Lehninger Principles of Biochemistry 5/e

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1 David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 22 Biosynthesis of Amino Acids, Nucleotides, and Related Molecules 2008 W. H. Freeman and Company

2 Amino acid 의생합성 1) 필수 a.a: 음식으로부터섭취가능 ex)val, Leu, Trp, Phe, His, Met, Thr, Lys, Ile 2) a.a 생합성의개관 Glucose Glucose 6-phosphate Ribose-5-phosphate Histidine 3-Phosphoglycerate Serine Glycine, Cysteine Erythrose 4-phosphate Phosphoenolpyruvate citrate oxaloacetate α-ketoglutarate Trp, Phe, Tyr Pyruvate Ala, Val, Leu Asn, Met, Thr, Lys, Ile Aspartate Glu Gln, Pro, Arg

3 The nitrogen cycle

4 Allosteric regulation of glutamine synthetase

5 adenylyltransferase uridylyltransferase Second level of regulation of glutamine synthetase

6 Proposed mechanism for glutamine amidotransferases

7 * Overview of amino acid biosynthesis

The TCA Cycle Can Provide Intermediates For Biosynthesis Figure 19.

8 The TCA Cycle Can Provide Intermediates For Biosynthesis Figure The TCA cycle provides intermediates for biosynthesis. Amino acids are highlighted in orange. All 20 of the common amino acids can be made from TCA cycle intermediates.

10 *

11 *

12 Biosynthesis of serine from 3-phosphoglycerate and of glycine from serine in all organisms

13 22-14 Biosynthesis of cysteine from homocysteine and serine in mammals

14 *

15 Biosynthesis of six essential amino acids from oxaloacetate and pyruvate in bacteria: methionine, threonine, lysine, isoleucine, valine, and leucine

16 Biosynthesis of six essential amino acids from oxaloacetate and pyruvate in bacteria: methionine, threonine, lysine, isoleucine, valine, and leucine

17 Biosynthesis of six essential amino acids from oxaloacetate and pyruvate in bacteria: methionine, threonine, lysine, isoleucine, valine, and leucine

18 Biosynthesis of six essential amino acids from oxaloacetate and pyruvate in bacteria: methionine, threonine, lysine, isoleucine, valine, and leucine

19 Biosynthesis of six essential amino acids from oxaloacetate and pyruvate in bacteria: methionine, threonine, lysine, isoleucine, valine, and leucine

20 *

21 Biosynthesis of chorismate, an intermediate in the synthesis of aromatic amino acids in bacteria and plants

22 Biosynthesis of tryptophan from chorismate in bacteria and plants

24 *

25 Biosynthesis of histidine in bacteria and plants

26 Allosteric regulation of isoleucine biosynthesis

27 22-22 Interlocking regulatory mechanisms in the biosynthesis of several amino acids derived from aspartate in E. coli

28 Amino acid 로부터유도되는여러가지분자 - a.a 의역할 : 단백질구성단위, hormone cofactor nucleotide alkaloids 세포벽중합체 porphyrin antibiotics pigment ( 색소 ) 신경전달물질의전구체 1) Porphyrin 의생합성 1 전구체 : Glycine 2 역할 : Hb, cytochrome 과같은 heme 단백질중의 porphyrin 핵의구성성분 3 유전적결함 : Porphyria 적혈구, 혈액, 간에서 porphyrin 전구체의축적을야기하는 glycine 으로부터 porphyrin 에이르는생합성에서의효소의결핍 2) 담즙색소 : heme 의분해 bilirubin 생성 : 혈청 albumin 과결합 / 간으로 bilirubin diglucuronide ( 담즙색소 ) : 소장으로분비 - bilirubin: 간기능손상의결과로담즙분비가폐쇄될때혈중으로새어나와황달 (jaundice) 야기 - GeorgeⅢ 과협혈기 : 치아형광, 소변적색, heme 부족 : 흡혈귀

29 Animal Plant, bacteria Biosynthesis of γ-aminolevulinate

30 Biosynthesis of heme from γ-aminolevulinate

32 Bilirubin and its breakdown products

33 Bilirubin and its breakdown products

34 Bilirubin and its breakdown products

35 3) Creatine 과 Glutathione (GSH) 의생합성 1 creatine 과 phosphocreatine 의생합성 a) 역할 : 골격근의 E 저장물질 b) 과정 : Amidino Creatine transferase Methyltransferase creatine kinase Glycine guanidino acetate Phospho-creatine 2 GSH 생합성 a) 역할 : 단백질의 SH 를환원상태로유지, heme 의 Fe 2+ 유지, glutaredoxin 에대한환원제, peroxide 의제거 b) 과정 : 4) 방향족 a.a 1 Phe, Tyr Arg ornithine Cys, ATP ADP+P i adomet adohcy Lignin : 식물조직에풍부 Tannin : 포도주산화방지, morphine (alkaloids), 계피유, 육두구, 정향 (clove), Vanilla, 고추 향미성분 ATP ADP Glu [γ-glu-cys] GSH 산화형 : GSSG Gly, ATP ADP+P i 환원형 : GSH 2 Trp Indole-3-pyruvate: 식물의성장 H. auxin: 식물세포의생물학적과정조절

36 Biosynthesis of creatine and phosphocreatine

37 Glutathione metabolism

38 Glutathione metabolism

39 결핵치료제 Amino acid racemase inhibitors: antibacterial drug

40 Biosynthesis of two plant substances from amino acids

41 5) Neurotransmitter ( 신경전달물질 ) 의생합성 1 Tyr DOPA 2 Glutamate 3 Trp 5-hydroxytryptophan 4 His PLP PLP PLP Dopamine Norepinephrine. Epinephrine 부족 ( 파킨슨씨병 ) VS 과잉 ( 정신분열증 ) 간질발작 GABA : 억제성신경전달물질 간질, 고혈압증의치료 PLP serotonin ( melatonin) histamine : 혈관확장제 cf) cimetidine: antagonist, 위산분비억제 polyamines ⅰ) putrescine, spermidine, spermine ⅱ) 역할 - 세포의성장인자 - (+)charge로핵산안정화 - tumor marker : 암진행시 putrescine을생합성시키는 ornithine decarboxylase 활성 Africa 수면병의치료 1) 증상 : 발열지속 사망 2) ornithine decarboxylase의기전 : ornithine + PLP DFMO (difluoromethylornithine) ⅰ) 자살저해제 ⅱ) ornithine decarboxylase를불활성화시킴 H 2 O CO 2 Schiff base putrescine H 2 O

42 Biosynthesis of some neurotransmitters from amino acids

43 H2 antagonist: cimetidine(tagamet)

44 22-30 Biosynthesis of spermidine and spermine

45 아프리카수면병 : trypanosome( 파동편모충 ) 원생동물감염 발열

46 Mechanism of ornithine decarboxylase reaction

47 원생동물에는치명적 difluoromethylornithine Suicide inactivators

48 6) NO 의생합성 1 NO 의역할 : 신경전달물질, 혈액응고, 혈압조절 2 생합성과정 : Arg [Hydroxy Arg.] Cit + NO NADPH 의의존적반응 3 NOS 의종류 a) inos: inducible ( 염증 ) b) bnos: brain ( 기억력 ) Nucleotide 의생합성과분해 nucleotide 의역할 ⅰ) DNA, RNA 의전구체 NADPH O NADP + 2 H 2 O ⅱ) 화학 E 의운반체 : ATP, GTP c) enos: endothelial ( 혈관확장 ) ⅲ) Coenzyme 의구성성분 (NAD, FAD, S-adenosyl Met, Coenzyme A) & 활성화된생합성중간체의성분 (UDP-Glucose, CDP-diacyl glycerol) ⅳ) 세포의 2 nd messenger: camp, cgmp ½NADPH O 2 ½NADP + H 2 O

49 NO synthase(nos) : inos, bnos, enos Biosynthesis of nitric oxide

50 1) Nucleotide 생합성의경로 1 De novo pathway: amino acid, Ribose-5 phosphate, CO 2, NH 3 를전구체로합성 2 Salvage pathway: 유리염기, nucleotide 를재이용 2) Purine nucleotide 의생합성 1 전구체 : PRPP (Phosphoribosyl Pyrophosphate) 2 Asp formic acid N C N CO 2 N N Gln Gly formic acid Gln O N O N Asp <purine> CO 2 <pyrimidine>

51 3) Ribonucleotide 의 deoxyribonucleotide 환원 dndp: deoxy의 nucleotide NDP: RNA의 nucleotide HS Glutaredoxin HS GSSG Ribonucleotide reductase Glutaredoxin reductase S S Glutaredoxin 2GSH S S Thioredoxin Ribonucleotide reductase FAD SH SH thioredoxin reductase SH SH Thioredoxin FADH 2 S S NADPH + H + NADP + NADPH + H + NADP + 전자전달 4) Ribonucleotide Reductase 억제 : DNA 합성억제 항암효과

52 4) dump dtmp 1 dtmp의생성 : Ribonucleotide reductase에의해촉매 (CDP dcdp, UDP dudp) 2 dump dtmp dctp dutp Thymidylate synthase dump N5,N10-methylene tetrahydrofolate 7,8-Dihydrofolate dtmp Glycine PLP DHFR NADPH + H + NADP + Serine Tetrahydro folate *DHFR(dihydrofolate reductase) DNA 합성조절可 항암치료

53 Origin of the ring atoms of purines

54 Asp formic acid N C N CO 2 N N Gln Gly formic acid De novo synthesis of purine nucleotides: construction of the purine ring of inosinate (IMP)

55 Biosynthesis of AMP and GMP from IMP

56 Regulatory mechanisms in the biosynthesis of adenine and guanine nucleotides in E. coli.

57 Carbamoyl phosphate synthetase II (cytosol) Asp Gln amidotransferase Gln O Asp N O N CO 2 <pyrimidine> De novo synthesis of pyrimidine nucleotides: biosynthesis of UTP and CTP via orotidylate

58 Channeling of intermediates in bacterial carbamoyl phosphate synthetase

59 or Reduction of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase

60 Ribonucleotide reductase

61 Ribonucleotide reductase

64 Regulation of ribonucleotide reductase by deoxynucleoside triphosphates

65 Biosynthesis of thymidylate (dtmp)

66 Conversion of dump to dtmp by thymidylate synthase and dihydrofolate reductase

67 Catabolism of purine nucleotides

68 5) 요산의과잉생산의문제점 : 통풍 (gout) 1 증상 : 관절에요산나트륨의결정이이상침착되어염증유발, 통증 + 관절염 2 원인 : 과잉의 uric acid 생성 (purine 대사에관련된효소의유전적결손 ) 3 치료 a) 식이요법 : nucleotide, 핵산의함량이높은음식물 ex) 간장, 우유제품 b) 약물요법 : allopurinol 요산의 purine 대사물인 xanthine, hypoxanthine 과구조적유사 경쟁적저해제 6) 화학요법제 1 암세포의특성 a) 정상조직세포보다빠른성장 nucleotide 요구성大 b) nucleotide 생합성의저해제에대한감수성大 2 Glutamine amidotransferase 저해 : azaserine, acivicin 에의해저해 suicide inhibitor 3 Thymidylate synthase & dihydrofolate reductase(dhfr) 를저해 a) Fluorouracil 세포내에서 FdUMP 로변환시켜이것이효소와결합하여저해 b) Methotrexate: DHFR 저해제 folate 의유사체로경쟁적저해제로작용 c )Aminopterin: DHFR 저해제

69 Catabolism of purine nucleotides

70 Catabolism of purine nucleotides

71 Catabolism of a pyrimidine

72 Allopurinol, an inhibitor of xanthine oxidase

73 Anticancer agent Azaserine and acivicin, inhibitors of glutamine amidotransferases

74 Fluorouracil Thymidylate synthesis and folate metabolism as targets of chemotherapy

75 요로감염 (antibiotics) Anticancer agent Thymidylate synthesis and folate metabolism as targets of chemotherapy

76 Conversion of dump to dtmp and its inhibition by FdUMP

77 Purine nucleotide 합성의 salvage pathway ( 재이용경로 )

78 Nucleotide metabolism 대사의주요개념도

Lehninger Principles of Biochemistry 5/e

David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 18 Amino Acid Oxidation and the Production of Urea 2008 W. H. Freeman and Company Dietary proteins Synthesis