products 38 Hemiterpenes (C5) ■ IPP and DMAPP: reactive hemiterpene intermediates ■ Isoprene: volatile of woody trees 39 Mevalonate Pathway 3 X \ SCoA HOOC OH O acetyl-CoA mevalonic acid C5 unit (isoprene) squalene betulinic acid 40 Mevalonate Pathway SCoA O Acetyl CoA 斗r^r SCoA O O Acetoacetyl CoA 서 " 丄 OH • HOOC COSCoA —► 3-hydroxyl-3-methyl- gl utaryl-CoA (HMGCoA) HOOC 、＞ CH2OH Mevalonic acid 41 Mevalonate Pathway Deoxy xylulose phosphate Homi terpenes (C5) diinethylally 1 PP (OMAPI그) (C5) isopenteny 1 PP (IPP) (C5) Monoterpenes (C10) Iridoids Scs이uitcrpcncs (C15) Di terpenes (C20) Scstcrlcrpcncs (C25) Triterpenoids (C3O) 1r 5>toroids (으?！ 오— "Tclralcrpcncs (C?4o) Carotcrioids 42 Joining isoprene units Head-to-Tail individual isopr ene units join h ead-to-tail 수 an extra bond Tail-to-Tail larger terpenoid units dimerize t ail-to-tail The terms head-to-tail and tail-to-tail are often used to describe how the isoprene units are joined. 43 head to tail limonene 스 diagram showing how two isoprene units combine to form the limonene skeleton from lemon and orange peels 44 45 Monoterpenes (C10) - volatile oil: from mevolonate pathway or shikimate pathway - citronellol (rose oil), geraniol (geranium oil) - geranial (lemon oil), linalyl acetate (lavender oil) 46 Volatile Oils Monoterpenes (C10) Terpene cyclases - LPP is preferred substrate - GPP: E stereochemistry of double bond being unfavorable for ring formation Iridoids (Monoterpene) - found in variety of plants/medicinal plant - plant for defense against herbivores or M/O infection - cardiovasular, antihepatoxic, antitumor Sesquiterpenes (C15) - Three C5 units - sesqui: ‘one and a half times’ (Latin) - generally synthesized via themevalonate pathway than MEP Sesquiterpenes (C15) Diterpenes (C20) ^OPP fa mesyl PP (FPP) IPP electrophilic tertiary cation geranylgeranyl PP (GGPP) addition gives 52 Paclitaxel ® (Taxol ) ■ Taxus brevifolia Nutt ■ Wani et al JACS 1971, 93, 2325­ 2327. ■ Antimitotic ■ Paclitaxel: Taxol® (BMS); ovarian, breast, non-small cell and small cell lung, head, and neck cancers. ■ Docetaxel: Taxotere®(Aventis); im proved water solubility; Breast, gastri c, ovarian, and prostate cancer. Paclitaxel R1 = COCH3, R2 = C6H5 Doxetaxel R1 = H, R2 = (CH3)3CO Paclitaxel (Taxol®) 上-------- 원료 공급 문제 (1.2 ton 주목나무 껍질今10g taxol 분리): 반합성 및 plant cell culture, total synthesis - Solubility Structure Activity Relationship of Taxol Baccatin III Acetyl or acetoxy group may be re moved without si gnificant loss of a ctivity. Some acyl analos have MDR -reversing activit Reduction improves activity sli ghtly May be esterifide, epimerized or rem oved without sign ificant loss of acti vity y Free 2'-hydroxyl group, or a hydrolysable ester there of required Removal of 1-OH group reduces activity slightly Removal of acetate red uces avtivity; some ac yl analogs have impro ved activity Acyloxy group essesntial; certain sub stituted benzoyl groups and other acy l groups have improved activity 55 Taxol Biosynthesis cyclization by electrophilic addition giving tertiary cation generation oj cation by protonation of alkene; leads to electrophilic cyclization paclitaxel (taxol) sever이 I esterifications 今---- paclitaxel (taxol) <=i L-Phe many steps; oxygenation ofditerpene system and esterifications 1 ac리yl-CoA 10-deacetylbaccatin III Diterpen e 56 Et3sleI.Py 23oC 20h AcCLPy OoC. 48h (7 식%) 10-deacetylbaccatin III 유사종（ 유럽 주목） 잎이 생산하는 전구체로 부터 반합성 DPC.DMAP PhMe 73oC. 100b (80%) TAXOL 0.5%HCI EtOH/H2O OoC. 48h (89%) 57 Taxol and Epothilone Mevalonate pathway, Plant origin Acetate pathway, Bacteria origin Triterpenes (C30) Squalene: shark liver, rat liver, yeast sequence of W-M 1,2-hxdmle and I,2-meth、i shifts protost이yl cation loss of proton leads to cxclopropcme loss 시 proton f^ives alkene 59 Liquorice （ 감초） ■ ■ ■ Glycyrrhiza glabra Glycyrrhiza uralensis 50–150 times as sweet as sucrose D-glucuronic acid HO CO2H \ “-〜义〜노〉0\ \ triterpene OH D-glucuronic acid glycyrrhetic acid G glycyrrhizic acid 60 Panax ginseng (Triterpene) protonation of double bond gives tertiary cation and allows formation of ether by attack of hydroxyl •' protopanaxadiol (panaxoside) both 2OR~ and 2OS-panaxadi<》l are formed, with the 20R-epimer ginsenoside Rh_] predornifiating; since both isomers (31—6 —Ara—G 1c (pyranose) ginsenoside Rh-2 |31—6 —Ara—Glc (furanose) ginsenoside Rc are produced、this implies an equilibration, probably through, loss of H2O and generation of a 너 carbocation at C-20 in protopanaxadiol 日아 panaxadiol ginsenoside Rd OGly1 ginsenoside (panaxoside) ginsenoside protopanaxatriol panaxatriol as mixture of20R and 2OS 아rimers; see notes on panaxadiol above Rha—Glc— ginsenoside Rt ginsenoside Rg. ginsenoside R) |31->2 Rha—Glc— 61 ■ Acremonium fusidioides (fungi, formerly Fusidium coccineum). ■ reversibly inhibits protein biosynthesis at the translocation step by binding to the larger subunit of the ribosome 62 Female Sex Hormones • C21 pregnane skeleton • A4-3-keto oestrone) estradiol (oestradiol) (oestriol) • Cjs estrane skeleton • aromatic A ring (consequent loss of C-10 methyl) • no side-chain 63 흐 Natural Products with Estrogenic Activity Genistein -isoflavone Estrogenic activity Causes infertility in Austrian sheep Coumestrol . -coumarin More potent estrogenic activity Diethylstilbestrol -stilbene 64 OH HO Estrane 65