regulation of carbohydrate metabolism Flashcards
1
Q
describe what happens in glycolysis? 6
A
- Metabolises glucose to produce
- Energy in the form of ATP by substrate level phosphorylation
- Glycerol-3-phosphate for fat synthesis
- Pyruvate for conversion to acetyl-CoA for TCA cycle or fat and cholesterol synthesis
- Amino acids
- Regulation of glycolysis occurs primarily at the level of glucose transport into the cell, PFK-1 and pyruvate kinase (in the liver)
2
Q
how do we regulate the metabolism of glycogen? 3
A
- Glycogenolysis and glycogen synthesis are reciprocally regulated to avoid futile cycling of glucose
- Regulatory mechanisms are allosteric
- Regulatory mechanisms are also hormonal
3
Q
describe the glycolytic pathway? 4
A
- Glycolysis occurs in all tissues
- This is important for energy in the brain and the RBC and also in contracting skeletal muscle
- RBC account for 10% of the body’s total usage
- The irreversible steps (shown in red) are where the pathway differs from gluconeogenesis
4
Q
describe gluconeogenesis? 7
A
- De novo glucose synthesis from non-carbohydrate precursors:
- Lactate from glycolysis
- Amino acids from protein breakdown
- Glycerol (but not fatty acids) from fat metabolism
- .
- It occurs in the liver (and kidney)
- Maintains blood glucose during fasting, starvation or when glycogen reserves are depleted to preserve glucose-dependent cerebral function and RBC metabolism
- Not a simple reversal of glycolysis, has unique enzymes to overcome energetically unfavourable reactions and introduce points of control
5
Q
what are the requirements for gluconeogenesis? 4
A
- A source or carbon is required for the formation of glucose molecules
- These are provided by lactate, amino acids or glycerol released from Tgs by lipolysis in adipose tissue
- A source of energy for biosynthesis
- This is provided by metabolism of fatty acids released by lipolysis in adipose tissue
6
Q
describe the urea cycle? 5
A
- Increased rates of gluconeogenesis are always coupled with increased rates of urea synthesis
- To use amino acids as a source of carbon skeletons for glucose production, must first be transaminated to lose their ammonia
- Ammonia is toxic to cells, so must be eliminated from their body. Converted to the urea in the liver, then passed out into the bloodstream and excreted by the kidneys
- NH3 + CO2 + 2H2O + 3ATP + aspartate urea + fumarate + 2 ADP + AMP + 2Pi + PPi
- Fumarate is converted to oxaloacetate in the cytoplasm thereby generating a substrate for gluconeogenesis
7
Q
describe the gluconeogenic pathway? 3
A
- Irreversible steps in glycolysis are overcome by the expression of specific gluconeogenic enzymes. These are also sites of regulation
- Glycolysis and gluconeogenesis are essentially opposite processes so must be reciprocally regulated
8
Q
describe the regulation of glycolysis? 3
A
- PFK-1 is subject to energy-dependent allosteric regulation by ATP, AMP and H+
- ATP inhibits= sign of high energy levels in the muscle. Prevents glucose being utilised by glycolysis when ATP is available. Co-ordinates glycolysis with glycogen breakdown via phosphorylase
- AMP (present when ATP is depleted- during muscle contraction or anoxia) leads to activation. Competes with ATP. Increases glycolysis and energy production. Co-ordinates glycolysis with glycogen breakdown via phosphorylase
9
Q
describe the regulation of PFK-1 by H+ ions? 3
A
- H+ increased during anoxia (insufficient oxygen for aerobic muscle contraction) or anaerobic muscle contraction as a result of lactic acid production
- Inhibits glycolysis to prevent cellular pH falling too low and damaging the cellular machinery
- In heart this can be overcome by high AMP resulting in cellular damage and chest pains experienced in heart attacks and angina
10
Q
describe the regulation of PFK-1 by nutrients? 4
A
- PFK-1 is also subject to allosteric regulation by Fru-6-P, Fru-2,6-P and citrate
- Fru-6-P activates- sign of high rates of glucose entry of glycogen breakdown. Stimulated glycolysis to allow utilisation for energy production or fat synthesis
- Fru-2,6-P is also a signal of high rates of glucose entry or glycogen breakdown and leads to activation. Most potent allosteric activator known. Stimulates glycolysis to allow utilisation for energy production or fat synthesis. Potent inhibitor of fructose-1,6-biphosphatase. Not involved in metabolic pathways acts solely to re-enforce allosteric control on PFK-1
- Citrate inhibits- signals TCA cycle overload (more acetyl CoA than can be oxidised) or fatty acid oxidation (starvation) and the need to conserve glucose by inhibition of glycolysis
11
Q
what is glycolysis inhibited by? 3
A
- Presence of sufficient energy
- Fatty acid oxidation (citrate), indicating the need for glucose sparing
- H+ ions (lots of lactate)
12
Q
what is glycolysis activated by? 2
A
- Low levels of energy (AMP)
- Lots of glucose or its metabolites
13
Q
Does lots of available glucose always signal the need for glycolysis?
A
not in the liver
14
Q
describe the extra control of F-2,6-BP in the liver? 7
A
- Muscle uses glucose and glycogen for energy production by increasing F-2,6-BP and stimulating glycolysis
- Liver uses glucose produced via gluconeogenesis and glycogen to maintain blood glucose to glycolysis is inhibited
- In the liver, there has to be control at the level of PFK-1, but also in the reverse reaction of gluconeogenesis at F-1,6-BPase to allow reciprocal control of the two reactions
- In the liver PFK-2 and F-2,6-BPase are a single tandem enzyme with two active sites
- Phosphorylation inhibits PFK-2 and stimulates F-2,6-BPase which decreases the amount of F-2,6-BP
- Neither PFK-1 not F-1,6-BPase are directly controlled by hormones through phosphorylation but by the level of F-2,6-BP which is affected by hormones
- It is the level of F-2,6-BP which controls the rates of glycolysis and gluconeogenesis
15
Q
describe the activation of gluconeogenesis? 3
A
- Increased fatty acid oxidation leads to an increase in acetyl CoA- an allosteric activator of pyruvate carboxylase and inhibitor of pyruvate dehydrogenase- so favours gluconeogenesis over glycolysis
- Increased glucagon inhibits PFK-2 activity and stimulates F-2,6-BPase by phosphorylating (via cAMP- dependent protein kinase) resulting in a fall in F-2,6-BP
- Decreased F-2,6-BP levels reduce activation of PFK-1 (inhibits glycolysis) and relieve the inhibition of F-1,6-BPase (stimulates gluconeogenesis)
