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PHAR150GGluconeogenesis_studentcopy1.pptx

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PHAR 150G Biochemistry

Gluconeogenesis

Vicky Mody, PhD

Associate Professor of Pharmaceutical Sciences

Office: Rm 3034,

Email: [email protected]

Phone: 678-407-7386

Objectives

Importance of Gluconeogenesis

Steps involved in the synthesis of Glucose

Difference in gluconeogenesis vs glycolysis

Precursors for the synthesis of glucose

Hormonal regulation of Gluconeogenesis

Sid is a high school student who has decided to start exercising before school. After eating an early dinner the night before and skipping breakfast that morning, Sid goes to the gym. He feels fine at first, but shortly into his work out he begins to experience muscle fatigue, heavy breathing, increased heart rate, lightheadedness. Sid begins to hyperventilate and passes out and is transported to the emergency room. Doctors run tests and find he has low blood glucose.

Why was her glucose level low.

What would be body’s hormonal response under low glucose levels.

Case 1

Gluconeogenesis

Must Know very Important

Gluconeogenesis, the process by which glucose is synthesized from noncarbohydrate precursors, occurs mainly in the liver under fasting conditions.

Under the more extreme conditions of starvation, the kidney cortex also may produce glucose.

For the most part, the glucose produced by the kidney cortex is used by the kidney medulla, but some may enter the bloodstream.

Starting with pyruvate, most of the steps of gluconeogenesis are simply reversals of those of glycolysis. In fact, these pathways differ at only three points.

Enzymes involved in catalyzing these steps are regulated so that either glycolysis or gluconeogenesis predominates, depending on physiologic conditions.

Most of the steps of gluconeogenesis use the same enzymes that catalyze the process of glycolysis. The flow of carbon, of course, is in the reverse direction.

Gluconeogenesis

Must Know very Important

Glycolysis vs Gluconeogenesis

Glucose

Glucose 6-phosphate

Fructose 6-phosphate

Fructose 1,6-bisphosphate

PEP

Pyruvate

Glycolysis

Gluconeogenesis

Glycolysis vs Gluconeogenesis

Must Know very Important

Pyruvate to PEP

Must Know very Important

Including reactions

Next two are Hydrolytic Reactions in Gluconeogenesis

In Glycolysis phosphofructokinase catalyzes:

fructose-6-P + ATP  fructose-1,6-bisP + ADP

In gluconeogenesis Fructose-1,6-bisphosphatase catalyzes:

fructose-1,6-bisP + H2O  fructose-6-P + Pi

Hydrolysis Reaction in Gluconeogenesis

Must Know very Important

Including reactions

In glycolysis; Hexokinase or Glucokinase catalyzes:

glucose + ATP  glucose-6-phosphate + ADP

However, in gluconeogensis Glucose-6-Phosphatase catalyzes:

glucose-6-phosphate + H2O  glucose + Pi

Hydrolysis Reaction in Gluconeogenesis

Must Know very Important

Including reactions

Comparison of Enzymes

Glycolysis and Gluconeogenesis

GLYCOLYSIS	GLUCONEOGENESIS
Hexokinase	Glucose 6-phosphatase
Phosphofructokinase	Fructose 1,6-bisphosphatase
Pyruvate Kinase	Pyruvate carboxylase
	Phosphoenolpyruvate carboxykinase

Must Know very Important

Including reactions

Major Precursors for Gluconeogenesis

Major Precursors of Gluconeogenesis

Must Know very Important

Including reactions

Major precursors are

Lactate

Alanine

Amino acids (AA) from TCA cycle

Glycerol from fats

Major Precursors of Gluconeogenesis

Must Know very Important

Including reactions

Lactate for Gluconeogenesis

Lactate

Lactate is produced by muscle during exercise and by red blood cells.

Must Know very Important

Including reactions

Amino Acids for Gluconeogenesis

Amino Acids

Amino acids are released from muscle whenever insulin is low or when cortisol is elevated.

Amino acids are also available for gluconeogenesis when the dietary intake of protein is high and intake of carbohydrate is low.

Must Know very Important

Including reactions

Other AA contribution to Gluconeogenesis

Aspartic acid can transaminate to yield oxaloacetate and

Glutamate can transaminate to yield a-ketoglutarate.

Both of these are intermediate for TCA cycle

Must Know very Important

Including reactions

3- most important pairs in transamination reaction

Alanine - Pyruvate

Aspartate – Oxoloacetate

Glutamate – a-ketoglutarate

Transamination Reaction to yield oxaloacetate

Glutamic Acid

Aspartic Acid

PLP is synthesized from Vitamin B6 in the body

3- most important pairs in transamination reaction

Alanine - Pyruvate

Aspartate – Oxoloacetate

Glutamate – a-ketoglutarate

Transamination Reaction to yield a-ketoglutarate

Glutamic Acid

Aspartic Acid

PLP is synthesized from Vitamin B6 in the body

Pyruvate-lactate

Pyruvate-Alanine

Cycle

Must Know very Important

Including reactions

Fatty Acids contribution for Gluconeogenesis

Glycerol

Glycerol is released from adipose tissue whenever the levels of insulin are low and the levels of glucagon or the “stress” hormones, epinephrine and cortisol (a glucocorticoid), are elevated in the blood

Must Know very Important

Including reactions

Regulation of Gluconeogenesis

Remember the purpose of gluconeogenesis is to maintain blood glucose during fasting!

Since glycolysis and gluconeogenesis share the same pathway, but in opposite directions, they must be regulated reciprocally

Cannot stress how important this is

Must Know very very very Important

Glucagon and Epinephrine

Moment to moment regulation is primarily by glucagon, epinephrine and availability of gluconeogenic substrates.

Glucagon stimulates gluconeogenesis by 3 mechanisms:

Activation of 1,6 bisphosphatase and hence inhibition of phosphofructokinase

Inactivation of pyruvate kinase.

Induction of PEP-carboxykinase gene.

Cannot stress how important this is

Must Know very very very Important

Regulation by 1, 6, biphosphatase

Activation of 1,6 bisphosphatase and hence inhibition of phosphofructokinase

1,6 Bisphosphatase

In general, via a very complex mechanism Glucagon activates 1, 6, biphosphatase and inactivates phosphofructokinase.

Regulation by Glucagon

Inactivation of Pyruvate Kinase

Pyruvate kinase activity is inhibited under low glucose conditions by covalent phosphorylation of the enzyme.

Regulation of Pyruvate kinase in glycolysis

Please note this happens in glycolysis

So what happens to Pyruvate Kinase during Gluconeogenesis

Effect of Glucagon on Pyruvate Kinase

Cannot stress how important this is

Must Know very very very Important

Effect of Glucagon on Pyruvate Kinase

Covalent modification of enzymes: Glucagon activates adenylate cyclase  cAMP  protein kinase A which phosphorlyates pyruvate kinase and inactivates it decreasing the conversion of PEP to pyruvate.

Cannot stress how important this is

Must Know very very very Important

Induction of enzyme synthesis:

Glucagon increases the transcription of the PEP-carboxykinase gene   availability of this enzyme. .

Effect of Glucagon on PEP carboyxkinase Gene

Effect of Fasting on Fatty acids and their role in Gluconeogenesis

Effect of Fasting on Fatty acids and Gluconeogenesis

During fasting, fatty acid breakdown leads to increased beta-oxidation  activation of pyruvate carboxylase by acetyl CoA while pyruvate dehydrogenase (PDH) is inactivated by acetyl CoA & NADH.

Effect of Fasting on Glucocorticoids and their role in Gluconeogenesis

Glucocorticoids

Secreted by the adrenal cortex and synthesized in unregulated manner by adipose tissue or from exogenous sources

Enhance hepatic catabolism of Amino acids (AA)s due to induction of AST & ALT & key enzymes of gluconeogenesis

Inhibit glucose utilization in extrahepatic tissues

Growth hormone:  FFA mobilization and  muscle uptake of glucose

Cannot stress how important this is

Must Know very very very Important

Activator and Repressors of Gluconeogenetic Enzymes

Activator and Repressor of various Gluconeogenetic Enzymes

Cannot stress how important this is

Must Know very very very x1000 Important

Why was her glucose level low.

What would be body’s hormonal response under low glucose levels.

Case 1

Summary

Importance of Gluconeogenesis

Steps involved in the synthesis of Glucose

Difference in gluconeogenesis vs glycolysis

Precursors for the synthesis of glucose

Hormonal regulation of Gluconeogenesis