생약의성분

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1 생약의성분

2 생약의성분이란? - 16 세기 Paracelsus 에의해생약에약효를나타내는성분이있음을제안 - 19 세기 Seturner 가아편에서 morphine 분리 - 생약성분은식물형태와함께식물유전자 (genotype) 의다른표현형 (phenotype) 의하나 - 대부분생물 ( 식물, 동물, 미생물 ) 의 2 차대사산물이대부분을차지함 - 넓음의미로의생약성분은 약리작용을가지는천연유기화합물 (pharmacologically active natural organic compound) 로정의함 - 현재의약품선도화합물로서새로운역할이재조명됨

3 1. 생약성분의분류 (1) 화학구조에따른분류 ; terpenoid, steroid, flavonoid (2) 물성에의한분류 ; alkaloid, saponin, tannin, 식물색소, 정유.. (3) 생리활성에의한분류 ; 항생물질, 비타민, 호르몬, 강심배당체.. (4) 기원에의한분류 ; 식물, 동물, 균류의대사산물, 지의류.. (5) 생합성경로에의한분류 ; polyketide, shikimate, mevalonate amino acid, 혼합경로

4 2. 식물성분생합성 à ombination of building blocks 1, methyl LSD üsecondary metabolism H N H 3 übuilding block 5, isoprene NH 2 üonstruction mechanism N Lysergic acid Indole. 2 N N Indole, 2 N

5 일차대사산물과이차대사산물 천연물성분대부분은생물을기원으로하며천연물성분은생물의대사활 동으로인하여생산됨 hn A TYPIAL PLANT Glycolysis Photosynthesis (daytime) Respiration (nighttime) H N 2 TRAE METALS Na, a, K, Mg Fe, u, o, Mo H 2 N bacteria N 2- /N 3- /NH 4 +

6 일차대사산물 (Primary Metabolite) - 광합성을포함한대사과정에서생산되며간단하고모든식물에분포하는 저분자화합물을생산하는대사과정에서나온생산물을일차대사산물이라 정의 carboxylic acids, amino acids carbohydrates, fatty acids proteins, nucleic acid - 생물의생존유지에반드시필요한물질및에너지공급 - 2 차대사산물을위한에너지와전구체 (precursor) 를공급

7 이차대사산물 (Secondary metabolite) - 정의하기어렵다 - 한정된종류의생물에의해생산되며생명유지에꼭필요한물질은아님 - 역할은확실하지않으나식물의생존에이익 (well being) 을줌 toxic material for predators volatile attractant colouring agent for attraction or warning - 일차대사산물에비하여다양하고복잡한구조를가짐 - 의약품용도로사용되는생약의생리활성성분은대부분이차대사산물 - 같은식물일지라도이차대사산물의변화는아래의예와밀접하게관련되어있다. 개화조건 (Flowering) 기후조건 (Season, temperature) 서식지 (Habitat) 일조량 (Length of daylight) 외부상처 (Exposure of wound)

8 이차대사산물의역할 - 독성의약화또는제거 (Detoxification) - 생리적과정에관여 (Physiologically active) - 체내전달물질 (interorganismic signals) - 종내전달물질 (Intraspecific signal) - 생태학적상호관계매개 (Mediating ecologic relationships)

9 A. 독성의약화또는제거 (Detoxification) 1. 완전히분해되지않는일차대사산물로부터의생합성 L-histidine, L-tryptophan 이차대사산물의전구체로사용되며이후땀, 오줌등의형태로 체외로배설됨 2. 일차대사산물의분해산물이독성이있을때이를이차대사산물로생합성함 Sulfur taurine and hypotaurine Nitrogen urea but not as strong ammonium ion 3. 배설이어려운이차대사산물을배설이용이한형태로전환 Epinephrine vanillic acid

10 B. 생리적 과정에 관여 (Physiologically active) 1. ofactor (oenzyme) NAD (Nicotinamide adenine dinucleotide), NADP FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide) 2. 생리적 과정에 관여 - 세포막 형성에 관여 + sterols hopanoids- PK sterol, carotenoids- EK - 물리적 힘에 대한 지지체 (lignin) - 저항성 증가 (surface lipids, suberin) - 영양물질의 저장 (starch, glycogen) lignin suberin

11 . 체내화학전달물질 (Intraorganic signals) - 동물호르몬 vertebrate hormones (many), juvenile hormones (JH-1 etc.) ( 유충호르몬 ) ecdysone, ecdysterone ( 변태호르몬 ) - 식물호르몬 생장촉진 : auxin, kinetin, gibberellins, brassinolides 생장저해 : jasmonic acid 휴면유발 : abscicic acid 성숙및노화유발 : ethylene - Neurotransmitters

13 H R 1 H H H H H inokosterone, R 1 =H, R 2 =H, R 3 =H ecdysterone, R 1 =H, R 2 =H, R 3 =H R 3 R 2 ponasteroside A, R 1 =Glc, R 2 =H, R 3 =H H H H H rubrosterone Achyranthes bidentata (p166)

14 D. 종내전달물질 (Intraspecific signals) - Microorganisms sirenin (Allomyces macrogynus 의성페로몬 ) - Plants fucoserraten (Fucus serratus의성페로몬 ) ectocarpen ( 갈조류의성페로몬 ) multifiden (utleria multifida의성페로몬 ) fucoserraten multifiden ectocarpene - Insects bombykol ( 나방의성페로몬 ) cis-verbenol pyrrole compound queen substance (9-oxo-2-decenoic acid) bombykol H 3 H N 3 pyrrole H H cis-verbenol H 9-oxo-2-decenoic acid

15 - Mammals muscone ( 사향성분 ) propionic acid butyric acid androsterone crotylmercaptane isopentylmercaptane 겨드랑이냄새? 사향 : 사향노루의향낭주머니 butyric acid muscone H 3 H H androsterone deriv.

16 E. 생태학적상호관계매개 (Mediating Ecologic Relationship) - For defense tetrodotoxin à Tetrodon ( 복어 ) 속성분 : 간, 난소, 고환에다량함유 epibatidine à Epipedobates tricolor 에콰도르독개구리성분 ): Morphine 보다 배강력한진통효과 samandarin à Salamandra salamandra 의 steroidal alkaloid, 근육경련, 고혈압유발 bufotoxins à 강심배당체 formic acid à?

17 - Plant-Plant interactions [Allelopathy: Allelo (mutual) + Pathy (harmful)] juglone from Juglans regia typical allelophathic compound

18 - Plant-Animal interactions - attraction of pollinators: nectars, colors, scent - seed dispersal: color, smell, taste - repelling predator: cardenolides, sinigrin, warbuganal S-Glc H 2 H H 2 N S 3 K H H H H sinigrin cardenolide (digitoxigenin) H H H H warbuganal

19 일차대사과정과이차대사과정 (Plant)

20 Erythrose-4 phosphate Shikimic acid pathway Flavonoid Tannin photosynthesis 2 + H 2 arbohydrate (glucose) Phosphoenol pyruvate pyruvate Glycoside, Mono, oligopolysaccharide Phenol Quinone Polyacetylene Fatty acid, lipid Phenylpropanoid oumarin Lignan Quinone Mevalonate pathway Acetyl-oA Krebs cycle 2 [H] polyketide pathway Respiratory cycle Energy H2 Steroid Terpenoid Amino acid pathway Protein N-heterocyclic compound Alkaloid Nucleic acid Porphyrin

21 Intermediates linking primary and secondary metabolism Primary Metabolite Intermediate Secondary Metabolite Fatty acid Sterols Proteins Aromatic amino acids Acetyl oa Mevalonic acid Amino acid Shickimic acid polyketides terpenes Alkaloids Phenolic compounds

22 Building Blocks? ombination of building blocks 1, methyl H N H 3 5, isoprene N Lysergic acid Indole. 2 N NH 2 N Indole, 2 N

23 Building Block ( 단위구조 ) 의종류와유래 1 - 가장단순한단위구조하나의탄소로만구성 - 일반적으로메틸기로존재하며산소나질소를붙이기도한다. - L-methionine 의 S- 메틸기에의해생성 - methylenedioxy 기 (-H 2 -) 가대표적

24 2 - 탄소두개로구성된단위구조는 acetyl oa 에의해서생성 - Acetyl oa 는반응성이높은 malonyl oa 로먼저합성된후 긴탄소사슬의생합성에이용됨

25 5-5 isoprene 단위는 mevalonate 또는 deoxyxylulose phosphate 에서유래 - Mevalonate 그자체는 acetyl oa 세개의결합으로만들어져여섯개의탄소를 가지지만그중에서다섯개로만 isoprene 을구성 - Deoxyluluose phosphate 는골격을 methylerythritol phospahte 로재구성한후 isoprene 을구성

26 6 3 - 주로 phenylpropyl기로주로존재하는단위체 - Shikimate 경로에서유래된두개의방향족아미노산인 L-phenylalanine, L-tyrosine의탄소골격에서유래 - Side chain의탄소가탈락되어 6 2 또는 6 1 형태역시 6 3 골격에서 유래

27 6 2 N - L-phenylalanine 이나 L-tyrosine 에서유래. - 일반적으로 L-tyrosine 에의한경우가많고아미노산에서 H 가 제거되어생성

28 Indole- 2 N - 방향족아미노산인 L-tryptophan 에서카르복시기가제거되어 indole- 2 N 을생성

29 4 N - Pyrrolidine 골격에서주로발견되며 L-ornithine 에서유래 N 과 indole. 2 N 단위와는다르게 d- 아미노질소를제공 Pyrrolidine

30 5 N - 4 N 과유사하지만단지 L-lysine 이전구체임. - e- 아미노질소가얻어지며주로 piperidine 환을이룸 Piperidine

31 예 ) MVA, Deoxyxylulose-phosphate 1, methyl L-Met H N H 3 5, isoprene N Lysergic acid Indole. 2 N NH 2 N Indole, 2 N L-Trp

32 Acetyl oa L-Phe L-Tyr L-Met MVA Deoxyxylulosephosphate

33 L-Phe L-Tyr Acetyl oa Acetyl oa L-Trp L-Met MVA Deoxyxylulosephosphate L-Phe L-Tyr

34 onstruction Mechanism - 이차대사과정의대부분의반응은효소특이적반응에의해촉매됨 - 이차대사과정에관여하는효소는기질특이성에따라두개의그룹으로분류 (1) 이차대사산물의기본골격을형성하는데관여하는효소는매우높은기질특이성을가짐 (1, 2의경우 ) (2) 기본구조를변형하는효소들 (dehydrogenases, monooxygenases, methyltransferases, glycosyltransferases) 은상대적으로낮은기질특이성을가짐 (3, 4, 5) Þ metabolic grids ( 대사격자 ) 3 G A 1 B 2 3 E H D 3 F I 5 K

35 대표적인생합성반응 - Alkylation Reactions; Nucleophilic Substitution - Alkylation Reactions; Electrophilic Additions - Wagner-Meerwein Rearragement - Aldol & laisen Reaction - Schiff Base formation & Mannich Reaction - Transamination - Decarboxylation Reaction - xidation & Reduction Reaction; Dehydrogenase, oxidase, Monooxygenase, Dioxygenase, Amine xidase - Phenolic xidative oupling Reactions - Glycosylation Reactions

37 Paclitaxel Ú 1958 년부터 NI 주도하에 1,550 속, 3,390 종의식물의 114,000 개추출물로항암제 개발을위한검색을실시하였으며그결과물중하나 - Diterpenene 유도체 - Pacific yew (Taxus brevifolia, 태평양주목 ) 의껍질에서분리 (0.01~0.02% 함유 ) 년정도성숙한주목에서약 1g 을얻을수있음 - 1 년요구량은 200kg - Taxol 은등록된상표명 (1993 년 ) - 난소암, 유방암, 폐암등에유효 (antimitotic agent) - Docetaxel (Taxotere ) 은 Paclitaxel 의유도체 - 약 12 억달러 ( 약 1 조 4 천억원 ) 이상매출

40 Polyketide pathway (Acetate-malonate pathway)

42 AETYL ENZYME A - A TW-ARBN BUILDING BLK Acetyl oa H 3 S oa an be used like a molecular Lego piece.. well, sort of

43 Keto acids

44 LAISEN vs. ALDL laisen condensation Base-catalyzed condensations between ester and compound posessing active methylene groups R 2 H 5 + R' H 2 2 H 5 R H 2 H 5 R' Aldol condensation ondensation of two carbonyl compounds (e.g., aldehyde and ketone) to form an aldol (b-hydroxy carbonyl compounds) R 2 R 1 H R 3 a ketone + H R 4 an aldehyde R 2 H R 1 R 3 H R 4

45 LAISEN vs. ALDL 두분자의 ethyl acetate 반응 à ethyl acetoacetate 형성두분자의 acetaldehyde 반응 à aldol 형성 Aldol: aldehyde alcohol b-hydroxy keton

46 2 분자의탄소를갖는 acetate 단위구조 acetyl oa H 3 H acetic acid H 3 S oa acetate unit Adenosine triphosphate

47 Differences between an oxygen ester and a thioester: Thioesters are more prone to enolization. Thioesters are more reactive. THIESTERS

48 AETYL oa UNITS ARE LINKED BY A LAISEN-LIKE LIKE NDENSATIN Acetyl oa는 ATP와보조효소 biotin의도움을받아서 2 와결합해카르복시산화됨으로써 malonyl oa를형성 Acetyl-oA 로부터 malonyl-oa 로의과정 (1) a 위치의수소가두개의 carbonyl 탄소의영향을받아산화성이증가 (2) 반응성이더좋은친핵기를제공하여사슬을쉽게추가함

49 THE ENZYMES THAT ASSEMBLE AETYL-oAoA UNITS USE A DEARBXYLATIN F MALNYL-oA Enz-B: HAIN EXTENDER malonyl oa Enz-B:.. H 2 S oa x2 H x1 acetyl oa H 3 S oa STARTER H 3 H 2 H 2 H 2 H 2 SoA - 2 x5 x4 H.. H 2 H 3 H 2 S oa S oa x3 Acetoacetyl-oA H H2 S oa 2 a polyketide chain H 3

50 Acetate-malonate pathway (= Polyketide pathway) : acetyl oa 또는 acyl oa 를출발물질로하여 malonyl oa 가지속적으로반응하여생성 H 3 SoA H 3 SoA H 3 SoA acetyl-oa laisen reaction H 3 H 2 SoA H 3 H 2 H 2 SoA n acetoacetyl-oa laisen reaction poly-b-keto ester acetyl-oa H 3 SoA H 2 H SoA laisen reaction H 3 SoA H 3 H 2 H 2 SoA acetoacetyl-oa SoA malonyl-oa 2 nucleophilic attack on carbonyl with simultaneous loss of 2 malonyl-oa 2 H 3 H 2 H 2 n SoA poly-b-keto ester

51 2-UNIT 의 polyketide 는가능한 2 개의 reactive carbonyl carbon 을가진다. H.. H 2 S oa H 3 S oa H 3 H S oa BRANHED LINEAR mevalonic acid H 3 H H 3 H H 2 S oa H 3 H H2 2 SoA H 2 H 2 H 2 H H 2 H 2 H SoA PLYKETIDE HAINS TERPENES STERIDS AETGENINS

20 A. Mechanism 1) Base-catalyzed aldol reaction a 3 2 new bond 3-ydroxybutanal ( -hydroxyaldehyde, racemic mixture) 2 + a + pk a 20 arbanion En

20 A. Mechanism 1) Base-catalyzed aldol reaction a 3 2 new bond 3-ydroxybutanal ( -hydroxyaldehyde, racemic mixture) 2 + a + pk a 20 arbanion En 19 hap 19 : Enolate Anions and Enamines 19.1 Formation and eactions of Enolate Anions : An verview α- of aldehydes or ketones : acidic (pk a = 20) 2 : Alkylation by S2 substitution Br a + 2 + a + 2 arbanion