METABOLISM

Catabolic: digestion, absorption, transport, storage of carbohydrates, lipids and proteins; mobilization/oxidation to Acetyl-coA.
Energy: oxidation of Acetyl-coA; reduction of NAD/FAD; production of ATP.
Anabolic: synthesis of carbohydrates and lipids; essential amino acids; essential fatty acids; eicosanoids.
Metabolic regulation: control of all of the above and derangement of control.

CATABOLIC METABOLISM
CARBOHYDRATES
• Monosaccharides:
o Glucose, Fructose, Galactose, Inositol (Hexose – 6 carbon)
o Ribose, Deoxyribose (Pentose – 5 carbon)
• Disaccharides:
o Sucrose (fructose and glucose)
o Maltose (2 glucoses)
o Lactose (galactose and glucose)
• Polysaccharides
o Starch
o Cellulose
o Glycogen

DIGESTION AND ABSORPTION OF CARBOHYDRATES

• We only digest polysaccharides with α1-4 or α1-6 (no β1-4 bonds) i.e. starch and glycogen vs. cellulose.
• Starch and glycogen differ in the number of α1-6 bonds. These bonds are start points for side-chains ∴ dictate complexity
of structure → glycogen is complex, and starch has few (amylopectin) or no side chains (amylose). Starch/glycogen →
maltose + maltotriose (amylopectin/glycogen → +α-limit dextrins).
• Disaccharides → monosaccharides (enzymes of intestinal mucousal cells).
• The monosaccharides enter liver via hepatic portal vein (specific carrier mediated mechanisms).
• Non-digestible polysaccharides broken down by bacteria in the large intestine or egested (fibre).

GLYCOGENESIS
1. Glucose ATP Glucose-6-PO ADP; Enzymes: Glucokinase in liver, and hexokinase for other tissues. Stimulated
by insulin, and inhibited by adrenaline and glucagon.
2. Glucose-6-PO  Glucose-1-PO ; Enzymes: Phosphoglucomutase.
3. UTP ADP  UDP ATP
4. Glucose-1-PO UTP  UDP-Glucose PPi; Enzymes: Glucose-1-Phosphate Uridylyl Transferase
5. UDP-Glucose Glycogen Glycogen-Glucose UDP; Enzymes: Glycogen synthase (active → dephosphorylated;
inactive → phosphorylated. Stimulated: insulin; inhibited: glucagon, adrenaline, growth hormone and cortisol).
UDP = uridine diphosphate. After several glucoses with α1-4 bonds are added to the glycogen, a side chain with α1-6 bonds is
added. This process of glycogenesis occurs in muscle tissue, except for energy needs of muscle cells.

METABOLISM
GLYCOGENOLYSIS
• α1-4 and α1-6 bonds in glycogen are broken down to release glucose; done via 2 enzymes: (glycogen) phosphorylase (α1-
4 bonds) and debranching enzyme.
• Phosphorylase works till a α1-6 bond is reached and then the rest of the side chain is removed in 2 steps by the
debranching enzyme, thereafter phosphorylase continues.
• This produces glucose-1-phosphate (using free PO4 in cell) → (isomerised) glucose-6-phosphate.
• Glucose-6-phosphatase removes the phosphate → glucose. Glucose moves out of liver into the plasma. This step doesn’t
happen in muscle as it doesn’t have glucose-6-phosphatase.
• Glycogen phosphorylase (inhibitor: insulin; stimulants: glucagon, adrenaline, growth hormone and cortisol) is inactive
when dephosphorylated and active when phosphorylated.
• If a genetic disease causes the glycogen synthesis or breakdown enzymes to malfunction then it is considered to be a
glycogen storage disease. A phosphate needs to be attached to the glucose for it to be metabolised; however, it has to be
phosphate-free for it to be transported.
Glucose 1 Glucose-6-PO4 Fructose-6-PO4
GLYCOLYSIS (GLUCOSE HYDROLYSIS)
• Serves energy metabolism except in liver (fatty acid 2

synthesis) and adipose (lipid synthesis).

• Aerobic (brain) or anaerobic (blood: no mitocndria; Glyceraldehyde Dihydroxyaceto Fructose-1,6-
-3-PO4 (x2) ne-PO4 BISPO4
muscles both)
• Anaerobic: glucose-6-PO4 → pyruvate → lactate; 3

whereas, aerobically it will be converted to Acteyl-coA

1,3-
instead (or oxaloacetate or alanine). 3 Phospho- 2 Phospho-
Bisphospho- 4 8
glycerate glycerate
• Enolase is inhibited by fluoride both in glycolysis and glycerate

the gluconeogenesis. 1. Gluco/Hexokinase (ATP → ADP) 5

      2. Phosphofructokinase-1
(PFK-1) (ATP → ADP)
Phosphoenol
• Most important enzymes: PFK-1 and pyruvate 3. Pi +NAD → NADH•H+ Pyruvate 6
Pyruvate
4. ADP ↔ ATP
kinase (catalyse the two irreversible steps of 5. Enolase 6. Pyruvate Kinase (ADP → ATP)
glycolysis) and gluco/hexokinase (phosphorylates the glucose).
• PFK-1 is stimulated by AMP, Pi and fructose-2, 6-bisphosphate (made by PFK-2 from fructose-6-phosphate);
+
but inhibited by ATP, H and citrate.

Pyruvate

Aerobic Anaerobic
  !"# ## #$%$ &##
E: pyruvate E: pyruvate E: alanine E: Lactate dehydrogenase
dehydrogenase carboxylase transaminase NADH2 → NAD + H2

Citrate

 
 

METABOLISM
 • Galactose and mannose → G6P;
• Fructose → F1P (+little F6P) → dihydroxyacetone phosphate and glyceraldehyde → glyceraldehyde-3-PO4.
  

    


 

3x Ribulose-5-PO4

2x Xylulose-5-PO4 1x Ribose-5-PO4

       -. 

 /

 !"#$%&'()(*+,  0!1$"!%&'(2(*+,

1x Glyceraldehyde-
3-PO4

• Anaerobic; produces NADPH2 (used for anabolic metabolism) and Ribulose-5-phosphate from G6P.
• R5P is converted to ribose-5-phosphate (used for nucleotide and nucleic acid synthesis).
st
• 2 stages, 1 stage (irreversible):
+
o Glucose-6-PO4  6-Phosphogluconate [NADP + H2O → NADPH2)
+
o 6-Phosphogluconate  Ribulose-5-PO4 [NADP → NADPH2 + CO2]
• The second stage only occurs if the R5P is not needed for nucleotide and nucleic acid synthesis.
• If the R5P is needed then it becomes ribose-5-PO4, otherwise the second stage occurs:


• Occurs in the liver and requires the alcohol dehydrogenase.
st
• 1 step converts ethanol (CH3CHOH) to acetaldehyde (CH3CHO) and requires NAD as a coenzyme
producing NADH2.
nd
• 2 step converts acetaldehyde to acetate (CH3COOH → Acetyl-coA) and requires NAD (→ NADH2).
• The NADH2 must be converted to NAD to keep this and glycolysis going. This is done by shunting the
pyruvate to lactate (also done via the electron transport chain), and the conversion is a co-reaction.
• However, pyruvate is required for gluconeogenesis in the liver and ∴ glucose concentrations drop.
• Methanol is metabolised in the same way, but instead of acetaldehyde, formaldehyde is produced as
the final step; the formaldehyde accumulates, “preserves” the tissue leading to death.

METABOLISM
PROTEINS
• Various enzymes in the stomach, duodenum and ileum break the peptide bonds between (types of)
amino acids (aa):
o Pepsin (stomach) breaks aromatic (e.g. tyrosine) and dicarboxylic (e.g. glutatmate) aa’s.
o Chymotrypsin: lysine or arginine.
o Elastase: neutral aa’s.
o Carboxypeptidases: remove carboxyl terminal aa.
o Aminopeptidases (ileum): removes amino terminal aa.
o Dipeptidases from outside ileal mucousal cell walls.
• Aa’s are absorbed into ileal cells by specific transporter molecules.
• Aa’s that you cannot produce or produce enough of are called essential aa’s.
• Methionine can be converted into cysteine and cystine and phenylalanine to tyrosine.
• Excess aa’s broken down by liver:
o Serine, Alanine, Cysteine, Cystine, Methione, Theronine and Valine → pyruvate (feeds into
energy metabolism or glucose synthesis).
o Proline, Histidine, Arginine, Glutamine and Glutamate, → α-ketoglutarate (feeds into TCA
cycle)
o Lysine and Leucine → acetoacetate (feeds into FA or ketone synthesis).
o Phenylalanine, Isoleucine, Tryptophan, and Tyrosine → oxaloacetate and acetoacetate (feeds
into TCA cycle and FA/Ketone synthesis).
o This is done by removing the amino group, which is added to α-ketoglutarate converting it to
glutamate (common intermediate in breakdown of aa’s) and the leftovers are above.
o The movement of the aa is transamination, which occurs via transaminase enzymes. These
enzymes require pyridoxine (vitamin B6) as a coenzyme.

Amino acid keto acid

Transaminase

ketoglutarate glutamate

Glutamate dehydrogenase

NH4+ + NADH2 NAD

o Most common transaminases: aspartate transaminase (aa = aspartate; α-keto = oxaloacetate)
and alanine transaminase (aa = alanine; α-keto = pyruvate).
+
o The most efficient method of ridding the body of excess aa nitrogen is to convert the NH4
(acidic and effects pH of the plasma) to urea (2 amines: 1 carbon)

METABOLISM
   !"#"$
→ 


  
H2O →3H+
2ATP→2ADP +Pi

 
 

  
 
  
%&!"#"$ ATP → AMP + PPi

LIPIDS
• Defined based on common properties rather than structure. They are a chemically heterogenous group,
insoluble in water and soluble in organic solvents (this holds for mammals’ lipids).
• Mammalian lipids: ester of long chain fatty acids with glycerol, sphingosine or sterol. They can be
divided into neutral (visible fat) and polar (invisible fat).
o Tri/di/monoacylglycerols: esters with 3/2/1 FA’s with glycerol
o Sterols: polycyclic alcohols
Neutral lipids
o Sterol esters: polycyclic alcohols with a FA.
o Sphingolipids: esters of a FA with sphingosine.
o Phosphoglycerides: esters of 2 FA’s with glycerol, and a PO4 and base
group attached
Polar lipids
o Lysophospholipids: esters of 1 FA with glycerol and a PO4 and base
group attached.
• Most common sphingolipid is sphingomyelin → component of myelin sheath around nerve fibres.
Common in brain and is vital for neural structure and function.
• Coenzyme A attaches to a fatty acid, which traps the fatty acid inside the membrane; and most
metabolism requires FA’s to be in the coenzyme derivative form.

.FATTY ACIDS
• FA’s have hydrocarbon backbone with carboxyl group at one end; FA’s are referred to as “acyl-”, and
“acetyl-” is only 2 carbons.
• Saturated FA’s are important for metabolism, and unsaturated (one or more double bonds) for cell
structure and as specific hormone precursors. There are monounsaturates and polyunsaturates (divided
into mega 3 [N3] and omega 6 [N6]).
• Naturally occurring unsaturated FA’s have the “cis” configuration, and some of those bacteria and the
intermediates in β-oxidation have “trans” configuration.
• “Cis” are converted irreversible to “trans” during oil extraction and food processing.
• “Trans” can’t be used by the body as unsaturates ∴ treated as saturates.

METABOLISM
 • FA naming starts on the methyl end (“N”) as chain elongation/shortening happens at the carboxyl end.

LIPID DIGESTION
• The liver produces bile salts, which reduce the size of the particles in emulsion and form micelles.
• Bile salts are compounds from cholesterol and have a taurine/glycine group attached.
• Pancreas releases several lipolytic enzymes into the duodenum. Pancreatic lipases act on tri/di/
monoacylglycerols and phosphor lipases A1, A2, B, C and D on lyso/phosphoglycerides.
"#$%&'()*+,' (-,.(
• Stomach (large lipid droplets) /00000000000001 Duodenum (micelles – small droplets → fatty acids and
monoacylglycerols) → jejunum.
• The final products of lipid digestion are fatty acids, monoacylglycerol, phosphate, base groups and
glycerol. These enter the cells by diffusion, and are activated by attaching coenzyme A.
• They are then re-esterfied and reform triacylglycerol, which cannot pass through the membrane, so
cholesterol, phosphoglyceride and apoprotein is added to make a lipoprotein (chylomicrons) which is
exocytosed into the lymphatic system. They enter circulation where the lymph system joins the aorta.
• They are broken down into FA and glycerol by enzymes in the capillary lining. The FA’s pass into adipose
tissue (activated, and then esterified to glyceraldehyde-3-phosphate, to form triacylglycerol for storage)
and the glycerol is taken up by the liver.

LIPOPROTEINS
• Lipids and proteins associated together, that form 5 classes:
o Chylomicrons (largest): transport mechanism for lipids of dietary origin.
o Very low density lipoproteins (VLDL): transport mechanism for lipids from liver to adipose or
muscle for storage.
o Low density lipoproteins (LDL): transport mechanism for cholesterol out of the liver.
o High density lipoproteins (HDL): opposite of LDL.
o Albumin-free FA’s (smallest): transport form of FA’s from adipose to muscle/liver; it has 8 sites
to carry FA’s by association.
• All these lipoproteins (except albumin-free FA’s) are composed of triacylglycerols, phosphoglycerides,
cholesterol and apoproteins in varying proportions.
• Apoproteins: specialised globulin proteins; lipophilic and partially hydrophobic; 4 classes: A, B, C and E,
which occur in different profiles in different plasma lipoproteins.
• Excess cholesterol that LDL doesn’t transport, is deposited in aterial endothelial linings → atherogenic
plaque and then onto atherosclerosis and heart attack.
• HDL blocks LDL uptake, and causes LDL to return to the liver.
• Cholesterol is transported in the plasma in solution in the form of cholesterol esters, which are made:
o In the liver, using cholesterol, FA and cholesterol acyl transferase.
o In the plasma, using cholesterol, phosphoglyceride and lecithin acyl transferase.
• Look at flow charts for metabolism of lipoproteins.

LIPID CATABOLISM

METABOLISM
 • Adrenaline stimulates hormone-sensitive lipase in adipose tissue (break down triacylglycerols).
• The glycerol goes into solution in plasma, and the FA’s are transported by albumin-free FA’s.
• The albumin-free FA complex enters the liver and is activated with coenzyme A.
• It then moves to the mitochondria, and through the outer membrane but not the inner membrane.
• ∴ carnitine acyl transferase (on inner membrane) removes coenzyme A and replaces it with carnitine
(aa) forming fatty acyl carnitine, which moves in and then has another carnitine acyl transferase replace
the carnitine with coenzyme A, using 2 ATP and producing fattyl acyl coenzyme A for β-oxidation.
• β-oxidation reduces even C number FA’s by 2 C’s until only 2 C fractions are left; these are acetyl-coA
which is used in energy metabolism:
o A trans bond is introduced between C2 and C3 (carboxyl end)
o The H’s removed are added to FAD to make FADH2; then water is added, and the hydroxyl is
removed from the water and added to hydrogen to make a keto group.
o The H’s from the water make NAD→NADH2.
o The C2-3 bond is broken, removing 2C’s as acetyl-coA; this repeats until only acetyl-coA is left.
o Each cycle yields FADH2, NADH2 and acetyl-coA (2 on the last cycle), which are metabolised.
o “Cis” double bonds have the double bonds in the wrong position so they don’t feed into β-
oxidation very easily.
o Cis- unsaturated fatty acids undergo β-oxidation till the “cis” bond is reached, which is then
changed to a “trans” bond, and then the molecule undergoes further β-oxidation until another
“cis” bond is reached or until the molecule is β-oxidised fully.
o This acetyl-coA can be converted to ketones, which are used in the brain for energy; this
process produces acetoacetate and β-hydroxybutyrate.

2 Acetyl-coA → AcetoacetylCoA

AcetoacetylCoA + acetyl-coA → hydroxymethylglutarylCoA

HydroxymethylglutarylCoA is then used for cholesterol synthesis, or converted to
coASH, acetyl-coA or acetoacetate.

Acetoacetate and 3 (β)-hydroxybutyrate (product of conversion of acetoacetate; other
possibility is acetone) are ketones found in plasma.

ENERGY METABOLISM
• Fat is the main form of energy storage – greatest energy yield and stored anhydrously.
• The energy released by a substance depends on the number of H’s that pass along ETC to cause the
synthesis of ATP and to make water.
• Metabolism is very inefficient as 60% of the energy is lost as heat ∴ only 40% is captured in ATP.
• Most tissues metabolise FA’s and monosaccharides, except RBC’s (glucose) and brain cells (glucose
and/or ketones).

TRICARBOXYLIC ACID CYCLE

• The TCA cycle (a.k.a. Citric acid or Kreb’s Cycle), along with electron transport chain (occurs in
mitochondria) reduces acetyl-coA to CO2 and H2O, produces heat and ATP.

METABOLISM
 1. Acetyl-
CoA

9. Enzyme 1
Oxaloacetate 2. Citrate

8. Malate 3. Isocitrate

TCA
Cycle Enzyme 2

7. Fumarate 4. α-
ketoglutarate
Enzyme 4 Enzyme 3

5. Succinyl-
6. Succinate CoA

• Main enzymes of TCA:

1) Citrate synthase: oxaloacetate + acetyl-coA → citrate (energy in coA bond used).
2) Isocitrate dehydrogenase: isocitrate → α-ketoglutarate (makes NADH2 and CO2).
3) α-ketoglutarate dehydrogenase: α-ketoglutarate → succinyl-coA (makes NADH2 and CO2).
4) Succinate dehydrogenase: succinate → fumarate (makes FADH2)
1. Uses water to carry on.
2. Its formation releases CoASH.
-
3. Uses NAD and COO to carry on.
4. Its formation releases NADH2 and CO2. Uses NAD and CoASH to carry on.
5. Its formation produces NADH2 and CO2. Uses GDP and Pi to carry on.
6. Its formation produces GTP and CoASH. Uses FAD to carry on.
7. Its formation produces FADH2. Uses H2O to carry on.
8. Uses NAD to carry on.
9. Its formation produces NADH2.
• Overall reaction:
234 256278 3:8; 1<8; 1=;> >? 23A 5 225A 3:8;3A 1<8;3A 18B> 27863
• Controls for TCA cycle:
o Only occurs with presence of oxygen (needed to reformation of NAD).

METABOLISM
 o ATP inhibits citrate synthase (slows cycle) ∴ faster with low [ATP]
o ADP stimulates isocitrate dehydrogenase ∴ speeds up cycle.
o i.e. High [substrate] and low [product] speed up cycle.
• Several of the intermediates of the cycle may be used elsewhere:
o α-ketoglutarate: glutamate and other amino acid synthesis
o Succinyl-coA: porphyrin synthesis
o Oxaloacetate: glucose and amino acid synthesis.
o Malate: glucose synthesis
o Acetyl-coA: FA, aa and sterol/steroid synthesis.
o ∴Cycle is catabolic as well as anabolic.

ADENOSINE TRIPHOSPHATE
• Uses in the body:
o Muscle contraction: ATP broken down during relaxation phase.
o Transport of molecules and ion across membranes: active transport ∴ needs ATP.
o Activation of compounds e.g. glucose → G6P uses ATP
o Control of enzyme activity: the activation/deactivation (through de/phosphorylation) uses ATP.
o Activation energy for some reactions.
• ATP concentrations are greater in the cytoplasm than in the mitochondria (site of production) as ATP is
transported out of the mitochondria very rapidly.
• ATP is a nucleotide triphosphate. GTP, CTP and UTP are some of the other ATP analogs.
• ATP can also be produced with energy released from PEP → pyruvate or from the phosphate of creatine
phosphate in muscles.

ELECTRON CARRIER MOLECULES

• 2 classes:
o Pyridine nucleotides – NAD/NADH2; NADP/NADPH2; based on vitamin B3 (niacin nicotinamide).
o Flavins - FAD/FADH2; based on vitamin B2 (riboflavin).
o The H’s in the ECM’s are supplied by the breakdown of substrates.
o NADP/NADPH2 is used in anabolic reactions instead of energy metabolism.
o NADH2 and FADH2 are dehydrogenated by the ETC chain, with oxygen as the H acceptor.
• Approximately, 31kJ/mol are needed to produce 1 ATP.
• The ECM’s are only available in small amounts in the cell ∴ constantly recycled.
• NAD is usually used in catabolic reactions; these are generally:
o Alcohol + NAD → Ketone + NADH2
• NADP is usually used in anabolic reactions (e.g. G6P → 6-phosphogluconate), which are very similar but
are usually irreversible. NADPH2 is often used as a hydrogen source in fatty acid and steroid synthesis, in
glutathione reconstitution and toxin removal in liver.
• FAD is used in catabolic reactions:
o Saturated/Single bonds + FAD ↔ Unsaturated/double bond + FADH2

METABOLISM
 o Reversible in isolation, but in mammals re-oxidised quickly in ETC ∴ virtually irreversible.
• FMN is an ETC acceptor, accepting electrons from NADH2.
• Other carrier molecules include:
o Coenzyme A (FA and acetate metabolism)
o Thiamine pyrophosphate (carbonyl groups)
o Biotin (CO2 carrier)
o Uridine diphosphate (glucose transport)
o Tetrahydrofolate (single carbon group carrier)

ELECTRON TRANSPORT CHAIN

• The hydrogen’s that are removed from acetyl-coA along with water, are made into more water releasing
energy (stored in ATP or released as heat to maintain body temperature).
• 2 insertion points for:
o NADH2: feeds into NADH-Q reductase, providing an extra energy-rich step ∴ 3 ATP produced,
o FADH2: feeds in via succinate-Q reductase (only 2 ATP produced)
o They each provide 2 energy rich steps, which move hydrogen through the inner mitochondrial
membrane into the inner-membrane space.
o They both link to coenzyme-Q-cytochrome-C reductase (via coenzyme Q/ubiquinone), which
links to cytochrome oxidase and catalyses water formation (oxygen + hydrogen from NADH2
and FADH2).
o The hydrogen re-enters the mitochondria via ATP synthase, which has 2 parts: the membrane-
straddling proton channel (F0) and the ATP synthase realm (F1).
o All these enzymes, are multi-enzyme complexes.
• All of the functions of the ETC occur as a linked sequence.

ETC COENZYMES/COFACTORS
• NADH-Q reductase contains iron and an analoge of FAD called FMN.
• Coenzyme-Q-cytochrome-C reductase contains cytochrome B, cytochrome C and iron.
• Cytochrome-C oxidase contains cytochrome A and A3 and copper.

ENERGY BALANCE OF TCA CYCLE AND ETC CHAIN

• The oxidation of NADH2 produces 220kJ/mol, and 93kJ of this is made into ATP ∴ 44%.
• The oxidation of FADH2 produces 170kJ/mol, and 62kJ of this is made into ATP ∴ 36%.
• ∴Approximately 40% efficiency.
• 3 NADH2 (9 ATP) + 1 FADH2 (2 ATP) + 1 GTP (1 ATP) → 12 ATP
• Each glucose (6C) yields 32 ATP, whereas each FA (18C) yields 151 ATP ∴ 1.6 times more.

MEASUREMENT OF TCA/ETC FUNCTION

• ADP/Oxygen ratio gives a measure of proportions of NADH2 versus FADH2 ∴ indicates the proportion of
glucose and FA’s being metabolized.

METABOLISM
 • Respiratory control index (RCI) measures oxygen consumption rate with excess ADP for the ETC,
indicating functioning of ETC (normal is 7-9).
• Reduced RCI (i.e. reduced oxygen use and ETC function) can indicate:
o Defect in the ETC and/or TCA
o Deficiency of acetyl-coA
o Deficiency of NAD and/or FAD
o Vitamin deficiency
o Poisoning/inhibition of the ETC
• Rotenone and barbiturates block hydrogen transfer from NADH-Q reductase to coenzyme Q.
• Anticancer agent antimycin A inhibits coenzyme-Q-cytochrome-C reductase.
• Cyanide and carbon monoxide blocks cytochrome-C oxidase.

UNCOUPLING OF ETC
• Caused by a genetic condition or poisoning, or during hibernation in brown adipose tissue (maximise
heat production for minimal fuel use).
• Brown adipose tissue metabolises lipids, by uncoupling the ETC from the ATP synthesis, causing all the
energy to be released as heat.
• This is unnecessary if one can shiver, but human neonates aren’t able to shiver ∴ need brown adipose.
• 2,4 dinitrophenol, P-cresol and pentachlorophenol can cause uncoupling, but they are very toxic.
• Polyunsaturated fats stimulate production of uncoupling proteins (thermogenins) in brown adipose.

ANABOLIC METABOLISM
GLUCONEOGENESIS
• Process by which glucose is synthesised from non-monosaccharides (not possible in mammals).
• There are 3 irreversible steps in glycolysis that have to be circumvented in gluconeogenesis:
o Phosphoenolpyruvate (PEP) → pyruvate:

Catalysed by pyruvate kinase.

Reversed (in mitochondrion) by converting pyruvate to oxaloacetate via pyruvate
carboxylase (uses 1 ATP), and then to malate (uses 1 NADH2).

Malate is converted (in cytosol) back to oxaloacetate (produces 1 NADH2) and then
phospoenolpyruvate caboxy kinase converts that to PEP (costs 1 GTP).
o F6P → F1,6BISPO4:

Reversed by fructose-1, 6-bisphosphatase.
o Glucose → G6P

Reversed by glucose-6-phosphatase.

G6P is only used in the liver (glucose regulation) and kidney (glucose excretion
regulation).
• Pyruvate → glucose:
o Lactate → pyruvate (lactate dehydrogenase)

METABOLISM
 o Aa’s → intermediates through transamination (2 common: alanine (pyruvate) and aspartate
(oxaloacetate)).
o Glycerol from triclycerol breakdown can be used via dihydroxyacetone phosphate.
o Fructose, mannose and galactose can also feed into gluconeogenesis.
• Gluconeogenesis is controlled by the same factors as glycolysis e.g.:
o Fructose-1, 6-BISPhosphate inhibited by AMP and Fructose-2, 6-BISPhosphate.
o Pyruvate carboxylase stimulated by acetyl-coA.

DERIVATIVES OF AMINO ACIDS

• GABA (γ-amino butyric acid; neurotransmitter in brain) from glutamate.
• Melanin from tyrosine, which is broken down by tyrosinase.
• Tyrosine can also be converted into dopamine (brain neurotransmitter), which can become
norepinephrine and then epinephrine (via the conversion of S-adenosyl methionine to S-adenosine),
which are neurotransmitters and adrenal hormones.
• Tyrptophan can be converted to 5-hydroxytryptophan, which becomes 5-hydroxytryptotamine (a.k.a.
serotonin – important brain neurotransmitter).

CLINICAL PROBLEMS
• Lack of urea cycle enzymes: increased excretion of intermediates (especially NH3); vomiting, lethargy,
irritability, mental retardation, coma, seizures and death.
• Phenylketonuria: lack of phenylalanine hydroxylase; can’t convert phenylalanine → tyrosine; mental
retardation and death.
• Albinism: lack of tyrosinase:; blocks melanin production.
• Alkaptonuria: no conversion of tyrosine → homogentisic acid; highly alkaline urine.
• Maple syrup disease: no conversion of valine, leucine and isoleucine to keto acids and coA derivatives;
urine smells/tastes like maple syrup.
• Parkinosim: no conversion of tyrosine → dopamine; motor disturbances.
• Schizophrenia: excess dopamine production; mental disturbances.
• Migraine: imbalance of serotonin production and specific 5-HT receptor function; headaches.

FATTY ACID SYNTHESIS/LIPOGENESIS

• Needs supply of acetyl-coA (from glycolysis) and correct hormonal conditions and occurs mostly in liver.
• 2 intermediates:
o 1 AcetylACP: coA in acetyl-coA replaced by acyl carrier protein (ACP).
o Several malonylcoA: CO2 (from biotin) added to acetyl-coA using acetyl-coA carboxylase.
o These 2 are condensed to form butyrylcoA (releases ACP and CO2); driven by fatty acid
synthase enzyme complex; requires NADPH2 (from pentose phosphate pathway), releases
NADP.

METABOLISM
 • CoA in butyrylcoA replaced with ACP, and this butyrylACP reacts with malonylcoA to increase chain
length (6C – hexanylcoA). This coA is swapped for ACP, and then 2 C’s (3 added and then 1 removed) are
continuously added until required chain length is reached (occurs in cytosol).
• Final product is a saturated FA (even number of C’s), and liver can insert one C for monounsaturated;
and, polyunsaturated FA’s are obtained from diet.
• Used to synthesise:
o Triacylglycerol: in liver (3C skeletons; glycerol → glycerol-3-PO4, 2 FA’s added → phosphatidic
acid, PO4 removed and FA added) and adipose tissue (only differs from liver with 2 FA’s added
to glyceraldehyde-3-PO4 from glycolysis → phosphatidic acid); differing backbones.
o Phosphoglyceride: in liver; phosphatidic acid also produced identically and then used as
precursor for choline, ethanolamine, serine and inositol phosphoglycerides (made by replacing
H with base group).

STEROL/STEROID SYNTHESIS
• Cholesterol is most common and its synthesis requires acetyl-coA.
• 2 acetyl-coA’s joined → acetoacetyl-coA (one coA released); another acetyl-coA condensed with it →
hydroxymethylglutaryl-coA (HMGCoA; another coA released).
• Pyrophosphate (PPi) is added to HMGCoA, and CoA, CO2 and O2 is released → mevalonylPPi (“isoprene
unit” – 5C); 6 units condensed → squalene → lanosterol (rings closed, double bonds lost) → cholesterol.
• A sterol is converted to steroid by removing (most of) the side chain (irreversible).
• Common precursors for steroids include pregenolone and then progesterone.
• Progesterone → testosterone (→ estrone) or corticosterone (→ aldosterone).

ESSENTIAL FATTY ACIDS (EFA)

• 2 polyunsaturates required by mammals:
o Linoleic acid: 18C’s; 2 double bonds between C6-7 and C9-10 ∴ N 6 polyunsaturate.
o α-linolenic acid: 18C’s; 3 double bonds between C3-4, C6-7 and C9-10 ∴ N 3 polyunsaturate.
o Only double bonds closer than the C9 carboxyl end can be inserted by mammals; and the bonds
further than this are inserted by plants.
• 2 families of polyunsaturates come from these 2 via the desaturase enzyme cascade.
• This is a result of different combinations of alternations of desaturations (double bond insertion) and
elongation (addition of 2C’s to carboxyl end).
st
o The 1 enzyme and rate-limiting step is ∆-6-desaturase (adds double bond between C12-13).
o Elongase adds 2C’s at carboxyl end → CIS-C20.
o ∆-5-desaturase adds a double bond between C15-16.
o Elongase adds 2 carbons → CIS-C22.
o ∆-4-desaturase adds a double bond between C18-19.
• Herbivores and most carnivores (except felinae and older humans, which don’t have ∆-6-desaturase)
have desaturases ∴ they are able to obtain derivative polyunsaturates.

METABOLISM
 • In fact, Inuit’s have completely lost ∆-6-desaturase activity.
• Polyunsaturates are used for/in:
o Membrane structre/fluidity.
o Electrical insulation.
o Skin waterproofing.
o Hormone transmission and production.
• EFA deficiency/imbalance symptoms are:
o Increased metabolic rate o Poor sperm quality and fertility
o Poor hair condition and hair loss o Poor growth
o Dry, scaly skin o Distorted birth sex ratio
o Open sores and wounds o Self mutation
o Anoestrus and infertility o Death
• Their diseases/conditions are:
o Cardiovascular disorders o Rheumatoid arthritis
o Obesity o Multiple sclerosis
o Alcoholism o Schizophrenia
o Hyperactivity o Aging
o Premenstrual syndrome o Diabetes
o Benign breast disease o Cancer
o Dermatitis o Epilepsy
o Atopic eczema o Psoriasis

EICOSANOIDS
• 3 N3 and N6 polyunsaturates are converted into 3 series of hormones:
o Prostalandins
o Prostacyclins
o Thromboxanes
o Leukotrienes
• The 1 series is derived from dihomo-γ-linoneni acid; the 2 series from arachdonic acid and the 3 series
from eicosapetaenoic acid.
• All 3 series are produced identically, only their substrates are different.
o The polyunsaturate is folded around C11.
o This is a precursor for leukotriene (side groups added via lipoxygenase (lipox) for stabilsation).
o A bond is formed between C9 and C13 for prostaglandin, prostacyclin or thromboxane forming
a ring and losing 2 double bonds (precursor), which is catalysed by cyclo-oxygenase (cox).
o 1 series from a 3 double bond polyunsaturate that lost 2 ∴ 1 series; similarly 2 series from a 4
double and 3 series from a 5 double bond polyunsaturate.
• Eicosanoid production is local, and the substrates are stored in the membrane phosphoglyerides.
• The initial step (the release of the polyunsaturate) is catalysed by phospholipase A2, after which lipox or
cox acts on it.

METABOLISM
 • Corticosteroids inhibit phospholipase A2, and non-steroidal anti-inflammatory drugs (NSAID’s) inhibit
lipox and cox. Aspirin, paracetemol and ibuprofen block cox and benoxaprofen blocks lipox.

FUNCTIONS
• Generally, they have antagonistic effects.
• Platelets produce prostaglandin G2 (PGG2; precursor for 2 series). If taken up platelets it is converted to
thromboxane A2 (causes platelets to aggregate), and if taken up by endothelium of blood vessel,
converted to prostacyclin I2 (repels platelets ∴ when wall damaged, and PGI2 production reduced,
platelets adhere to wall and plug the damaged area.
• Eicosanoids are needed for the female reproductive cycle, and they are found in plenty in seminal fluid.

PURINES AND PYRIMIDINES

• Basic building blocks of nucleosides (purine/pyrimidine with deoxy/ribose attached) and nucleotides
(de/oxyribose is phosphorylated) → ATP, ADP, AMP, GTP, GDP, GMP, c-AMP, c-GMP, UTP, UDP, FAD,
NAD, NADP, coenzyme A, RNA and DNA.
• Adenine and guanine are 2 common purines, and uracil, thymine and cytosine are common pyrimidines.
• When AMP (or similar) is phosphorylated further → ADP → ATP. The AMP can also become cyclic (c-
AMP – hormone second messenger) through the use of adenyl cyclase.
• Purine synthesis starts with ribose-5-PO4; pyrophosphate (ATP) is added → phosphoribosylpyrophos-
phate (PRPP), which is converted to inosine monophosphate (IMP), which can become AMP or GMP.
• Purine breakdown: ATP breaks down into hypoxanthine, which (along with GTP) breaks down into
xanthine, and then into uric acid (all down using xanthine oxidase).
• Pyrimidine synthesis:
o Glutamate, Asparatate, CO2 and ATP all condense with PRPP to form UMP, which is
phosphorylated → UTP, which is converted into CTP or TDP.
• CTP is broken down into cytosine → uracil, and TDP into thymine, and both of these into CO2 and NH3.
• Gout is a condition where there is excess intake/production of uric acid (possibly a result of excess
xanthine oxidase, which is inhibited by allopurinol).
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Adenine Adenosine Adenosine monophosphate
 
  Guanine Guanosine Guanosine monophosphate

Cytosine Cytidine Cytidine monophosphate

 

 Uracil Uridine Uridine monophosphate
 
Thymine Thymidine THymidine monophosphate

METABOLIC REGULATION
• It is the ability of the body to adapt and respond to changes in its internal/external environment.
o Gradual e.g. seasonal

METABOLISM
 o Moderate e.g. circadian
o Rapid e.g. sudden activity
• Metabolic control happens at 2 levels:
o Intracellular: within cell; reflects local condition e.g. cytosolic glucose concentration; controlled
via substrate/product availability.
o Intercellular: outside cell; reflects tissue/organ and whole body conditions e.g. plasma glucose;
hormonal or neural control.
• The pathways that are controlled are a combination of:
o Equilibrium reactions: reversible; respond to changes in [reactant]; enzymes used rarely
saturated with substrate ∴ can speed up.
o Non-equilibrium reactions: irreversible by same enzyme; enzymes saturated with substrate ∴
operating at maximum.
• The rate-limiting enzyme controls the rate of the entire reaction, and is usually the point of control.
• Regulation occurs in two ways:
o Intracellular: substrate/production concentration; used in absence of intercellular.
o Intercellular: over-rides intracellular.
• The activity of glucokinase (directly) and glucose-6-phosphate (indirectly) is controlled by glucose.
• In glycogenesis the rate-limiting step is glycogen synthase and in glycogenolysis it is phosphorylase; and
both of these are controlled by de/phosphorylation.
• The main hormones for metabolic regulation are:
o Insulin and anti-insulin hormones (glucagon, adrenaline, cortisol and growth hormone):
controls blood glucose levels.
o Thyroid hormones: controls metabolic rate.

INSULIN
• β-cells of islets of Langerhans (pancreas).
• Dipeptide with α-chain of 21 aa’s and a β-chain of 30 aa’s.
• Stimulated by increased plasma [glucose]:
o Decreased plasma glucose by increasing tissue uptake, glycolysis and glycogenesis.
o Decreased plasma lipids by increasing tissue storage and TAG synthesis
o Increased protein synthesis
• Causes dephosphorylation of enzymes i.e. activating glycogen synthase, and inhibiting phosphorylase.

ANTI-INSULIN HORMONES
• Glucagon, adrenaline and cortisol all cause the following:
o Increased adipose tissue lipolysis (HS-lipase) ∴ increased plasma FA’s
o Increased ketogenesis from acetyl-coA from increased β-oxidation.

GLUCAGON
• α-cells of islets of Langerhans.

METABOLISM
 • Monopeptide with a chain of 29 aa’s.
• Stimulated by decreased plasma [glucose]:
o Increased liver glycogenolysis and gluconeogenesis ∴ increased plasma glucose.
o Increased liver glycolysis and lipogenesis.
• Cause phosphorylation of enzymes.

ADRENALINE
• Adrenal medulla.
• Causes: increased liver and muscle glycogenesis, but glucose only for internal muscle use.
• Stimulate glycogenolysis in liver and muscle,

CORTISOL
• Adrenal cortex.
• Causes:
o Increased liver glycogenolysis and gluconeogenesis ∴ increased plasma glucose.
o Increased protein breakdown to release aa’s for gluconeogenesis in liver.

GROWTH HORMONE
• Pituitary.
• Causes release of cortisol.

THYROID HORMONES
• Thyroid gland
• T3/T4 increase metabolic rate ∴ mobilization of fuel stores, and decrease storage.

MUSCLE GLYCOGEN
• Glycogen synthesis in muscle is controlled by hexokinase (activity controlled by intracellular [G6P]).
• Insulin stimulates hexokinase via glucose uptake in muscles.
• Generally same control mechanisms in liver and muscle, except:
o No glucagon receptors in muscle ∴ cannot stimulate glycogenolysis in muscle.
o Adrenaline and insulin are the main hormonal stimuli.
o Most stimuli of glycogenolysis is neural (via calcium).

GLYCOLYSIS
• Used to convert excess glucose to fat in liver and adipose, and for energy elsewhere.
• Hexokinase/glucokinase, PFK-1 and pyruvate kinase regulate glycolysis.
• PFK-1 is stimulated by AMP, ADP, and Fructose-2, 6- BISPhosphate (in liver only); and inhibited by ATP,
+
H , citrate and phosphocreatine (muscle only).
• Pyruvate kinase stimulated by Fructose-1, 6- BISPhosphate and inhibited by ATP.
• Pyruvate can be converted to: lactate/alanine (directly reversible); oxaloacetate (indirectly reversible);
and acetyl-coA (irreversible; uses pyruvate dehydrogenase – PDH).

METABOLISM
 • PDH is active when dephosphorylated and inactive when not. The dephosphorylation occurs as a result
of PDH kinase (stimulated by acetyl-coA, NADH2 and ATP; inhibited by increased pyruvate), and
phosphorylation as a result of PDH phosphatase (stimulated by calcium and insulin; inhibited by ADP).
• PDH phosphatase switches off in type I diabetes (insulin deficiency) ∴ blocking glucose use.

GLUCONEOGENESIS
• Regulated hormonally by:
o Glucagon: inhibits liver PFK-1, PFK-2 and pyruvate kinase and stimulates fructose- 1, 6-
BISPhosphatase → inhibits glycolysis, stimulates gluconeogenesis.
o Insulin works oppositely.
o Cortisol stimulates muscle protein breakdown to provide aa’s for gluconeogenesis.
o Alcohol inhibits gluconeogenesis, as its breakdown produces 2 NADH2 (NAD regenerated by
shunting pyruvate to lactate).

DIABETES MELLITUS
• Failed action of insulin. Absolute deficiency = type I; relative deficiency = type II.
• Type I requires insulin-replacement therapy and is caused by:
o Genetic predisposition
o Viral attack
o Autoimmune response
• Type II is reduced insulin receptor function and number and caused by long-term obesity.
• Both the diabetes cause increased plasma glucose concentrations, but the uptake into the cells is
reduced ∴ can relate to starvation. This is compounded by increased glucagon.
• The decreased insulin and increased glucagon cause decreased glucose uptake and lipogenesis and
increased gluconeogenesis and lipolysis.
• Diabetes is monitored in the short term by plasma glucose, and in the long term by glycosylated and
haemoglobin.
• Cushings syndrome (and other conditions with similar symptoms) are caused by chronically increased
plasma cortisol levels, with the following symptoms (can be of hypothalamic, pituitary or adrenal origin):
o Truncal obesity
o Muscle wasting in limbs
o ‘Moon’ face
o Increased protein breakdown in peripheral tissues
o Increased TAG breakdown (except in liver and abdomen)

METABOLISM