생명현상의 Overview: 생명현상의 분자기전 Information 생체정보: hormone, cytokines, neurotransmitter → 세포 → 유전 O2/영양분 cytokines neurotransmitters Hormones 1st messenger 지질→저장 (비만, 동맥경화) 당질 (당뇨병) -omics 2nd messenger °Physiome Southern blot Northern blot Genome=gene+chromosome -sequencing -SNP chip Western blot Transcriptome: DNA chip, mRNA seq AAA a.a Hormesis E小 Vt C, E NADH themogenin Cell homeostasis 열 단백질 Maintenance Vt B TCA Protein (생리기능) ATP Proteome -2D/Maldi-Top Mass mRNA Cell proliferation (replication) E多 Seven processes that affect the steady-state concentration of a protein * 호르몬과 표적기관 Physiological information cascade GHRH(GH) GnRH(CH,FSH) TRH(TSH) CRH(ACTH) T3/T4 glucocorticoid aldosterone calcitonin : C세포에서 분비 Ca저하 GHIH PRIH 뼈에서 유리 신장 재흡수 * Cellular signal transduction Cortisol Insulin GFs Glucagon Epinephrine Tyr kinase Akt SREBP ChREBP Tf 인산화 <세포의 자극에 의한 유전자 발현 조절> Intracellular Receptor Steroid hormone Carrier에 의해 표적세포까지 이동 carrier 해리 단순수송 intracellular receptor 핵공 통과 DNA 결합 전사조절 Protein Kinase A (cAMP) CREB: CRE binding protein Receptor Tyrosine Kinase Receptor tyrosine kinases (TKs or RTKs) phosphorylate specific tyrosines on a small set of intracellular signaling proteins. Insulin EGF, VEGF, M-CSF PDGF, HGF, IGF-1 FGF, NGF Insulin ligand binding에 의한 dimerization autophosphorylation 신호반응의 종결 Protein tyrosine phosphatase에 의한 탈인산화 반응 Receptor의 endocytosis로 lysosome 에서 분해 IL-1 IL-1R TNFα ㅑ Insulin ㅜ TNFR IR Shc TRAF6 TRAF2 TRADD IRAK IRS-1 IRS-2 Cell proliferation IKK NF-κB Inflammation COX-2 INF Akt Cyclin D/E mTOR Cell cycle Fasting Glucagon SIRT1 (NAD) AMPK (AMP) PI3K MAPKs NIK Epinephrine GSK3 Cholesterol synthesis HMG-CoA reductase Squalene synthase SREBP2 G protein PKA Glut4 translocation GS SREBP1 CREB ChREBP 4E-BP 4E Autophagy (protein degradation) Glycogen synthesis cAMP ATP Glucose uptake PGC-1α FA FAS, ACC synthesis Glycolysis FOXO PPARs HNF-4 FA synthesis Translation (protein synthesis) Gluconeogenesis PEPCK Biosignaling in inflammation and metabolism G6Pase Small RNA a) small nuclear RNA(snRNA): splicing, 100-200b b) small nuleolar RNA(snoRNA): rRNA modification, cleavage, 60-300b c) microRNA(miRNA): RNA 번역억제, 절단, gene regulation, 22b, genome 1%, by RNase III d) si RNA: small interfering RNA, RNA절단 RNA interference(RNAi): siRNA, shRNA : RNase III의 일종 :RNA-induced silencing Complex(RISC) cf) RNA interference(RNAi) siRNA, shRNA FIGURE 26-28 Synthesis and processing of miRNAs. eIF-4E 번역조절인자 mTOR eIF-4F의 eIF-4E 소단위체가 4E-BP와 결합하면 번역 저해 신장인자가 4E-BP에서 인산화되면 4E-BP와 elF-4E와 결합방해, 단백질합성촉진 translation Stage 5: Folding and posttranslational processing ① N-/C- terminal modifications: N-acetylation ② Loss of signal sequence ⅰ) amino말단의 polypeptide서열∋15∼30 residues ⅱ) 단백질을 세포내 최종 목적지로 인도 ⅲ) 운반되는 도중 or 최종목적지에 도달한 후 제거 ③ Modification of individual amino acids a) Phosphorylation: Serine, Threonine, Tyrosine의 hydroxyl기가 ATP에 의해 phosphorylation ex) casein ∋ phosphoserine기 多 ⇒ Ca2+와 결합 ⇒ 유아에게 영양소공급 효율적 -signaling: kinase b) Carboxylation : L-glutamic acid의 변형 ex)Prothrombin∋ γ-carboxylglutamic acid residue: VitK 필요 ⇒ Ca2+와 결합 ⇒ 혈액응고 mechanism 개시 c) Methylation: 대부분의 조직의 calmodulin은 특이적 위치에 하나의 trimethyl residue 지님; Histone-Ac ,-Meth, -P, ④ Attachment of carbohydrate side chains: glycoproteins : N-결합형 올리고당, O-결합형 올리고당, “proteoglycans” (Asn) ( Thr, Ser) ⑤ Addition of isoprenyl groups : Ras단백질, Proto-oncogene산물, G단백질, Lamin에 isoprenyl기를 부가 세포막에 존재케 → 발암 *항발암 활성: Ras 단백질의 isoprenyl기 제거 → 암화학요법제 (cancer chemotherapy) ⑥ Addition of prosthetic groups : biotin, cytochrome C의 heme분자 ⑦ Proteolytic processing : Insulin, 단백질가수분해효소 ⑧ Formation of disulfide cross-links <4> Receptor-Mediated Endocytosis: coated pits, clathrin, caveolin <5> Protein Degradation 1) Lysosomal: major a) endocytosis b) autophagy 2) Cytosolic ubiquination/proteasome What is Autophagy? A process of cellular self-degradation of cytoplasmic components via the lysosomal pathway Macroautophagy/Microautophagy/Chaperone-mediated autophagy (CMA) Macroautophagy mitophagy/micorpexophagy or macropexophay/reticulophagy piecemeal microautophagy of the nucleus/ribophagy Proteasome FIGURE 27-48 Three-dimensional structure of the eukaryotic proteasome Cancer - Chemical/Radiation>>mutation>>transformation>>proliferation>>cancer - Virus>>oncogene>>> 발암촉진 *Oncogene 활성화: mutation, translocation, deletion *Tumor suppressor gene(anti-oncogene): p53, Rb mutation>>hypermethylation *Cell cycle-p53, Rb Carcinogenesis 암예방, 항암 Gene therapy RNAi - GFs signaling: Tyr kinase Apoptosis Differentiation Epigenetic regulation Anti-angiogenesis Immunotherapy Lipid Metabolism, diseases, and Drugs 1. Lipid peroxidation: aging, carcinogenesis, atherosclerosis 2. Trans fatty acid: vascular disease -Linoleic acid – 암발생 -α-Linolenic acid - 암 억제 3. Lipoprotein - LDL/HDL, oxidized LDL(atherosclerosis) 4. Apo E alleles: dementia Apo E3 alleles(78%), Apo E2(7%): ApoE4 homozygous(70세 이하에서 16 배) 5. Lipoxygenase/Ac-COX-2: lipoxin, protectin, resolvin 6. Eicosanoids: COX inhibitor PGE2(발열, 동통, 위 점막 보호), PGI2(혈관이완) PGD2(수명), PGF2α(자궁 평활근 수축), TXA2(혈전형성), LTs(기관지 평활근 수 축, allergy) 7. ω3 Fatty acids - PGE 3, PGI 3 /TXA 3 생성 - PGE2, PGI2/TXA2 생성 억제 - resolvin, protectin 생성 - Cardiovascular diseases, cancer, dementia 예방 Lipid Metabolism, diseases, and Drugs 8. TG: obesity, hyperlipidemia 9. Insulin resistance: Metabolic syndrome 10. Cholesterol synthesis - Cancer와의 연관성: Ras activation - HMG-CoA reductase inhibitors: statin 유도체 11. Phospholipid: metabolic enzyme deficiency Hexosaminidase A: Tay-Sachs disease – ganglioside GM2 Spingomyelinase :Niemann-Pick disease– spingomyelin 축적 12. Ketoacidosis: diabetes, fasting 13. PAF(platelet-activating factor): 면역세포, 기관지 과민증, 염증 FIGURE 17-7 Stages of fatty acid oxidation. FIGURE 17-12 Coordinated regulation of fatty acid synthesis and breakdown MAT MAT FIGURE 21-6 Sequence of events during synthesis of a fatty acid. FIGURE 21-44 Regulation of cholesterol formation balances synthesis with dietary uptake. Phospholipids ㊀ Glucocorticoids Inhibit induction PhospholipaseA1 Arachidonate ㊀ Cyclooxygenase 1 and 2 ㊀ COX/LOX inhibitors ㊀ 5-lipoxygenase 5-HPETE Cyclic endoperoxides PGI2 PGF2α LTA4 TXA2 vasodilator, hyperalgetic, inhibits platelet aggregation stimulate platelet aggregation, vasoconstrictor PGD2 broncoconstrictor, inhibits platelet aggregation, myocardial vasodilator contraction 5-lipoxygenase inhibitors PGE2 Vasodilator, hyperalgetic LTB4 (chemotaxin) LTC4 LTD4 LTE4 Bronchoconstrictors, Increase vascular permeability Figure 8.2 Inflammatory/anti-inflammatory lipid biosynthesis pathway and functions. Overview of metaboilsm 단백질합성 Glycogenesis Glycogenolysis S70S6K mTOR F-1,6-bisphosphatase Glu Insulin Glut4 Phosphofructokinase F-6-P Glu Glucagon Epinephrine IR IRS GProtein PI3K GSK3β Akt GS SREBP-1,2 Glycogen 합성 FOXO1,HNF-4 cAMP PKA PGC1 α Phosphoenolpyruvate kinase((PEPCK) PPAR α/β Pyr dehydrogenase Pyr carboxylase Chol synthesis HMG-CoA reductase Cholesterol 청소차 대포차 유조차 유조선 FIGURE 21-40a Lipoproteins and lipid transport. • Insulin 저항성과 IRS-1 Ser 인산화 FFA IKKβ TNFα JNK Resistin mTOR 과영양 Ser 307 IRS-1 PH PTB1 PI3K binding site Ser 632 Ser 612 MAPK endothelin PMA PKCξ IKKβ TNFα Resistin mTOR Steroid 5α-Reductase is a Factor in Male Baldness and Prostatic Cancer Steroid 5α-Reductases are membrane-bound enzymes that catalyze NADPH-dependent reduction of testosterone to dihydrotestosterone (above). Finasteride is a specific inhibitor of type II 5α-reductase. Nucleotide metabolism 대사의 주요 개념도
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