BIOCHEMISTRY

G L U C O N E O G E N E S I S

I N T R O D U C T I O N T O B I O C H E M I S T R Y ( S C I 2 6 0 ) L E C T U R E 5

D R . O M A R I J . B A N D E L E

OVERVIEW OF GLUCONEOGENESIS • Brain cells and red blood cells (RBC) need a constant supply of glucose for

energy.

• Gluconeogenesis is a metabolic pathway that produces glucose from non- carbohydrate molecules.

– Non-carbohydrate molecules: glycerol, lactic acid, and some amino acids

• Gluconeogenesis is needed to: (1) provide brain cells and RBCs with glucose and (2) avoid hypoglycemia (i.e., low blood glucose levels).

• Where does gluconeogenesis occur in the body? – Major site: Liver – Minor site: Kidney

• Glycolysis: Glucose à Pyruvate

• Gluconeogenesis: Pyruvate à Glucose Lecture 5 2

GLUCONEOGENESIS IS NOT THE EX ACT REVERSE OF GLYCOLYSIS

WHY NOT? • Because glycolysis has 3 irreversible reactions

– ΔG of glycolysis = -74 kJ/mol (favorable pathway)

– ΔG of gluconeogenesis = +74 kJ/mol (unfavorable pathway)

• The 3 irreversible glycolysis reactions must be bypassed for gluconeogenesis to be favorable (-ΔG).

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• Gluconeogenesis uses many of the same enzymes as glycolysis.

• 7 glycolysis rxns are reversible and also used during gluconeogenesis.

• 3 gluconeogenesis reactions and enzymes are different from glycolysis.

– These 3 rxns make gluconeogenesis a favorable (-ΔG) pathway for the production of glucose from pyruvate.

REACTIONS OF GLUCONEOGENESIS

http://www.wiley.com/college/boyer/0470003790/ani mations/gluconeogenesis/gluconeogenesis.htm

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G LY C O G E N M E T A B O L I S M I N T R O D U C T I O N T O B I O C H E M I S T R Y ( S C I 2 6 0 )

L E C T U R E 5 D R . O M A R I J . B A N D E L E

GLYCOGEN

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• A large polymer made of glucose molecules

– Contains up to 120,000 glucose molecules

• Glucose is stored in the body as glycogen.

• In glycogen, glucose molecules are joined by α(1-4) and α(1-6) glycosidic linkages.

– Remember: α(1-6) glycosidic linkages create branches

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GLYCOGEN

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• Glycogen provides an immediate source of glucose during hypoglycemia.

– Note: This process is separate from gluconeogenesis.

• What is the advantage of glycogen having branches?

– Glucose is released from the end of each branch, one glucose at a time.

– More branches increases the number of ends available for glucose to be released.

• Liver and muscle are the primary sites where glycogen is stored in the body.

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LIVER GLYCOGEN LEVELS BET WEEN MEALS

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PROCESSES OF GLYCOGEN AND GLUCOSE METABOLISM • Degradation processes end in “–lysis”

• Synthesis processes end with “–genesis”

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GLYCOGEN BREAKDOWN BY GLYCOGEN PHOSPHORYL ASE

• Glycogen phosphorylase breaks the α(1-4) glycosidic linkage between glucose molecules in glycogen.

– Glycogen phosphorylase acts only at the ends of glycogen branches

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GLYCOGEN BREAKDOWN TO GLUCOSE 6- PHOSPHATE IN THE LIVER • Glycogen phosphorylase removes glucose

molecules from the ends of glycogen branches.

– This produces glucose 1-phosphate (G1P)

• G1P is converted to glucose 6-phosphate (G6P)

– G6P is trapped inside the cell and enters glycolysis to produce ATP

OR

– G6P is converted to glucose and released from liver cells

Lecture 5 Trapped inside the cell

Released from the cell

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DIFFERENCE BET WEEN GLYCOGEN METABOLISM IN LIVER AND MUSCLE • Liver cells have the enzyme glucose 6-phosphatase

(removes phosphate from G6P) which produces glucose.

• Muscle cells don’t have glucose 6-phosphatase

WHY? • Liver cells release glucose into the blood to be delivered to

the brain and other tissues (“unselfish”). – Increases blood glucose levels to prevent hypoglycemia.

• Muscle cells retain G6P and uses it for energy only in the muscle (“selfish”).

– Phosphorylated glucose cannot get outside of muscle cells.

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H O R M O N A L R E G U L AT I O N O F G LY C O G E N M ETA B O L I S M Glucagon: • Active during a fast (low glucose) to prevent hypoglycemia

• Stimulates glycogen breakdown – Releases glucose for energy (ATP) production via glycolysis, TCA cycle, & ETC/OXPHOS

• Inhibits glycogen synthesis – This occurs because the body does not need to store glucose when it is in need of energy.

Insulin: • Active after a meal (high glucose) to prevent hyperglycemia

• Stimulates glycogen synthesis – Stores glucose for later use when the body is in need of energy (ATP)

• Inhibits glycogen breakdown – This occurs because the body does not need to release glucose for energy production

because ATP is plentiful after meal. Lecture 5 13

P E N T O S E P H O S P H AT E P AT H W AY

I N T R O D U C T I O N T O B I O C H E M I S T R Y ( S C I 2 6 0 ) L E C T U R E 5

D R . O M A R I J . B A N D E L E

OVERVIEW • The pentose phosphate pathway is another pathway for

the metabolism of glucose.

Phase 1 (Oxidative Phase): • Production of NADPH

– Used to make fatty acids, cholesterol, steroid hormones, and amino acids

– Used to detoxify drugs and poisons • Production of ribulose 5-phosphate

Phase 2 (Non-oxidative Phase): • Ribulose 5-phosphate is used to make nucleotides, DNA,

and RNA • Production of glycolysis intermediates

– Fructose 6-phosphate and glyceraldehyde 3-phosphate • No ATP is produced OR used during the pentose

phosphate pathway. Lecture 5 15

PENTOSE PHOSPHATE PATHWAY: PHASE 1

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• Two (2) NADPHs are produced for each glucose that is metabolized during the pentose phosphate pathway.

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PENTOSE PHOSPHATE PATHWAY: PHASE 2

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Glyceraldehyde 3-phosphate (G3P) and fructose 6-phosphate (F6P) are products of the PPP that can be used in glycolysis.

NADH VS. NADPH • NADH and NADPH are both electron (H+) carriers.

• The phosphate group on NADPH allows it to interact with different types of enzymes compared to NADH.

– NADH and NADPH are nearly identical except for the presence of a phosphate group on NADPH (see figures to the right).

• NADH is used in catabolic reactions that break down molecules and release energy (e.g., glycolysis)

• NADPH is used in anabolic reactions that consume energy to synthesize molecules (e.g., fatty acids, cholesterol, etc.)

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NADH

NADPH

18 Phosphate group

SUPPLEMENTAL VIDEOS Gluconeogenesis https://www.youtube.com/watch?v=ydhr0QAyxYg Note: gluconeogenesis uses different enzymes to bypass the 3 irreversible glycolysis steps

Glycogen https://www.youtube.com/watch?v=3Ceq-5iYBuc https://www.youtube.com/watch?v=q6cp4M5Pw8M https://www.youtube.com/watch?v=4Jyy3YXK3rw Note: We’ll discuss glucagon and epinephrine in more detail later. You don’t have to worry about some of the other info (i.e., thyroid hormone and cAMP)

Pentose Phosphate Pathway https://www.youtube.com/watch?v=XnrVo3aJ6NY Note: You can stop watching at the 1 min 56 sec mark (1:56)

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