Topic 14- GLucose Metabolism

Glucose At Heart of Metabolism pt1

• Metabolism of glucose is at heart of metabolism

  • A. Major metabolic fuel for all body cells

  • B. Average body consumption ~ 160 – 200 g/day

• II. Brain is major consumer of glucose (~ 120 g/day)

  • A. Glucose is its major energy source

    • 1. Cannot synthesize glucose & can only
      store a limited amount
      

Glucose At Heart of Metabolism pt2

• I. RBCs absolutely require glucose

  • A. Do not possess mitochondria & cannot do aerobic metabolism

    • 1. Depend exclusively on anaerobic metabolism for energy needs

• II. Approximate body glucose reserves (in 70 kg man after overnight fast)

  • A. Extracellular glucose ~ 4 – 5 g

  • B. Liver glycogen ~ 80 g

  • C. Muscle glycogen ~ 150 g

Regulation of Blood Glucose Levels

• I. Blood glucose levels must be tightly maintained

  • A. Due to high body demand vs. moderate body reserves

  • B. [Glucose]Blood = 70 – 100 mg/dL

• II. 2 key organs regulate [glucose]Blood

  • A. Pancreas: produces hormones regulating glucose metabolism

  • B. Liver: major site of glucose metabolism
    

Hyperglycemia pt1

• I. High [glucose]Blood

  • A. Normally occurs after the consumption of a carbohydrate-rich meal

• II. beta cells of pancreas produce & secrete the hormone insulin

  • A. Insulin stimulates glucose uptake from blood into muscle, adipose tissue, heart, & liver
    

Hyperglycemia pt2

• Insulin-stimulated ↑ [glucose]Intracellular is dealt with in 2 ways

  • A. Glycolysis (in all cells): breakdown & utilization of glucose

  • B. Glycogenesis (in liver & skeletal muscle): storage of glucose as glycogen (glucose uptake + storage)

Hypoglycemia pt1

• I. Low [glucose]Blood

  • A. Normally occurs ~ 4 hours after end of last meal or during prolonged, intense physical activity that increases metabolic demand

• II. alpha cells of pancreas produce & secrete the hormone glucagon (liberation and release of glucose)

  • A. Glucagon stimulates liver to produce more glucose for release into blood

Hypoglycemia pt2

• I. Increased glucose demand is met in 2 ways

  • A. Glycogenolysis (in liver & skeletal muscle): liberation of glucose from glycogen

    • 1. Liver does this to release glucose into blood

    • 2. Muscle does this to release glucose for its own use (skeletal m.)

  • B. Gluconeogenesis (in liver & kidneys): production of glucose from noncarbohydrate precursors

    • 1. Produced glucose is released into blood

Glucose in Fight-or-Flight Response

• During this response, body needs ready access to adequate amounts of metabolic fuel

  • A. Adrenal glands produce & secrete the hormone
    epinephrine

    • 1. Targets liver & skeletal muscle

      • i. In liver, stimulates glycogenolysis & gluconeogenesis, followed by glucose release into blood

      • ii. In skeletal muscle, stimulates glycogenolysis & glycolysis to facilitate muscle action

Glycogenesis

• I. Synthesis of glycogen

• A. Occurs through sequential, 1-at-a-time addition of glucose monomers to nonreducing ends of glycogen
  

• 𝐆𝐥𝐮𝐜𝐨𝐬𝐞 + 𝐆𝐥𝐲𝐜𝐨𝐠𝐞𝐧(𝐧 𝐠𝐥𝐮𝐜𝐨𝐬𝐞 𝐮𝐧𝐢𝐭𝐬) —𝐨𝐧𝐭𝐨 𝐍𝐨𝐧𝐫𝐞𝐝𝐮𝐜𝐢𝐧𝐠 𝐄𝐧𝐝𝐬—> 𝐆𝐥𝐲𝐜𝐨𝐠𝐞𝐧 _{(n + 𝟏 𝐠𝐥𝐮𝐜𝐨𝐬𝐞 𝐮𝐧𝐢𝐭𝐬)}
  B. Also involves formation of branches in
  glycogen molecule
  

Glycogenesis: Step 1

• I. Catalyzed by hexokinase (muscle) & glucokinase
  (liver)

• A. 1st step of glycolysis: ATP-Mg2+-mediated phosphorylation of glucose to produce G6P

• 1. Remember G6P is branch point connection of metabolism

• i. Instead of continuing through glycolysis a different metabolic branch
  will be chosen

Glycogenesis: Step 2

• Catalyzed by phosphoglucomutase

  • A. Isomerizes G6P into glucose-1-
    phosphate (G1P)

Glycogenesis: Step 3

• Catalyzed by UDP-glucose pyrophosphorylase

  • A. Combines G1P with UTP to produce uridine diphosphate glucose (UDP-
    glucose; UDPG)

    • 1. “High-energy” compound that supplies G to drive glycogenesis

• B. To drive this reaction, UTP is hydrolyzed to UMP & PPi (1st high-energy
  bond cleavage), followed by PPi hydrolysis into 2 Pi by inorganic
  pyrophosphatase (2nd high-energy bond cleavage)

Glycogenesis: Step 4

• Catalyzed by glycogenin

  • A. Responsible for synthesis of nascent (i.e., brand new) glycogen molecules

  • B. Hydrolyzes UDPG to produce UDP & glucose bound directly to enzyme

  • C. Hydrolyzes next UDPG to produce UDP & 2nd glucose bound to 1st
    glucosyl residue via alpha(1→4) glycosidic bond

  • D. Repeats this reaction until a chain of 7 – 9 glucosyl residues is made; it then passes chain off to next enzyme
    

    
    

Glycogenesis: Step 5

• Catalyzed by glycogen synthase (glycogen synthase 1 in muscle; glycogen synthase 2 in liver)

  • A. Receives glycogen primer from glycogenin

  • 1. Cannot synthesize nascent chains, can only extend pre-existing glycogen molecules

  • B. Hydrolyzes UDPG to produce UDP & glucose attached to a nonreducing end of glycogen chain via
    alpha(1→4) glycosidic bond

    • 1. Reaction is repeated until all available UDPG are used up

  • C. Rate-limiting step of glycogenesis

    
    

Glycogenesis: Step 5.5

• I. Bc UTP hydrolysis drives this process, liberated UDP from glycogenin & glycogen synthase reactions must be reconverted to
  UTP

  • A. Nucleoside diphosphate kinase uses ATP to phosphorylate these UDP molecules to produce UTP & ADP

Glycogenesis: Step 6

• Catalyzed by glycogen branching enzyme

  • A. Cleaves a terminal heptaglucosyl segment off nonreducing end of a glycogen chain that is at least 11 glucosyl residues long

  • B. Attaches heptaglucosyl segment to an internal glucosyl residue of a glycogen chain via alpha(1→6) glycosidic bond

    • 1. New branch must be at least 4 glucosyl residues away from other branches

      • i. Glycogen synthase can extend length of these branches

        
        

Glycogenolysis

• Breakdown of glycogen

  • A. Occurs through sequential, 1-at-a-time removal of individual glucose monomers from nonreducing ends of glycogen

  • 𝐆𝐥𝐲𝐜𝐨𝐠𝐞𝐧_{(𝐧 𝐠𝐥𝐮𝐜𝐨𝐬𝐞 𝐮𝐧𝐢𝐭𝐬)} —𝐟𝐫𝐨𝐦 𝐍𝐨𝐧𝐫𝐞𝐝𝐮𝐜𝐢𝐧𝐠 𝐄𝐧𝐝𝐬—> 𝐆𝐥𝐲𝐜𝐨𝐠𝐞𝐧 _{(n- 𝟏 𝐠𝐥𝐮𝐜𝐨𝐬𝐞 𝐮𝐧𝐢𝐭𝐬)} + 𝐆𝐥𝐮𝐜𝐨𝐬𝐞

  • B. Highly branched structure allows for rapid release of glucose units from end of every branch

  • C. Also involves the debranching of glycogen molecule

Glycogenolysis: Step 1

• Catalyzed by glycogen phosphorylase

• A. Utilizes pyridoxal phosphate (PLP) cofactor & Pi to cleave terminal alpha (1→4) glycosidic bond in a nonreducing end of glycogen to liberate a G1P
  molecule

  • 1. Will only cleave off glucosyl residue if it is more than 4 glucosyl residues away from a branch point

• B. Reaction will occur over & over again until glucose needs are met

• C. Rate-limiting step of glycogenolysis

Glycogenolysis: Step 2

• Catalyzed by glycogen debranching enzyme

  • A. Possesses 2 enzymatic functions

    • 1. Works on limit branches (tetraglucosyl unit) by cleaving alpha(1→4) glycosidic bond between branch point glucosyl residue & 2nd glucosyl residue of limit branch

      • i. Transfers liberated triglucosyl unit to a nonreducing end of glycogen (this allows glycogen phosphorylase to break it down)

    • 2. Liberates branch point glucosyl residue by cleaving alpha(1→6) glycosidic bond, releasing it as glucose
      

Glycogenolysis: Step 3

• Glycogenolysis: Step 3

• I. Catalyzed by phosphoglucomutase (same enzyme as in glycogenesis)

  • A. Performs reverse reaction to isomerize G1P into G6P

    • 1. In muscle, G6P & glucose liberated from glycogen will feed directly into glycolysis for energy production

    • 2. Additional steps are needed in liver

Glycogenolysis: Additional Steps In Liver pt1

• G6P imported into hepatocyte ER lumen to beacted upon by glucose-6-phosphatase (G6Pase) enzyme complex

  • A. Composed of 4 subunits

    • 1. G6P translocase subunit 1 (G6PT1): transports G6P from cytosol into ER lumen

    • 2. G6Pase: catalytic subunit that dephosphorylates G6P to produce glucose &
      Pi
      

Glycogenolysis: Additional Steps In Liver (2)

• Composed of 4 subunits (continued...)

  • A. G6P translocase subunit 2 (G6PT2): transports glucose from ER lumen into
    cytosol

  • B. G6P translocase subunit 3 (G6PT3): transports Pi from ER lumen into cytosol

    • II. Glucose exported into blood through GLUT2
      

Regulation of Glycogen Metabolism

• I. Major points of control are the rate-limiting steps

  • A. Glycogenesis: glycogen synthase

  • B. Glycogenolysis: glycogen phosphorylase

• II. Control of these processes is primarily driven by action of insulin, glucagon, & epinephrine

Allosteric Regulation of Glycogen Metabolism

• I. Liver

  • A. Glucose: allosteric inhibitor of glycogen phosphorylase a

  • B. G6P: allosteric activator of glycogen synthase b & PP1

• II. Muscle

  • A. G6P: allosteric activator of glycogen synthase b & PP1; allosteric inhibitor of glycogen phosphorylase b

  • B. AMP: allosteric activator of glycogen phosphorylase b

Hormonal Regulation of Hepatic Glycogen Metabolism: Glucagon and Epinephrine

Signalling for break down of glyco and preventing synthesis of glyco

a is active for b is inactive/inhibited

phosphorylation and binding of other protein to turn PP1 off

activating breakdown of glycogen and inhibit its synthesis 

Hormonal Regulation of Hepatic & Muscle Glycogen Metabolism: Insulin

• epi primary hormone receptor

• same mechanism as other one except with muscle mechanism AMPK (its a kinase sensitive to amp levels

• amp allosterically active ampk (extra mechanism to make sure glycogen happens) 

• JOb of enzyme to degrade secong messanger

• whole job: active glycogen synthesis and inhibit glycogen breakdown 

• feedback inhibition stronger in liver than in muscle

Why so much metabolic effort to use glycogen for G
storage when fatty acids are far more abundant in
body & are richer source of G?(Glycogen vs Fat)

• A. Muscles cannot mobilize FA (Fatty acid) as rapidly as glycogen

• B. FA cannot be metabolized anaerobically, but glucose can

• C. FA cannot fuel brain or RBCs

• D. FA cannot be converted into glucose, thus they cannot maintain proper [glucose]Blood

Glycogen Storage Diseases (GSD) pt1

• I. Rare recessively inherited disorders caused by mutations in enzymes involved in glucose metabolism (glycolysis & gluconeogenesis) &/or glycogen
  metabolism (glycogenesis & glycogenolysis)

• II. Typically leads to abnormal accumulation of glycogen (either too little or too much glycogen)

• III. Specific mutations affect specific organs

  • A. There are hepatic GSD (affecting liver), myopathic GSD (affecting muscle), & generalized GSD (affecting most organs) 

Glycogen Storage Diseases pt 2

• Know the names, the enzymes that are effected

Need for Other Sources of Glucose pt1

• Under fasting/starvation conditions, continuous vigorous exercise, or consumption of a low carbohydrate diet, glycogen can only supply a
  portion of the glucose that body (especially the brain) needs to function

• A. This portion decreases as period of fasting/starvation, vigorous exercise, or
  consumption of low carb diet increases in duration
  
  

Need for Other Sources of Glucose pt2

• I. Fasting conditions: glycogen depleted within 20 – 30 hours after last meal

• II. Continuous vigorous exercise: glycogen depleted within 2 – 3 hours (e.g., running marathon)

• III. Low carbohydrate diet: glycogen stores perpetually low/depleted

• IV. In these scenarios, body turns to gluconeogenesis to supply glucose

Gluconeogenesis

• I. Conversion of noncarbohydrate precursors into glucose

• II. Occurs primarily in liver, but also in kidneys in late stages of fasting/starvation

• III. Utilizes reverse reactions of glycolytic enzymes (occurs in cytosol)

  • A. Exception are 3 rate-limiting enzymes of glycolysis

    • 1. Different enzymes must be used; these are referred to as bypass reactions

Gluconeogenic Building Blocks pt1

• Several noncarbohydrate precursors can be used to make glucose

  • A. Lactate, pyruvate, glycerol, glucogenic amino acid C-skeletons, odd-chain fatty acids, branched-chain fatty acids

  • B. To be utilized to do this they must 1st be converted into OAA, the starting material for this process (exception is glycerol; it enters as DHAP)

    
    

Gluconeogenic Building Blocks pt2

• Substances that are broken down directly into acetyl-CoA CANNOT be used to make glucose

  • A. This includes Leu & Lys (ketogenic AA) , even- chain fatty acids, & ketone bodies

  • B. There is no pathway for converting acetyl- CoA into OAA

    • 1. Remember C atoms entering TCA cycle in form of acetyl-CoA are lost as CO2
      

Lactate in Gluconeogenesis

• I. Remember it was discussed that converting glucose into lactate was a huge waste of G, but that it is not

  • A. This is because of interorgan process called Cori cycle that occurs between liver & skeletal muscles

Cori cycle pt1

• During strenuous physical activity, skeletal muscles switch to anaerobic metabolism to meet rapid ATP demands of cell

  • A. Causes buildup of lactate in skeletal muscles

• II. Lactate is released from skeletal muscles into blood, where it is transported to liver

  
  

Cori cycle pt2

• I. In liver, lactate dehydrogenase catalyzes its reverse reaction by
  converting lactate into pyruvate

  • A. This pyruvate feeds into gluconeogenesis, which leads to production of new glucose

  • B. This new glucose can be stored as liver glycogen, or it can be released back into blood for use by skeletal muscles

• II. Gluconeogenesis requires G (hydrolysis of 4 ATP & 2 GTP)

  • A. Supplied by aerobic metabolism of fatty acids, which drives hepatic ATP synthesis

  • B. Represents net loss of 4 ATP ([6 NTP/Gluconeogenesis Used] – [2
    ATP/Glycolysis Generated})

    • 1. Why humans cannot do anaerobic metabolism indefinitely