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Home , Carbohydrate metabolism, Fructolysis, Glycogenesis, Glycogenolysis

Carbohydrate I & II - General concepts of metabolism - - - -TCA -

FScN4621W Xiaoli Chen, PhD Food Science and Nutrition University of Minnesota

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Central Aspects of Macronutrient Metabolism

Macronutrients (, , )

Catabolic metabolism

Oxidation Metabolites (smaller molecules)

Anabolic metabolism Energy (ATP) Synthesis of cellular components or energy stores Chemical Reactions Cellular Activities

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Central Aspects of Macronutrient Metabolism

 High-energy compounds ◦ ATP () ◦ NADPH (reduced nicotinamide adenine dinucleotide phosphate) ◦ NADH (reduced nicotinamide adenine dinucleotide) ◦ FADH2 (reduced flavin adenine dinucleotide)

Oxidation of macronutrients

NADH NADPH FADH2

ATP and NADPH are required ATP for anabolic metabolism 3

1 Unit I

General Concepts of Glucose Metabolism

 Metabolic pathways of glucose  Glucose  Glucose transport in tissues  Glucose metabolism in specific tissues

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Overview

, Absorption and Transport of Carbs ◦ Final products of digestion: ______, ______, and ______ Cellular fuels ◦ Glucose, fatty acids, ketone bodies, amino acids, other gluoconeogenic precursors (, lactate, propionate)  Glucose: primary metabolic fuel in humans ◦ Provide 32% to 70% of the energy in of American population  All tissues are able to use glucose as energy fuels ◦ Glucose has different metabolic fate in different tissues  Physiological states determine glucose metabolic fate ◦ Fed/fasted – glucose is metabolized through distinct pathways  Main goal – the maintenance of circulating glucose

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Overview

How your body metabolizes

 At the tissue and organ level ◦ Different tissues/organs have different roles in the regulation of energy metabolism (metabolic pathways and substrates and metabolite flows)

 At the subcellular level ◦ Each organelle or compartment has specific roles in the regulation of metabolic pathways

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2 General Concepts

 Anabolic pathways ◦ Synthesis of larger compounds/molecules from smaller precursors

 Catabolic pathways ◦ Breakdown of larger molecules

 Amphibolic pathways ◦ Links between anabolic and catabolic pathways ◦ Example: cycle (TCA cycle)

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General Concepts

 Aerobic pathway ◦ Aerobic is an adjective that means "requiring air", where "air" usually means

◦ Where does aerobic metabolism occur in the cell?

◦ What are the end products of aerobic metabolism?

◦ Example:

 Anaerobic pathway ◦ Anaerobic – without air, as opposed to aerobic

◦ Where does anaerobic metabolism occur in the cell?

◦ What are the end products of anaerobic metabolism?

◦ Example: 8

What you need to know about Carbohydrate Metabolic Pathways

Pathway Catabolic/ Physiological Tissue Function Anabolic State Glycolysis

Glycogenesis

Gluconeogenesis

Glycogenolysis

Pentose phosphate pathway

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3 What you need to know about Carbohydrate Metabolic Pathways

Pathway Rate-limiting Key How is it regulated reaction(s) by ? Glycolysis

Glycogenesis

Gluconeogenesis

Glycogenolysis

Pentose phosphate pathway

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Circulating Glucose

 Glucose levels in the blood are kept within a strictly regulated concentration range

◦ Postabsorptive state: 4.5-5.5 m mol/L ◦ In starvation: 3.3-3.9 m mol/L ◦ After ingestion of carbohydrate meal: 6.5-7.2 m mol/L

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Pathways of glucose metabolism

 Glycolysis

◦ the that converts glucose C6H12O6, into pyruvate  Glycogenesis = synthesis ◦ the process of glycogen synthesis  Gluconeogenesis ◦ Gluconeogenesis, (GNG) is a metabolic pathway that ◦ results in the generation of glucose from non-carbohydrate carbon substrates  Glycogenolysis = glycogen breakdown ◦ the breakdown of glycogen (n) to glucose-6-phosphate and glycogen (n-1).

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4 Glucose Homeostasis How dietary glucose is metabolized after a meal

In the fed state After a meal Glycolysis Other glycolytic Glycogenesis tissues Gluconeogenesis FAT Glycogenolysis 2-3% brain 20% of Glucose GLUT3 Glycolysis absorpted 22% GLUT1 glucose Glucose In the circulation insulin Glycolysis GLUT4 Glycogenesis Glycogenolysis muscle insulin Lactate Diet Glycolysis Glucose CHO conversion carbohydrate GLUT4 to Fat Small intestine 13

Glucose Homeostasis How the circulating glucose is maintained during fasting

FOOD

GLYCOGEN X Fed NON HEXOSE STORES PRECURSORS

FastCirculating Fast Glucose

Gluconeogenesis Glycogenolysis Prolonged Fast

Kidney

Gluconeogenesis 14

Glucose Uptake by Tissues

 A key regulatory step controlling glucose homeostasis

 Facilitated glucose uptake: mediated by glucose transporters

 Glucose transporters: GLUT1, GLUT2, GLUT3, GLUT4, GLUT5

 Different tissue expression and functional regulation of glucose transport

◦ Insulin-independent glucose uptake: GLUT1, GLUT2, GLUT3 and GLUT5 ◦ Insulin-dependent glucose uptake: GLUT4

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5 Glucose Uptake by Tissues

Transporter Major site Proposed function GLUT2 Liver, pancreatic β-cells, kidney, Glucose small intestine, regulation GLUT4 , cardiac Insulin-mediated muscle, adipose tissue glucose uptake GLUT5 Small intestine, adipose tissue, muscle transporter SGLT-1 Small intestine, kidney Glucose uptake

GLUT1 Placenta, brain,erythrocytes, Basal glucose adipose tissue uptake GLUT3 Brain, nerve, placenta, kidney High-affinity glucose uptake

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How GLUTs regulate glucose metabolism?

 In fed state, two main GLUTs are involved in glucose metabolism ◦ GLUT2 ◦ GLUT4

 Insulin-dependent glucose uptake via GLUT4 ◦ ~80% of blood glucose is transported into skeletal muscle ◦ ~20% of blood glucose to adipose tissue

 Insulin-independent glucose uptake via GLUT2 ◦ Liver ◦ Pancreatic β-cells

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How GLUT2 regulate glucose metabolism in fed state? Diet

Glucose

Liver Pancreas

Energy storage Glucose sensor

Glycogen Insulin Fatty acids 18

6 Glucose-stimulated insulin release (First-tier response to elevated blood glucose)

Pancreas -β cells: insulin -α cells:

GLUT2

1. Which tissue/organ produces insulin?

2. Why insulin is produced?

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Insulin-Stimulated Glucose Uptake by Tissues (Second-tier response to elevated blood glucose) 1st tier response Dietary glucose Insulin secretion 2nd tier response After a meal, elevated blood glucose triggers 1st tier response How insulin regulates Insulin starts 2nd tier response glucose uptake?

Glucose transporter and tissues are involved in 2nd tier response in glucose metabolism

• Glucose transporter : ______

• Tissues: ______, ______20

Insulin regulates GLUT4 translocation from the intracellular compartment to the cell surface Adipose tissue and skeletal muscle

basal + insulin Insulin-stimulated

Fed

Fasting

Insulin resistance Type2 21

7 Exercise stimulates GLUT4 translocation from the intracellular compartment to the cell surface

Skeletal muscle

Rest Exercise Exercise-stimulated

Exercise

Insulin resistance Type2 diabetes

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Different role of GLUT2 and GLUT4 in glucose homeostasis

 Tissue distribution  Role in body response to dietary glucose  What happens to glucose homeostasis if GLUT2 or GLUT4 is defective, respectively?

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Carbohydrate Metabolism in Liver

LIVER: Central organ for glucose Glucose homeostasis

• In liver glucose can be: - completely oxidized for energy - stored as glycogen - partially oxidized to provide carbon for synthesis of fatty acids & ribose-5-phosphate M

• Liver can also produce and release glucose to the circulation when glucose levels are down Liver Pathways: M: mitochondria Metabolite flows:

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8 in Skeletal Muscle

In skeletal muscle Glucose glucose can be:

• oxidized for energy • stored as glycogen

Pathways: M Metabolite flows: Q: Does skeletal muscle release glucose into blood? Muscle

M: mitochondria

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Carbohydrate Metabolism in Brain

Glucose In brain:

Complete oxidation of glucose for energy

(glycolysis and TCA cycle) Largely relies on glucose M as a fuel

Brain

M: mitochondria

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Carbohydrate Metabolism in Red Blood Cells

Glucose

In red blood cells

Glucose can be metabolized into lactate (glycolysis)

What is missing?

Red blood cell

Q: why glucose can not be completely oxidized in red blood cells?

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9 Carbohydrate metabolism in Adipose Tissue In adipose tissue Glucose

Glucose can be partially and/or Glucose completely oxidized for: Glucose 6-P

Fructose 1,6-biP • De novo fed Pyruvate (provide acetyl CoA for FA synthesis and glycerol Acetyl-CoA TCA

3-phosphate for TAG Fatty acids Glycerol 3-phosphate synthesis) • Release metabolic fuel: Triacylglycerol TAG is hydrolyzed to release fatty acids and Fatty acids + Glycerol fasting glycerol Fatty acids Adipose cell Liver 28

Carbohydrate metabolism in

Adipose Tissue Fed In adipose tissue Glucose

Glucose can be partially and/or Glucose completely oxidized for: Glucose 6-P

Fructose 1,6-biP • De novo lipogenesis fed Pyruvate (provide acetyl CoA for FA synthesis and glycerol Acetyl-CoA TCA

3-phosphate for TAG Fatty acids Glycerol 3-phosphate synthesis) • Release metabolic fuel: Triacylglycerol TAG is hydrolyzed to release fatty acids and glycerol Fatty acids Adipose cell Liver 29

Carbohydrate metabolism in

Adipose Tissue Fasting In adipose tissue Glucose X Glucose can be partially and/or Glucose X completely oxidized for: Glucose 6-P X X Fructose 1,6-biP X • De novo lipogenesis Pyruvate (provide acetyl CoA for X FA synthesis and glycerol Acetyl-CoA X TCA X 3-phosphate for TAG Fatty acids Glycerol 3-phosphate synthesis) • Release metabolic fuel: Triacylglycerol TAG is hydrolyzed to release fatty acids and Fatty acids + Glycerol fasting glycerol Fatty acids Adipose cell Liver 30

10 Unit II

Glucose Catabolic Pathways  Glucose Oxidation ◦ Glycolysis ◦ TCA

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Glycolysis

 First step in glucose utilization as energy

 Main pathway for metabolism of fructose, and other carbohydrates

 The enzymatic reactions take place in the of all cell types

 Some cell types depend solely on glycolysis for their energy requirements

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Glycolytic pathway *

* First stage

Priming of glucose:

• ATP expenditure • Break down of 6C into 2X 3C

1 Glucose (6C)

2 3-phosphate (3C)

• Two rate-limiting reactions catalyzed Glycerol 3-phasphate by / & Harper’s Chapter 17, page 138– Figure 17- 2 TAGs 33

11 Glycolytic pathway

2x

Second stage Anaerobic • Production of reducing condition equivalents and ATP * Skeletal muscle 2 Glyceraldehyde 3-phosphate

2 pyruvate

• The reoxidation of NADH via lactate formation allows glycolysis to proceed in the Aerobic anaerobic state TCA for complete oxidation Harper’s Chapter 17, page 138– Figure 17- 2 34

What happens in glycolysis? Where in the cell does it happen? 1 molecule of glucose

ATP

NADH ATP

ATP

2 molecules of pyruvate

How many ATPs are produced in aerobic condition?

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What happens in glycolysis?

1 molecule of glucose

ATP

NADH ATP

ATP

2 molecules of lactate

How many ATPs are produced in anaerobic condition?

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12 Consumption and Generation of ATP in Glycolysis

Reaction ATP change per Glu

Glucose  G-6-P - 1 ATP

F-6-P  F-6-BisP - 1 ATP

2 1,3-BisPGlycerate + 2 ATP

2 PEP  Pyruvate + 2 ATP

Via a substrate-level phosphorylation Net: + 2 ATP

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What happens to the pyruvate formed from glycolysis?

 Pyruvate is decarboxylated to acetyl CoA  Acety CoA enters TCA cycle for CELL

complete oxidation to CO2 and H2O  Acetyl CoA for and ketone body synthesis

 Pyruvate is reduced to lactate Fatty ◦ replaces NAD+ in glycolysis acids (red blood cells) (Fed) ◦ provides lactate for gluconeogenesis during fast (muscle and red blood cells)

Ketone bodies (Fasting only in liver) Mitochondrion

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Entry of Other Sugars into Glycolysis

Enzyme Activity in Different Tissues

Liver: Glucokinase : HIGH Hexokinase : LOW : HIGH Glucokinase : HIGH

Skeletal Muscle: Hexokinase: HIGH : HIGH

• Fructose doesn’t stimulate Aldolase B Phosphofructo-1-kinase insulin secretion and is mainly *Rate-limiting - metabolized by the liver

Aldolase A • provides - Pyruvate - Lactate Stipanuk’s39 Chapter 12, - Acetyl CoA Figure 12-5

13 - Fructose does not stimulate Entry of Other Sugars insulin secretion - Fructokinase is highly expressed into Glycolysis in liver

Glycogen

Why high fructose consumption Insulin Glucose increases obesity?

High fructose consumption

Aldolase B Phosphofructo-1-kinase Lipogenesis hydrolysis in liver

Aldolase A

Pyruvate Fatty liver Obesity Acetyl-CoA Citrate

Fatty acids 40

Entry of Other Sugars into Glycolysis

Fructose intolerance - Hereditary disease - Lacks Aldolase - Blood glucose falls Glucokinase

Fructose 1-phosphate accumulation blocks glycogen breakdown and glucose release Glycogen

Aldolase B X hydrolysis Glucose

Aldolase A

Stipanuk’s Chapter 12, Figure 12-5 41

Mitochondrion Structure

PDH

Respiratory chain ATP Synthase

PDH : Complex

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14 Pyruvate Dehydrogenase Complex

Enzyme Abbreviated Prosthetic Group

Pyruvate E1 Dehydrogenase E PDH pyrophosphate (TPP)

Dihydrolipoyl Lipoamide E2 Transacetylase E TA Dihydrolipoyl FAD E3 Dehydrogenase E DLD

PDH CoA CO2 Pyruvate Acetyl-CoA NAD+ NADH + H

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Regulation of Pyruvate Dehydrogenase Complex

End-product inhibitors: Acetyl CoA and NADH

Animo acids Fatty acids fatty acid oxidation Acetyl CoA - NADH - PDH

Pyruvate glycolysis

Glucose

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Acetyl CoA

glucose-6-P Glycolysis pyruvate O fatty acids Amino acids H3CCSCoA acetyl CoA ketone bodies acetyl-coenzyme A oxaloacetate citrate TCA Krebs Cycle

Acetyl CoA:  oxidized via Krebs Cycle, where the acetate moiety is further degraded to CO2 for energy production.  donor of 2 carbon units for synthesis of fatty acids, ketone bodies, & cholesterol. 45

15 TCA Cycle

 Amphibolic pathway: links between anabolic and catabolic pathway  Common pathway for oxidation of carb, lipid, and amino acids  Gluconeogenesis, lipogenesis and interconversion of amino acids

 Oxidation of 2 carbon fuel to CO2

 Supplies reducing equivalents for ATP production

Harper’s Chapter 16, Figure 16- 2 46

Glucose Fatty acid

TCA Cycle

Amino acid

Harper’s Chapter 16, Figure 16- 3 47

ATP Production from complete oxidation of one molecule of glucose

Reaction ATP production

Glycolysis 6-8 1 glucose to 2 pyruvate

Pyruvate dehydrogenase reaction 6 2 pyruvate to 2 Acetyl CoA + 2CO2

TCA 24 2 Acetyl CoA to 4 CO2 + 4 H2O

1 Glucose 6CO2 + 6H2O total ATP: 36-38

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16 Recommended Reading

Stipanuk’s 3rd edition  Carb Metabolism I ◦ Stipanuk’s Chapter 10 – Central Aspects of Macronutrient Metabolism ◦ Stipanuk’s Chapter 12 - Carbohydrate Metabolism  Cellular Intake and Metabolism of Glucose  Carb Metabolism II ◦ Stipanuk’s Chapter 12 - Carbohydrate Metabolism ◦ Glucose Utilization: Glycolysis ◦ Metabolism of other than glucose ◦ Harper’s Chapter 17 & 16  Glycolysis and the oxidation of pyruvate  TCA Cycle

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Assigned Reading

Stipanuk’s 3rd edition  Carb Metabolism I ◦ Stipanuk’s Chapter 12 - Carbohydrate Metabolism: Synthesis and Oxidation  Overview of Tissue-Specific Glucose Metabolism  Transport of glucose across cell membranes  Carb Metabolism II ◦ Stipanuk’s Chapter 12 - Carbohydrate Metabolism: Synthesis and Oxidation ◦ Glycolysis ◦ Metabolism of monosaccharides other than glucose ◦ Harper’s Chapter 17 & 16  Glycolysis and the oxidation of pyruvate  TCA Cycle

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