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Transcript
Metabolism 2015.10.27、28 Genomics – 25,000 Genes DNA RNA Transcriptomics – 100,000 Transcripts Protein Proteomics – 1,000,000 Proteins NH2 H OH Biochemicals (Metabolites) OH O CH NH2 N H O H2 C C CH3 CH CH3 N HO H HO H H OH N H N OH Confidential Metabolomics – 3,000 Compounds Obesity as epidemic disease Mankind is not Finished Evolving ? 2.5 million years 50 years Pathogenesis of health problems associated with obesity Cardiovascular diseases Stroke 2 3 Liver,gall bladder diseases Reproductive diseases Diabetes mellitus Metabolic syndrome 14 Cancer, Osteroarthritis, Thermogenesis in Brown Adipose Tissue (BAT) II.Metabolic pathways Glycolysis and Gluconeogenesis TCA Glycogen Metabolism Fatty Acid Metabolism Urea Cycle & Nitrogen Metabolism Glycolysis ADP ADP ATP ATP Glucose Hexokinase Glucose6-phosphate Phosphoglucose isomerase Fructose6-phosphate Phospho fructokinase ADP Aldolase NADH NAD ATP 2–Phospho glycerate Enolase Phospho glycerate mutase 3–Phospho glycerate Phospho enolopyruvate Phospho glycerate kinase 1, 3 Bisphospho glycerate Glyceraldehyde 3-phosphate dehydrogenase ADP NADH NAD ATP Pyruvate kinase Pyruvate Fructose1, 6-bisphosphate Lactate dehydrogenase Lactate Triose phosphate isomerase Dihydroxyacetone phosphate Glyceraldehyde 3-phosphate Pentose phosphate pathway NADPH NADP Glucose6-phosphate H2O Glucose 6-phosphate dehydrogenase Lactonase 6-Phospho gluconolactone Phosphoglucose isomerase 6-Phospho gluconate 6-Phosphogluconate dehydrogenase NADPH CO2 Phosphopentose epimerase Fructose6-phosphate Xylulose 5-phosphate Ribulose 5-phosphate Phosphopentose isomerase Sedoheptulose 7-phosphate Transketolase Erythrose 4-phosphate Transaldolase Glyceraldehyde 3-phosphate NADP Ribose 5-phosphate Glycogen synthesis I (Glycogen synthase - glycogenin) UTP UDP-Glucose UDP-glucose pyrophosphorylase Glucose-1phosphate Phosphoglucomutase Glycogen synthase Glycogen Glucose-6phosphate Pyruvate dehydrogenase Aconitase Citrate synthase Pyruvate Citrate NAD H2O NADH CO2 Aconitase cis-Aconitate Oxaloacetate Malate dehydrogenase H2O NADH NAD Isocitrate Citric acid cycle Malate Isocitrate dehydrogenase Fumarase H2O NAD NADH FADH2 Fumarate Succinate dehydrogenase CO2 NADH FAD CO2 GTP Isocitrate dehydrogenase NAD GDP -Ketoglutarate Succinate -Ketoglutarate dehydrogenase Succinyl-CoA synthetase Succinyl-CoA Oxalosuccinate Mitochondrial electron transport and oxidative phosphorylation H+ H+ NADH:CoQ Oxidoreductase (Complex I) Succinate:CoQ Oxidoreductase (Complex II) CoQ:Cytochrome c Oxidoreductase (Complex III) H+ Cytochrome c Oxidase (Complex IV) Cyt c Q Q 2 eQ Succinate DH (FAD) Q Q Cyt bc1 COX COX a b Mitochondrial Matrix Fumarate NADH + H+ NAD Succinate ADP + Pi H+ ATP Muscle Fatty acids metabolism Chylomicrons Albumin VLDL LDL LPL CD36 LPL ACS PAP1 DGAT GPAT AGPAT Mitochondrial β-oxidation and respiration AGPAT GPAT ACS Fatty acids synthesis Acetyl CoA carboxylase Oxaloacetate Malonyl CoA Citrate lyase ADP + Pi ATP Acetyl CoA Citrate ATP ADP + Pi Acetyl transacylase Malonyl transacylase Pantetheine -ketoacyl ACP-synthase Fatty acid synthase Pantetheine Enoyl-ACP reductase Pantetheine -ketoacyl ACP-reductase NADP NADP -hydroxyacyl ACP-dehydratase NADPH NADPH Pantetheine Mitochondrial matrix β-oxidation Palmitoyl carnitine Citric Acid Cycle Carnitine acyltransferase I Palmitoyl carnitine Acetyl-CoA Myristoyl CoA Palmitoyl CoA Palmitoyl CoA Carnitine acyltransferase II AMP Palmitoyl CoA ligase Palmitoyl CoA ATP 3-Ketopalmitoyl CoA FAD Carnitine FADH2 Acyl CoA dehydrogenase 3-Hydroxyacyl CoA dehydrogenase Palmitate Trans Δ2 enolopalmitoyl CoA Cytoplasm Intermembrane space NADH NAD Enoyl CoA hydratase H2O 3-Hydroxypalmitoyl CoA Choleesterol Biosynthesis e III.Metabolism and drugs A tale of two hormones • • • • • metabolic hormone Anabolic hormone catabolic hormone Insulin Leptin Frederick Banting (1891-1941), 1921 Insulin ,1922 Diabetes treatment The Discovery of Insulin (Toronto 1921) Frederick Banting (1891-1941) John J.R. MacLeod (1876-1935) Charles H. Best (1899-1978) James B. Collip (1892-1965) Marjorie (?-?) The Miracle of Insulin Leonard Thompson, December 15, 1922 February 15, 1923 What is Insulin? The Most Powerful Agent We Have to Control Glucose Discovery of Leptin The discovery of leptin • Ranson’s studies from the 1930s showing that lesions in the hypothalamus can cause obesity in rats, • In the 1950s, Gordon Kennedy proposed that adipose tissue mass is regulated by an endocrine system • In the 1970s, Doug Coleman at the Jackson Laboratory used parabiosis to characterize ob/ob mice and diabetic (db/db) mice • Coleman predicted that ob/ ob mice lack a blood-borne factor that regulates body weight and that db/db mice lack its eceptor • Body weight is regulated by an endocrine loop. ob gene encodes the key hormone, a receptor, encoded by the db locus Parabiosis • Many researchers at the time questioned the existence of a physiological system that regulates body weight and the relevance of the ob and db genes for human physiology • In 1986 we set out to clone the ob gene. Eight years later, my laboratory reported the identification of ob in mouse and human ： positional-cloning approach • I lived in constant fear that I would one day receive a phone call informing me that someone else had gotten to ob first. • Were this to happen, I often wondered, The thrill of discovery • “I’d wake up in the middle of the night just smiling.” A tale of two hormones Jeffrey M Friedman 2010 Albert Lasker Basic Medical Research Award Warburg effect Definition Cancer cells utilize glycolysis even in presence of O2 Otto Heinrich Warburg Biography Otto Heinrich Warburg: • Born-October 8, 1883 in Germany • Died-August 1, 1970 in Berlin, Germany • He won a Nobel prize in Physiology and Medicine for his Warburg effect in 1931. The Warburg Effect • In oncology, the Warburg effect is that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria like most normal cells. • Tumour cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful • He postulated that this change in metabolism is the fundamental cause of cancer Interpretations • His "Warburg effect" asserts that even when oxygen is plentiful, cancer cells continue to use glycolysis (a secondary system of producing energy, employed by normal cells only when oxygen is in short supply). • Thanks to Otto Heinrich Warburg, we can discover new ways of finding and treating cancer. PET-CT 1883-1970 Otto Warburg 18F-labeled 2-fluoro-2-deoxyglucose (FdG) Glycolysis and Cancer Continue to rely of Glycolysis even when O2 restored to tumor Treatment?? Blocking lactate dehydrogenase (block NAD regeneration turn off Glycolysis)
