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“Metabolic integration and

Regulation”

Assistant Prof. Dr. Panida Khunkaewla

kpanida@sut.ac.th

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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Catabolism of proteins, fats, and carbohydrates

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Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005

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Specialized Metabolic Functions of Mammalian Tissues

8http://en.wikibooks.org/wiki/Medical_Physiology/Basic_Biochemistry/Metabolic_Integration

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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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Acetyl CoA is central in energy metabolism

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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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Classes of Hormones

Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005

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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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The well-fed state

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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The Fasting State

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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Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus

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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.

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Drug design to treat diseases

Genetic engineering of organisms of biotechnological

interest

Genetic syndromes therapy

Relevant of manipulation of metabolic pathway