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05/05/2011

Contents • Aims and objectives • Glycolysis • TCA cycle • Insulin and glucagon

Metabolism

• Fed state

Created by Sophia Oxenburgh ©

• Fasting state • Summary

Aims and Objectives • For each metabolic pathway have an awareness of: – Substrate and product – Important enzymes – Main regulatory mechanisms

• An understanding of how pathways fit together • An understanding of the differences between fed and fasting states

Quick Reminder

Glycolysis • First step of cellular

Brain

Muscle

Glucose

Glucose

Ketone bodies

Ketone Bodies Fatty acids

respiration • There are LOTS of steps • Regulated by – hexokinase – PFK-1 – pyruvate kinase

• Aerobic v anaerobic

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Glucose

Tricarboxylic Acid Cycle

Glucose 6-P

Hexokinase/Glucokinase Pyruvate

Fructose 6-P

Fructose 1,6-bis-P

Phosphofructoskinase-1 Glyceraldehyde 3-P

1,3-bis-Phosphoglycerate

Pyruvate kinase

Dihydroxyacetone-P

Amino Acids Acetyl CoA

Pyruvate dehydrogenas e

Citrate

Glucose

Oxaloacetate

Isocitrate

CO2

Amino Acids αKetoglutarate

Malate

3-Phosphoglycerate

Amino Acids

CO2

2-Phosphoglycerate

Pyruvate dehydrogenase Phosphoenolpyruvate

Lactate

Pyruvate

Fed State

Amino Acids

Fumarate

Succinyl CoA Succinate

Amino Acids

Insulin and Glucagon • α vs β cells • GLUT-4 transporter • Control mechanisms

Glycogenesis Glycogen synthase

What happens to the excess glucose? Glucokinase/hexokinase

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Exogenous Pathway Dietary Fat and Cholesterol Free Cholesterol

Cholesterol and Bile Acids

Intestine

CM

Chylomicron

FFA

LDLR LRP

RLP Remnant Capillary

Adipose LPL

Nascent HDL

Free Fatty Acids

Endogenous Pathway Free Cholesterol

The big picture

LDLR

HTGL

Liver

LDL

LDLR LRP

B100

HTGL

Liver Free Cholesterol

ApoB

Free Cholesterol

SR-B1

LDLR

LDL

LDLR LRP

ApoB

Triglyceride

A1

Triglyceride

VLDL

IDL

CM

Glucose

LPL

RLP E

Nascent HDL

HDL

Free Cholesterol

B48

VLDL

Capillary FFA

Muscle

IDL

E

ABCA1

B100

Capillary

Peripheral Tissues Intestine

Free Fatty Acids (FFA)

LPL

Free Fatty Acids (FFA)

What happens to the excess?

Peripheral Tissues

Nascent HDL

Esterification Fatty acyl CoA synthetases

Fatty acid synthase

Glucose

Fatty acid

Fatty acyl CoA

Acetyl CoA carboxylase Glycerol phosphate dehydrogenase Pyruvate

Fatty Acid Glycolysis

DHAP

Glycerol phosphate

Acyltransferase Triacylglycerol

Malonyl CoA

Glycerol kinase

Acetyl CoA

Phosphatase Free glycerol

Oxaloacetate

Citrate

Pi

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Amino Acids • Essential vs non-essential amino acids • Nitrogen NOT stored in the body • Very complex mechanism

Fasted State

Glycogenolysis

Glycogen phosphorylase

Phosphoglucomutase

Glucose 6-phosphatase

Glucose

Lipolysis

Glucose 6-P

Hexkinase

Glucose 6-phosphatase Fructose 6-P

Hormone sensitive lipase

Glycerol

Fructose 1,6-bis-P

PFK-1

Β-oxidation

Fructose 1,6-bisphosphatase Glyceraldehyde 3-P

Triacylglycerol

1,3-bis-Phosphoglycerate

Pyruvate kinase

Pyruvate carboxylase PEP carboxykinase

3-Phosphoglycerate

2-Phosphoglycerate

Fatty acid

Fatty acyl CoA

Acetyl CoA

Fatty acid acyl CoA synthetase

Phosphoenolpyruvate

Lactate

Pyruvate

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Ketone Bodies 3-hydroxybutyrate dehydrogenase

HMG CoA synthase

3Hydroxybutyrate

Fatty acid

Acetoacetyl CoA

HMG CoA

Acetoacetate

Acetone

Acetyl CoA

HMG CoA lyase

Homework • Fructose metabolism • Oxidative phosphorylation • Urea cycle • Phenylketonuria

Summary • For each metabolic pathway have an awareness of: – Substrate and product – Important enzymes

– Main regulatory mechanisms

Any Questions?

• An understanding of how pathways fit together • An understanding of the differences between fed and fasting states

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Metabolism Presentation