Pathways of Carbohydrate and Lipid Metabolism
Glycolysis
• Is the conversion of glucose to pyruvate (Glucose a 6 Carbon molecule to pyruvate a 3 Carbon
molecule)
• It is a 10 step process, where you put in energy for the first stage (steps 1-5) and get production of
energy in stage 2 (steps 6-10)
• Need to know metabolite and enzyme of each step (according to lecturer)
Stage 1
• In stage 1, two ATP molecules are used
• Conversion of glucose into two carbon 3 molecules (Glyceraldehyde 3-phosphate (GAP) and
Dihydroxyacetone phosphate (DAP))
• Once a molecule is phosphorylated (becomes some sort of phosphate) it can no longer escape the
cell
Stage 2
• In stage 2, because you have the creation of two 3 carbon molecules in stage 1 (GAP and DAP), you
get 2 compounds for each step (that’s why you see a bracketed 2 in the diagram above)
• In stage 2, you get a production of 4 ATP molecules
• Overall, in glycolysis, you put 2 ATP molecules in for stage 1 and get 4 ATP molecules out for stage 2,
which gives you a net total of 2 ATP molecules
• Also have 2 NADH molecules made
• In glycolysis, 7 out of the 10 steps are at equilibrium and thus are reversible
• Although, 3 out of 10 are NOT reversible (one directional arrow in diagrams above). They are:
 Glucose to Glucose 6-phosphate via hexokinase
 Fructose 6-phosphate to Fructose 1,6-bisphosphate via phospho-fructokinase-1
 Phosphoenolpyruvate to pyruvate via pyrvate kinase
• Therefore, the control of glycolysis is via the 3 irreversible steps
 Hexokinase is inhibited by its production of glucose 6-phosphate
 Phospho-frucktokinase-1 activity is dependent on ATP, AMP and the energy state of the cell
 Pyruvate kinase is activated by AMP, fructose 1,6-bisphsphate and inhibited by ATP and
acetyl-CoA
• Glycolysis is important in cancer target drugs as tumours have approximately a tenfold increase in
glucose uptake than normal cells. Thus, targeting glycolysis could inhibit growth of tumours
Gluconeogenesis
• Is the synthesis of glucose from non-carbohydrate molecules such as amino acids or lipids
• Specifically, it can be thought of as the conversion of pyruvate to glucose (the reverse of glycolysis)
• It predominantly takes place in the liver (but also in renal cortex and small intestine epithelium)
• The synthesis of glucose from pyruvate utilises 7 out of the 10 steps/enzymes as glycolysis)
• The 3 out of the 10 irreversible steps seen in glycolysis are bypassed in gluconeogenesis
• 1st Bypass = pyruvate kinase (glycolysis) with pyruvate carboxylase and phosphoenolpyruvate
carboxykinase (gluconeogenesis)
• 2nd Bypass = phosphofrucktokinase (glycolysis) with fructose 1,6-bisphosphotase (gluconeogenesis)
• 3rd Bypass = hexokinase (glycolysis) with glucose 6-bisphosphotase (gluconeogenesis)
• In diagram below, the suns represent each bypass
• In gluconeogenesis, you get a net loss of
• The regulation of glycolysis and gluconeogenesis is important because if both are running together,
you will get a net energy loss and no net gain of any energy
• Thus, glycolysis and gluconeogenesis are reciprocally regulated
• The important regulatory enzymes/metabolites for glycolysis vs gluconeogenesis are
phosphofrucktokinase-1, fructose 2,6-bisphosphate and pyruvate kinase
• Phosphofrucktokinase-1 is the 3rd step in glycolysis. Can see in the diagram below that ATP and
citrate inhibit it whilst ADP (which represents low energy in cell) and AMP stimulate it
• Fructose 2,6-bishophate is a metabolite that regulates both glycolysis and gluconeogenesis. From
the diagram below, you can see that it stimulates phosphrucktokinase-1 (glycolysis) and inhibits
fructose 1,6-bisphosphotase (gluconeogenesis)
• Finally, pyruvate kinase
 ATP and acetyl-CoA inhibit pyruvate kinase  turn off glycolysis
 AMP and fructose 1,6 bisphosphate stimulate pyruvate kinase  turn on glycolysis
Link of glycolysis to citric acid cycle
• Pyruvate is converted to acetyl-CoA via pyruvate dehydrogenase (PDH) complex
• Pyruvate dehydrogenase (E1) is the first part of the PDH complex. You also have dihydrolipoyl
transacetylase (E2) and dihydrolipoyl dehydrogenase (E3) that from the other two parts of the PDH
complex
• When there is lots of ATP/NADH PDH is inactive. When there is lots of ADP/pyruvate PDH is
activated
• The PDH complex is also made up of 5 coenzymes and 4 vitamins
Citric Acid Cycle (Krebs Cycle)
• The cycle consists of 8 enzyme reactions
• The 2 Carbon acetyl-CoA condenses with the 4 Carbon oxaloacetate to form a 6 Carbon citrate
 The coenzyme A is released during this conversion
• 4/8 reactions are oxidations (those which form NADH and FADH 2)
• The net result of the cycle is generation of 3 NADHs, 1 FADH2, and 1 GTP (GTP is sometimes
interchangeably referred to as ATP because it is essentially converted to ATP very rapidly)
• The diagram above not only shows each step (enzymes + metabolites) of the cycle, but also factors
which are responsible for its regulation
• In regards to calcium, it is an indication of muscle contraction, this requires energy and that is why
the presence of calcium stimulates the citric acid cycle
• One thing which the diagram does not show is the production of 2 CO2 molecules for each acetylCoA that enters the cycle. They are release at the same time/place as the first two NADH molecules
Electron Transport Chain
• Is located at the inner membrane of the mitochondria
• It takes in the NADH and FADH2 molecules produced by the citric acid cycle
• The charge separation and concentration gradient help transport H + protons down to ATPase pump
which converts H+ protons into ATP
 The intermembrane space is positive and the matrix is negative
β-Oxidation
• Is a 4 step process where fatty acids are converted to acteyl-CoA
• Have two oxidation parts, a hydration and thiolysis part
• The whole process prepares the carboxylic end of fatty acid (or fatty acid can be called fatty acylCoA) for removal of the acteyl-CoA
• The product of 1 round of β-oxidation is an acetyl-CoA + the original acyl-CoA shortended by 2
carbons. You also get 1 NADH that feeds directly into Electron Transport Chain
Glycogen Synthesis/Breakdown
• The regulatory enzymes for glycogen synthesis/breakdown are glycogen synthase and glycogen
phosphorylase respectively
Summary of Pathways and Inter-relations