Lecture Notes

Regulation/ integration of carbohydrates & lipid metabolism
Learning objectives:

1. Describe the principle method of pathway regulation
2. Identify the key regulatory enzymes of carbohydrate metabolism (that we have discussed
throughout the course so far)
3. Describe in detail the allosteric and hormonal regulation of each of these enzymes
4. Describe and explain the important role of fructose-2,6-bisphosphate in carbohydrate
metabolism
5. Identify key regulatory enzymes in FA metabolism
(RED=NOT DONE)
6. Describe and explain changes in hormones and hence pathways activated/ down regulated
through a normal starve-fed cycle and during starvation

Where do we start?

1. Revisit our key themes
- Metabolic strategies and recurring motifs for regulation
2. Interplay of different in regard to the flow of molecules at 3 key crossroads: glucose-6-
phosphate, pyruvate and acetyl CoA
3. Finally, discuss differences in metabolic pattern in tissues and how this is altered in a variety
of metabolic perturbations (deviation of a system)

Revisiting key themes- metabolic strategies

 Strategy
- Metabolism is pretty simple
- Form ATP, reducing power & building blocks for biosynthesis and movement (ATP)
1. ATP
- Universal currency of energy due to high phosphoryl transfer potential
- Usd for biosynthesis (making unfavourable reactions favourable) and ordered movement
e.g. muscle contraction
2. ATP generation
- From oxidation of carbohydrate and lipids (FAs)- common intermediate acetyl Co
- Total oxidation gives CO2 and many electrons are carried by activated carriers e.g. NADH,
FADH2.
- ultimately these are used to pump protons across mitochondrial membrane to produce a
gradient that enable ATP synthase to produce 30 ATP (oxidative phosphorylation).
- Glycolysis also produced 2 ATP anaerobic.
3. NADPH and reducing power
- Pentose phosphate pathway produces NADPH
- This provides much of the reducing power required for anabolic biosynthesis
4. Building blocks
- Breaking down carbohydrates and lipids provide many of the building blocks required for
further anabolism of biopolymers e.g. making ATP and NADPH also produced acetyl CoA
(required for cholesterol and all steroids) and ribose sugars (DNA and RNA synthesis)
respectively
5. Biosynthetic and degradative pathways almost always distinct
- E.g. FA synthesis and degradation

, - Always separate as this allows both to be thermodynamically favourable at all times and
enable exquisite control

LO1. DESCRIBE THE PRINCIPLE METHODS OF PATHWAY REGULATION

Revisiting key themes- recurring motifs for regulation

 Anabolism and catabolism precisely coordinate by affecting the flow of molecules
 In most pathways this is determined primarily by activity of key enzyme that act on key
irreversible/ committed reaction in specific pathways
 These enzymes can be modulated by:
1. Allosteric interaction
- Binding of molecules to non-active sites causing change in conformation
- Last milisecs to secs
- E.g. phosphofrucktokinase in glycolysis
2. Covalent modification
- Certain key enymes are controlled through covalent modifictions e.g. phosphorylation
- Can be final step in amplifying a signal and can allow rapid switch on/off by low levels
triggering signal
- Lasts seconds to minutes
3. Enzyme levels
- Amount of enzyme
- Rate of synthesis and degradation can be altered hormonally
- Hours
4. Compartmentilisation
- Fate of molecules depend on location in cell
- I.e. no substrate = no reaction
5. Metabolic specialisation of organ
- In higher eukaryotes we have organs that do specific metabolic roles

You must know

 Must kno hw the following processes are regulated and controlled
1. Glycolysis
2. Gluconeogenesis
3. Glycogen biosynthesis and catabolism
4. Fatty acid biosynthesis and catabolism
5. Cholesterol biosynthesis/ regulation and steroid biocynthesis

LO2. IDENTIFY THE KEY REGULATORY ENZYMES OF CARBOHYDRATE METABOLISM (THAT HAVE
BEEN DISCUSSED THROUGHOUT THE COURSE SO FAR)

Interplay of different pathways: in flow of molecules at 3 crossroads

 Many important pathwys of metabolism have key junctions where the same molecule is used
 3 are key
1. Glucose (glucose-6-phosphate)
2. Pyruvate
3. Acetyl CoA
1. Glucose
- Glucose rapidly phosphorylated when enters cell (to stop it leaking out)

, - Glycolysis- degradation of pyruvate
- Gluconeogenesis – pyruvate to G6P
- Pentose phosphate pathway – to ribose and NADPH
- Stored as glycogen when ATP high




2. Pyruvates
 3-C alpha-ketoacid obtained from G6P, AA, lactate
 Fate
- Can be reduced to lactate to regenerate NAD+ and returned to pyruvate in other tissues
(cori cycle, etc to shift metabolic burden)
- Can produce alanine from it
- Carboxylation of it to oxaloacetate is 1 st step gluconeogenesis. 2nd is the irreversible step in
glycolysis by converting oxaloacetate to phosphoenolpyruvate (PEP)
- Finally, it is oxidative carboxylated to acetyl CoA
This is a irreversible reaction inside mitochondria that commits the C to
oxidation in the TCA cycle or synthesis of lipids- the pyruvate dehydrogenase
complex thus highly regulated.
3. Acetyl CoA
 Major source of this activated 2C unit for oxidative decarboxylation of pyruvate and FA
catabolism (β-oxidation)
 Fate: quite restricted
- Completely oxidated to CO2 by TCA/ citric cycle
- From 6C HMG-CoA- continue on to form cholesterol ad ketone bodies
- Form citric for FAsynthesis