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“Metabolic integration and
Regulation”
Assistant Prof. Dr. Panida Khunkaewla
School of Chemistry
Suranaree University of Technology
109700: Graduate Biochemistry
Trimester 2/2016
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Degradation Synthesis
Overview of metabolism
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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http://www.wormbook.org/chapters/www_intermetabolism/intermetabolism.html
Integration of Metabolic pathways
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Metabolic pathways for glucose 6-phosphate in the liver
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
Amino acid Metabolism
Synthesis of nonprotein
nitrogen-containing compound e.g. serotonin
Fat made from amino acid
carbon skeletons (liver cells only, and generally not much)
Glucose production from
amino acid carbon skeletons (liver and kidney cells only)
Synthesis of body proteins for cell
structure and other needed
components, such as enzymes
hormones, and muscle contractile proteins
Energy production from amino acid
carbon skeletons for body cells: yield on averages 4 kcal/g
Amino acids from cell breakdown
Amino acids from diet
Free NH3
Urea synthesis in live
Excretion of urea by the kidneys
Amino acid pool in cell
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Metabolism of Amino Acid in The Liver
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Metabolism of Fatty Acids in The Liver
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Metabolic pathway are controlled in different nutritional and disease states to maintain sources of energy and amino acids in the blood for all tissues.
Pathways that remove excess fuels from the blood (glycogenesis, glycolysis, fatty acid synthesis and lipogenesis) are active in the fed state.
Pathways that maintain adequate levels of fuel in the blood (glycogenolysis, gluconeogenesis, lipolysis, proteolysis, and ketogenesis) are active in the starved state.
Pathways are controlled by substrate availability, allosteric effectors, covalent modification, and induction or repression of key enzymes.
The changes in metabolism that accompany common disease state are variations on the themes that function in the fed and fasted states
Key concept of metabolic integration
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Metabolic control
The system returns to the steady state.
In a steady state
An equal rate of
Formation and consumption of intermediates
Changing of enzyme activities
Perturbation alters the rate
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Regulatory mechanisms maintain constant level of
key metabolites
ATP, ADP, AMP and NADH in cells
glucose in the blood
matching the use or storage of glycogen
to the organism’s changing needs.
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Metabolic regulation
Enzymes activities (Fast metabolic adjustment)
Allosteric
Covalent modification
Feedback inhibition regulation
Hormones or growth factor (Slow metabolic adjustment)
covalent modification
changing of enzyme synthesis or enzymes activities
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Factors that determine the activity of an enzyme
Association with regulatory protein
Sequestration(compartmentation)
Allosteric regulation
Covalent modification
Enzyme Amino acidsmRNADNA
nucleotides
transcription translation turnover
signal
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Glycolysis and Gluconeogenesis pathway
Hexokinase
Pyruvate kinase
Phospho-frucokinase-1
Fructose 1,6-bisphosphatase
Pyruvate carboxylase
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Regulation of pyruvate kinase
“This mechanism prevents the liver from consuming glucose by glycolysis when the blood glucose concentration is low”
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Glycogen synthesis
“Glycogen phosphorylase is regulated allosterically and homonally”
GSK3 = Glycogen synthase kinase-3Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Effects of GSK3 on glycogen synthase activity
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Control of glycogen synthesis from blood glucose in myocytes
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Regulation of carbohydrate metabolism in hepatocyte;
during high blood glucose
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Some of genes regulated by insulin
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Glucose regulation of insulin secretion by pancreatic cells
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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What happen in the first week of starvation?
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
33Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin © 2011 John Wiley & Sons, Inc.
The five phases of glucose homeostasis
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Regulation of carbohydrate metabolism in hepatocyte;
during high blood glucose
Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005
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Substrate and hormone level in blood of well-fed, fasting, and starving human
Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin © 2011 John Wiley & Sons, Inc.
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Metabolic interrelationships of tissues in type 1 diabetes mellitus.
Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin © 2011 John Wiley & Sons, Inc.
Type I diabetes: insulin-dependent diabetes (requires insulin to live) begins before age 20 caused by autoimmune destruction of -cells
Hyperglycemia: The inability of the insulin-dependent tissues to take up plasma glucose accelerated hepatic gluconeogenesis from amino acids derived from muscle protein
Hyperlipoproteinemia (chylomicrons and VLDLs)Low lipoprotein lipase activity in adipose tissue capillaries (an enzyme dependent on insulin for its synthesis)
Severe ketoacidosis.: Increase of lipolysis in the adipose tissue and accelerated fatty acid oxidation in the liver.
Glucose excreted into urine leads water excreted -> feel hungry + thirsty
Metabolic interrelationships of tissues in type 2 diabetes mellitus.
Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin © 2011 John Wiley & Sons, Inc.
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Hyperglycemia, often with hypertriglyceridemia.
The ketoacidosis characteristic of the insulin-dependent disease is not observed.
Increased levels of VLDL are probably the result of increased hepatic triacylglycerol synthesis
stimulated by hyperglycemia and hyperinsulinemia.