Regulation of Carbohydrate Metabolism Flashcards
The glycolic pathway
Glycolysis occurs in all tissues
Important in brain and abcs and in contracting skeletal muscle
RBCs account for 10% of the body’s total usage
The irreversible steps (in red) are where the pathway differs from gluconeogenesis
Gluconeogenesis
De novo synthesis from non-carbohydrate precursors e.g.: lactate from glycolysis, amino acids and glycerol (not fatty acids) from fat metabolism
Occurs in 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
Requirements for gluconeogenesis
A source of carbon for formation of glucose molecules -> provided by lactate, amino acids or glycerol released from TGs by lipolysis in adipose tissue.
A source of energy for biosynthesis -> provided by metabolism of fatty acids released by lipolysis in adipose tissue
The urea cycle
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 the body. Converted to urea in the liver, then passed out into the bloodstream and excreted by the kidneys
NH3 + CO2 + 2H2O + 3ATP + aspartate -> urea + fumarate + 2ADP + AMP + 2Pi + PPi
Fumarate is converted to oxaloacetate in the cytoplasm thereby generating a substrate for gluconeogenesis
Regulation of glycolysis - PFK-1 regulation by ATP and AMP
ATP inhibits - sign of high energy levels in 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 e.g. during muscle contraction or anoxia) leads to activation. Competes with ATP. Increases glycolysis and energy production. Co-ordinates glycolysis with glycogen breakdown via phosphorylase
Regulation of glycolysis - PFK-1 by H+ ions
H+ increased during anoxia 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 can be overcome by high AMP resulting in cellular damage and chest pains experienced in heart attacks and angina
Regulation of glycolysis - PFK-1 by nutrients
Fru-6-P, Fru-2,6-BP and citrate
Fru-6-P activates - sign of high rates of glucose entry or glycogen breakdown. Stimulates glycolysis to allow utilisation for energy production or fat synthesis.
Fru-2,6-BP 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.
Citrate inhibits. Signals TCA cycle overload (more acetyl CoA than can be oxidised) or fatty acid oxidation (e.g. starvation) and the need to conserve glucose by inhibition of glycolysis
Fructose 2,6 biphosphate
Synthesised from F-6-P by the enzyme PFK-21
F-6-P + ATP – PFK-2 –> F-2,6-BP
Most potent allosteric activator of PFK-1
Potent inhibitor of fructose-1,6-biphosphate
Not involved in metabolic pathways: acts solely to reinforce allosteric control on PFK-1
Another checkpoint for glycolysis
Glycolysis is inhibited by: Presence of sufficient energy (ATP); Fatty acid oxidation (i.e. citrate) indicating the need for glucose sparing; H+ ions (lots of lactate).
Glycolysis is activated by: Low levels of energy – AMP; Lots of glucose or its metabolites; In the liver, lots of available glucose does dot always signal the need for glycolysis
Fructose-2,6-biphosphate in liver
Liver controls glycolysis at the level of PFK-1 but also the reverse reaction of gluconeogenesis at F-1,6-BPase to allow reciprocal control of the 2 reactions.
In 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 = F-2,6-BP.
Neither PFK-1 nor F-1,6-BPase are directly controlled by hormones through phosphorylation but by level of F-2,6-BP which IS affected by hormones.
Activation of gluconeogenesis
Increased fatty acid oxidation leads to 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 phosphorylation (via cAMP-dependent protein kinase) resulting in a fall in F-2,6-BP.
Decreased F-2,6-BP levels reduces activation of PFK-1 (inhibits glycolysis) and relieves inhibition of F-1,6-BPase (stimulates gluconeogenesis)
Hormonal regulation of gluconeogenesis
Stimulated in the short term by glucagon and adrenaline by changes in protein phosphorylation or mobilisation of fatty acids and production of acetyl CoA
Long term stimulation occurs through enzyme induction by glucagon, glucocorticoids and thyroid hormones
Inhibited acutely by insulin via dephosphorylation and suppression of lipolysis and in the long term by suppression of gluconeogenic enzymes
