lecture connections 14 | glucose utilization and biosynthesis © 2009 jim-tong horng 15 | principles...
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Lecture Connections14 | Glucose Utilization and Biosynthesis
© 2009 Jim-Tong Horng
15 | Principles of Metabolic Regulation
16 | The Citric Acid Cycle
19 | Oxidative Phosphorylation
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CHAPTER 14 Glucose Utilization and Biosynthesis
Harnessing energy from glucose via glycolysis
Fermentation under anaerobic conditions
Synthesis of glucose from simpler compounds: gluconeogenesis
Oxidation of glucose in pentose phosphate pathway
Key topics:
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Four Major Pathways of Glucose Utilization
• When there’s plenty of excess energy, glucose can
be stored in the polymeric form (starch, glycogen)
• Short-term energy needs are met by oxidation of
glucose via glycolysis
• Pentose phosphate pathway generates NADPH that
is used for detoxification, and for the biosynthesis of
lipids and nucleotides
• Structural polysaccharides (e.g. in cell walls of
bacteria, fungi, and plants) are derived from glucose
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Glycolysis: Importance
• Glycolysis is a sequence of enzyme-catalyzed reaction by which glucose is converted into pyruvate• Pyruvate can be further aerobically oxidized
• Pyruvate can be used as a precursor in biosynthesis
• In the process, some of the oxidation free energy in captured by the synthesis of ATP and NADH
• Research of glycolysis played a large role in the development of modern biochemistry– Understanding the role of coenzymes
– Discovery of the pivotal role of ATP
– Development of methods for enzyme purification
– Inspiration for the next generations of biochemists
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Glycolysis: Overview
• In the evolution of life, glycolysis probably was one of the earliest energy-yielding pathways
• It developed before photosynthesis, when the atmosphere was still anaerobic
• Thus, the task upon early organisms was how to extract free energy from glucose anaerobically?
•The solution–Activate it first by transferring couple of phosphates to it
–Collect energy later form the high-energy metabolites of the activated glucose
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Glycolysis: The Preparatory Phase
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Glycolysis: The Payoff Phase
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Glycolytic enzyme 命名(1) Kinase 與 ATP 水解 or 合成相關之 enzyme
(2) Mutase( 轉換 )Transfer functional group from one position to another in the same molecule, 指~ P 由 C3 位置 C2 位置
(3) Isomerase 指 Aldose Ketose
(4) Aldolase 指產物各為 -Aldose 分子及 ketose 分子
(5) Enolase 產生 enol form 分子
-C=C- alcohol
※Mutase is a subclass of isomerase
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The Hexokinase Reaction
• The first step, phosphorylation of glucose, is catalyzed by hexokinase in eukaryotes, and by glucokinase in prokaryotes
• Nucleophilic oxygen at C6 of glucose attacks the last () phosphorous of ATP
• Bound Mg++ facilitates this process by stabilizing the negative charge in the transition state
• This process uses the energy of ATP
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Phosphohexose Isomerization
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The Second Priming Reaction; The First Commitment
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The Second Priming Reaction; The First Commitment
• ATP is the donor of the second phosphate group• This is an irreversible step• The product, fructose 1,6-bisphosphate is
committed to become pyruvate and yield energy• Phosphofructokinase-1 is negatively regulated by
ATP– Do not burn glucose if there is plenty of ATP
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Aldolases Cleave 6-Carbon Sugars
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Triose Phosphate Interconversion
• Aldolase creates two triose phosphates: DAP and GAP
• Only GAP is the substrate for the next enzyme
• DAP is converted enzymatically to GAP
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To remind you…..
• Class schedule
• Exam
• Class schedule
• Exam
University of Cambridge University of California, San Francisco
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Glyceraldehyde 3-Phosphate Dehydrogenase Reaction
• First energy-yielding step in glycolysis• Oxidation of aldehyde with NAD+ gives NADH• Phosphorylation yields an high-energy reaction
product
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First Substrate-Level Phosphorylation
• 1,3-bisphosphoglycerate is a high-energy compound that can donate the phosphate group to ADP to make ATP
• The reaction is reversible, the reverse process transfer of phosphate from ATP to phosphoglycerate
• Kinases are enzymes that transfer phosphate groups from molecules like ATP to various substrates
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Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate
• This is a reversible isomerization reaction• Enzymes that shift functional groups around are
called mutases
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Mechanism of the Phosphoglycerate Mutase Reaction
• Phosphoglycerate mutase employs covalent
catalysis
• One of the active site histidines is post-
translationally modified to phosphohistidine
• Phosphohistidine donates its phosphate to O2
before retrieving another phosphate from O3
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Mechanism of the Phosphoglycerate Mutase Reaction
• Notice that the phosphate from the substrate ends up bound to the enzyme at the end of the reaction
• The two negative charges in the product are fairly close now but 2-phosphoglycerate is not good enough phosphate donor
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Dehydration of 2-Phosphoglycerate
• The goal here is to create a better phosphoryl donor
• Loss of phosphate from 2-phosphoglycerate would merely give a secondary alcohol with no further stabilization …
• Enolase 產生 enol form 分子
-C=C- alcohol
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Second Substrate-Level Phosphorylation
• … but loss of phosphate from phosphoenolpyruvate yields an enol that tautomerizes into ketone
• The tautomerization effectively lowers the concentration of the reaction product and drives the reaction toward ATP formation
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Pyruvate Kinase is Subject to Regulation
• Pyruvate kinase requires divalent metals (Mg++ or Mn++) for activity
• Under physiological conditions, the activity of pyruvate kinase is limited by the level of Mg++
• When there is plenty of ATP, the Mg ions are sequestered by ATP; this slows down pyruvate kinase
• Increased concentration of metabolites in the glycolytic pathway slows down glucose utilization
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SUMMARY Glycolysis
Glucose+2NAD++2ADP+2Pi 2pyruvate+2NADH+2H+ +2ATP+2H2O
4e-
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Glycolysis Occurs at Elevated Rates in Tumor Cells
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BOX 14-1 FIGURE 1 The anaerobic metabolism of glucose in tumor cells yields far less ATP (2 per glucose) than the complete oxidation to CO2 that takes place in healthy cells under aerobic conditions (~30 ATP per glucose), so a tumor cell must consume much more glucose to produce the same amount of ATP. Glucose transporters and most of the glycolytic enzymes are overproduced in tumors. Compounds that inhibit hexokinase, glucose 6-phosphate dehydrogenase, or transketolase block ATP production by glycolysis, thus depriving the cancer cell of energy and killing it.
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Feeder Pathways for Glycolysis
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Mutation SymptomsGalactokinase- deficient (high galactose conc. is found in the blood and urine)
Cataracts ( 白內障 ) caused by deposition of galactose metabolite galactitol in the lens
Transferase-deficient Poor growth of children, speech abnormality, mental deficiency, and liver damage even when galactose is withheld from the diet
(more severe!)Epimerase-deficient Same as above but is less severe when dietary
galactose is carefully controlled.
Galactosemia
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Under Anaerobic Conditions, Animals Reduce Pyruvate to Lactate
• During strenuous exercise, lactate builds up in the muscle
• The acidification of muscle prevents its continuous strenuous work
• The lactate can be transported to liver and converted to glucose there
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Under Anaerobic Conditions, Yeast Ferments Glucose to Ethanol
• Both steps require cofactors– Mg++ and thiamine pyrophosphate in pyruvate decarboxylase
– Zn++ and NAD+ in alcohol dehydrogenase
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就一個國家而言,我們終究得到的是哪一種醫師就是我們自己的報應。 (Kenneth Ludmerer, Time to heal, 1999)
University of Cambridge University of California, San Francisco
就一個國家而言,我們終究教出的是哪一種醫師就是我們自己的報應 (福報 ?)。
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Gluconeogenesis: Precursors for Carbohydrates
• Notice that mammals cannot convert fatty acids to sugars
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Glycolysis vs. Gluconeogenesis
• Glycolysis occurs mainly in the muscle and brain• Gluconeogenesis occurs mainly in the liver
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The Cory Cycle
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Synthesis of Oxaloacetate
• Conversion of pyruvate to energy-rich phosphoenolpyruvate requires two energy-consuming steps
• In the first step, pyruvate is transported into mitochondria and converted into oxaloacetate by pyruvate carboxylase
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Oxaloacetate Picks Up Phosphate from GTP
• The phosphoenolpyruvate carboxykinase reaction occurs either in the cytosol or the mitochondria
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From Pyruvate to Phosphoenolpyruvate
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PEP carboxykinase-Rabbit liver : mitochondriaRat liver : cytosolicHuman liver : both
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Pentose Phosphate Pathway
• The main goals are to produce NADPH for anabolic reactions and ribose 5-phosphate for nucleotides
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NADPH Regulates Partitioning into Glycolysis vs. Pentose
Phosphate Pathway
• NADPH inhibits glucose-6-phosphate dehydrogenase
Whether glucose 6-phosphate enters glycolysis or thepentose phosphate pathway depends on the currentneeds of the cell and on the concentration of NADPin the cytosol.
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蠶豆症
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Chapter 14: Summary
• Glycolysis, a process by which cells can extract a limited amount of energy from glucose under anaerobic conditions
• Gluconeogenesis, a process by which cells can use a variety of metabolites for the synthesis of glucose
• Pentose phosphate pathway, a process by which cells can generate reducing power (NADPH) that is needed for the biosynthesis of various compounds
In this chapter, we learned about:
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