Carbohydrate Metabolism

An Overview of Metabolism

Adenosine Tri-Phosphate (ATP)  Link between energy releasing and energy requiring mechanisms  “rechargeable battery” ADP + P + Energy ATP

Mechanisms of ATP Formation  Substrate-level phosphorylation  Substrate transfers a phosphate group directly  Requires enzymes Phosphocreatine + ADP Creatine + ATP  Oxidative phosphorylation  Method by which most ATP formed  Small carbon chains transfer hydrogens to transporter (NAD or FADH) which enters the electron transport chain

 Metabolism is all the chemical reactions that occur in an organism  Cellular metabolism  Cells break down excess carbohydrates first, then lipids, finally amino acids if energy needs are not met by carbohydrates and fat  Nutrients not used for energy are used to build up structure, are stored, or they are excreted  40% of the energy released in catabolism is captured in ATP, the rest is released as heat Metabolism

 Performance of structural maintenance and repairs  Support of growth  Production of secretions  Building of nutrient reserves Anabolism

 Breakdown of nutrients to provide energy (in the form of ATP) for body processes  Nutrients directly absorbed  Stored nutrients Catabolism

 Cells provide small organic molecules to mitochondria  Mitochondria produce ATP used to perform cellular functions Cells and Mitochondria

Metabolism of Carbohydrates

Carbohydrate Metabolism  Primarily glucose  Fructose and galactose enter the pathways at various points  All cells can utilize glucose for energy production  Glucose uptake from blood to cells usually mediated by insulin and transporters  Liver is central site for carbohydrate metabolism  Glucose uptake independent of insulin  The only exporter of glucose

Blood Glucose Homeostasis  Several cell types prefer glucose as energy source (ex., CNS)  mg/dl is normal range of blood glucose in non-ruminant animals  mg/dl is normal range of blood glucose in ruminant animals  Uses of glucose:  Energy source for cells  Muscle glycogen  Fat synthesis if in excess of needs

Fates of Glucose  Fed state  Storage as glycogen  Liver  Skeletal muscle  Storage as lipids  Adipose tissue  Fasted state  Metabolized for energy  New glucose synthesized Synthesis and breakdown occur at all times regardless of state... The relative rates of synthesis and breakdown change

High Blood Glucose Glucose absorbed Insulin Pancreas Muscle Adipose Cells Glycogen Glucose absorbed immediately after eating a meal…

Glucose Metabolism  Four major metabolic pathways:  Energy status (ATP) of body regulates which pathway gets energy  Same in ruminants and non-ruminants  Immediate source of energy  Pentophosphate pathway  Glycogen synthesis in liver/muscle  Precursor for triacylglycerol synthesis

Fate of Absorbed Glucose  1 st Priority: glycogen storage  Stored in muscle and liver  2 nd Priority: provide energy  Oxidized to ATP  3 rd Priority: stored as fat  Only excess glucose  Stored as triglycerides in adipose

Glucose Utilization Glucose PyruvateRibose-5-phosphateGlycogen Energy Stores Pentose Phosphate Pathway Glycolysis Adipose

Glucose Utilization Glucose PyruvateRibose-5-phosphateGlycogen Energy Stores Pentose Phosphate Pathway Glycolysis Adipose

Glycolysis  Sequence of reactions that converts glucose into pyruvate  Relatively small amount of energy produced  Glycolysis reactions occur in cytoplasm  Does not require oxygen Glucose → 2 Pyruvate Lactate (anaerobic) Acetyl-CoA (TCA cycle)

Glycolysis Glucose + 2 ADP + 2 Pi 2 Pyruvate + 2 ATP + 2 H 2 O

First Reaction of Glycolysis Traps glucose in cells (irreversible in muscle cells)

Glycolysis - Summary Glucose (6C) 2 Pyruvate (3C) 2 ATP 2 ADP 4 ADP 4 ATP 2 NAD 2 NADH + H

Pyruvate Metabolism  Three fates of pyruvate:  Conversion to lactate (anaerobic)  Conversion to alanine (amino acid)  Entry into the TCA cycle via pyruvate dehydrogenase pathway (create ATP)

Pyruvate Metabolism  Three fates of pyruvate:  Conversion to lactate (anaerobic)  Conversion to alanine (amino acid)  Entry into the TCA cycle via pyruvate dehydrogenase pathway

Anaerobic Metabolism of Pyruvate to Lactate  Problem:  During glycolysis, NADH is formed from NAD +  Without O 2, NADH cannot be oxidized to NAD +  No more NAD +  All converted to NADH  Without NAD +, glycolysis stops…

Anaerobic Metabolism of Pyruvate  Solution:  Turn NADH back to NAD + by making lactate (lactic acid) (oxidized) (reduced) (oxidized)(reduced)

Anaerobic Metabolism of Pyruvate  ATP yield  Two ATPs (net) are produced during the anaerobic breakdown of one glucose  The 2 NADHs are used to reduce 2 pyruvate to 2 lactate  Reaction is fast and doesn’t require oxygen

Pyruvate Metabolism - Anaerobic PyruvateLactate NADH NAD+ Lactate Dehydrogenase  Lactate can be transported by blood to liver and used in gluconeogenesis

Cori Cycle Lactate is converted to pyruvate in the liver

Pyruvate Metabolism  Three fates of pyruvate:  Conversion to lactate (anaerobic)  Conversion to alanine (amino acid)  Entry into the TCA cycle via pyruvate dehydrogenase pathway

Pyruvate metabolism  Convert to alanine and export to blood Keto acidAmino acid

Pyruvate Metabolism  Three fates of pyruvate:  Conversion to lactate (anaerobic)  Conversion to alanine (amino acid)  Entry into the TCA cycle via pyruvate dehydrogenase pathway

Pyruvate Dehydrogenase Complex (PDH)  Prepares pyruvate to enter the TCA cycle Electron Transport Chain TCA Cycle Aerobic Conditions

PDH - Summary Pyruvate Acetyl CoA 2 NAD 2 NADH + H CO 2

TCA Cycle  In aerobic conditions TCA cycle links pyruvate to oxidative phosphorylation  Occurs in mitochondria  Generates 90% of energy obtained from feed  Oxidize acetyl-CoA to CO 2 and capture potential energy as NADH (or FADH2) and some ATP  Includes metabolism of carbohydrate, protein, and fat

TCA Cycle - Summary Acetyl CoA 3 NAD 3 NADH + H 1 FAD 1 FADH 2 1 ADP 1 ATP 2 CO 2

 Requires coenzymes (NAD and FADH) as H + carriers and consumes oxygen  Key reactions take place in the electron transport system (ETS)  Cytochromes of the ETS pass H 2 ’s to oxygen, forming water Oxidative Phosphorylation and the Electron Transport System

Oxidation and Electron Transport  Oxidation of nutrients releases stored energy  Feed donates H +  H + ’s transferred to co-enzymes NAD + + 2H + + 2e - NADH + H + FAD + 2H + + 2e - FADH 2

So, What Goes to the ETS??? From each molecule of glucose entering glycolysis: 1.From glycolysis: 2 NADH 2.From the TCA preparation step (pyruvate to acetyl-CoA): 2 NADH 3.From TCA cycle (TCA) : 6 NADH and 2 FADH 2 TOTAL: 10 NADH + 2 FADH 2

Electron Transport Chain  NADH + H + and FADH 2 enter ETC  Travel through complexes I – IV  H + flow through ETC and eventually attach to O 2 forming water NADH + H + 3 ATP FADH 2 2 ATP

Electron Transport Chain

Total ATP from Glucose  Anaerobic glycolysis – 2 ATP + 2 NADH  Aerobic metabolism – glycolysis + TCA 31 ATP from 1 glucose molecule

Volatile Fatty Acids  Produced by bacteria in the fermentation of pyruvate  Three major VFAs  Acetate  Energy source and for fatty acid synthesis  Propionate  Used to make glucose through gluconeogenesis  Butyrate  Energy source and for fatty acid synthesis  Some use and metabolism (alterations) by rumen wall and liver before being available to other tissues

Use of VFA for Energy  Enter TCA cycle to be oxidized  Acetic acid  Yields 10 ATP  Propionic acid  Yields 18 ATP  Butyric acid  Yields 27 ATP  Little butyrate enters blood

Utilization of VFA in Metabolism Acetate Energy Carbon source for fatty acids Adipose Mammary gland Not used for net synthesis of glucose Propionate Energy Primary precursor for glucose synthesis Butyrate Energy Carbon source for fatty acids - mammary

Effect of VFA on Endocrine System Propionate Increases blood glucose Stimulates release of insulin Butyrate Not used for synthesis of glucose Stimulates release of insulin Stimulates release of glucagon Increases blood glucose Acetate Not used for synthesis of glucose Does not stimulate release of insulin Glucose Stimulates release of insulin

A BRIEF INTERLUDE…

Need More Energy (More ATP)??  Working animals  Horses, dogs, dairy cattle, hummingbirds!  Increase carbon to oxidize  Increased gut size relative to body size  Increased feed intake  Increased digestive enzyme production  Increased ability to process nutrients  Increased liver size and blood flow to liver  Increased ability to excrete waste products  Increased kidney size, glomerular filtration rate  Increased ability to deliver oxygen to tissues and get rid of carbon dioxide  Lung size and efficiency increases  Heart size increases and cardiac output increases  Increase capillary density  Increased ability to oxidize small carbon chains  Increased numbers of mitochondria in cells  Locate mitochondria closer to cell walls (oxygen is lipid-soluble)

Hummingbirds  Lung oxygen diffusing ability 8.5 times greater than mammals of similar body size  Heart is 2 times larger than predicted for body size  Cardiac output is 5 times the body mass per minute  Capillary density up to 6 times greater than expected

Rate of ATP Production (Fastest to Slowest)  Substrate-level phosphorylation  Phosphocreatine + ADP Creatine + ATP  Anaerobic glycolysis  Glucose Pyruvate Lactate  Aerobic carbohydrate metabolism  Glucose Pyruvate CO 2 and H 2 O  Aerobic lipid metabolism  Fatty Acid Acetate CO 2 and H 2 O

Potential Amount of Energy Produced (Capacity for ATP Production)  Aerobic lipid metabolism  Fatty Acid Acetate CO2 and H2O  Aerobic carbohydrate metabolism  Glucose Pyruvate CO2 and H2O  Anaerobic glycolysis  Glucose Pyruvate Lactate  Substrate-level phosphorylation  Phosphocreatine + ADP Creatine + ATP

Glucose Utilization Glucose PyruvateRibose-5-phosphateGlycogen Energy Stores Pentose Phosphate Pathway Glycolysis Adipose

Pentose Phosphate Pathway  Secondary metabolism of glucose  Produces NADPH  Similar to NADH  Required for fatty acid synthesis  Generates essential pentoses  Ribose  Used for synthesis of nucleic acids

Glucose Utilization Glucose PyruvateRibose-5-phosphateGlycogen Energy Stores Pentose Phosphate Pathway Glycolysis Adipose

Energy Storage  Energy from excess carbohydrates (glucose) stored as lipids in adipose tissue  Acetyl-CoA (from TCA cycle) shunted to fatty acid synthesis in times of energy excess  Determined by ATP:ADP ratios  High ATP, acetyl-CoA goes to fatty acid synthesis  Low ATP, acetyl CoA enters TCA cycle to generate MORE ATP

Glucose Utilization Glucose PyruvateRibose-5-phosphateGlycogen Energy Stores Pentose Phosphate Pathway Glycolysis Adipose Glycogenesis

 Liver  7–10% of wet weight  Use glycogen to export glucose to the bloodstream when blood sugar is low  Glycogen stores are depleted after approximately 24 hrs of fasting (in humans)  De novo synthesis of glucose for glycogen Glycogenesis

 Skeletal muscle  1% of wet weight  More muscle than liver, therefore more glycogen in muscle, overall  Use glycogen (i.e., glucose) for energy only (no export of glucose to blood)  Use already-made glucose for synthesis of glycogen

Fates of Glucose  Fed state  Storage as glycogen  Liver  Skeletal muscle  Storage as lipids  Adipose tissue  Fasted state  Metabolized for energy  New glucose synthesized Synthesis and breakdown occur at all times regardless of state... The relative rates of synthesis and breakdown change

Fasting Situation in Non-Ruminants  Where does required glucose come from?  Glycogenolysis  Lipolysis  Proteolysis  Breakdown or mobilization of glycogen stored by glucagon  Glucagon - hormone secreted by pancreas during times of fasting  Mobilization of fat stores stimulated by glucagon and epinephrine  Triglyceride = glycerol + 3 free fatty acids  Glycerol can be used as a glucose precursor  The breakdown of muscle protein with release of amino acids  Alanine can be used as a glucose precursor

Low Blood Glucose Proteins Broken Down Insulin Pancreas Muscle Adipose Cells Glycogen Glycerol, fatty acids released Glucose released In a fasted state, substrates for glucose synthesis (gluconeogenesis) are released from “storage”…

Gluconeogenesis  Necessary process  Glucose is an important fuel  Central nervous system  Red blood cells  Not simply a reversal of glycolysis  Insulin and glucagon are primary regulators

Gluconeogenesis  Vital for certain animals  Ruminant species and other pre-gastric fermenters  Convert carbohydrate to VFA in rumen  Little glucose absorbed from small intestine  VFA can not fuel CNS and RBC  Feline species  Diet consists primarily of fat and protein  Little to no glucose absorbed  Glucose conservation and gluconeogenesis are vital to survival

Gluconeogenesis  Synthesis of glucose from non-carbohydrate precursors during fasting in monogastrics  Glycerol  Amino acids  Lactate  Pyruvate  Propionate There is no glucose synthesis from fatty acids Supply carbon skeleton

Carbohydrate Comparison  Primary energy substrate  Primary substrate for fat synthesis  Extent of glucose absorption from gut  MOST monogastrics = glucose  Ruminant/pre-gastric fermenters = VFA  MOST monogastrics = glucose  Ruminant = acetate  MOST monogastrics = extensive  Ruminant = little to none

Carbohydrate Comparison  Cellular demand for glucose  Importance of gluconeogenesis  Nonruminant = high  Ruminant = high  MOST monogastrics = less important  Ruminant = very important