B Topic 8 - Metabolism of Carbohydrates

METABOLISM OF
MACRONUTRIENTS
1
METABOLISM OF CARBOHYDRATES
• Begins at digestion
• Most dietary carbohydrates release glucose upon digestion
Amylase
• Starch Glucose
Maltase
• Maltose Glucose
Sucrase
• Sucrose Glucose +Fructose
Lactase
• Lactose Glucose + Galactose
2
 Glucose is the main and preffered source of energy
 CNS/Brain is dependent on glucose as primary source of fuel
 Uses about 120g glucose/day
 Glucose deficiency can impair brain function
 Red blood cells (RBCs) rely on glucose to supply their energy
needs
 RBCs lack mitochondria
3
Glucose and Energy production
 Energy is stored in the chemical bonds of glucose
 This energy is released when glucose is oxidized
 Glucose oxidation involves a series of enzyme catalyzed reactions

in which electrons are released from chemical bonds.
 The electrons are carried by coenzymes to the electron
transport chain where they eventually reduce oxygen to form
water.
 The energy released during the transfer of electrons is used to
produce ATP.
4
Coenzymes
• Most coenzymes are derived from vitamins
• Therefore the required vitamins must be supplied in the
diet to ensure that these co-enzymes are synthesized
Vitamin Coenzyme Function
Thiamin (vit Thiamine pyrophosphate Decarboxylation
B1) reactions
Riboflavin (Vit • Flavin adenine dinucleotide (FAD) Carriers of

B2) • Flavin mononucleotide (FMN) hydrogen and
electrons
Niacin (vit B3) • Nicotinamide adenine dinucleotide Carriers of
(NAD+) hydrogen and
• Nicotinamide adenine dinucleotide electrons
phosphate (NADP+)
5
Regulation of blood glucose concentration
 Important to regulate blood concentration in order to
 Ensure there is enough to meet energy needs of brain/CNS and
RBCs
 To avoid excess glucose which can cause adverse heath effects
 Normal blood glucose concentration-4.0-5.5mmol/L (72-

99mg/100ml).
 Glucose increases temporarily (up to 7.5mmol/L) on eating
carbohydrate rich meal .
 Hyperglycemia -glucose concentration above 7.5mmol/L
 Hypoglycemia -glucose levels of 3.0mmol/L or lower. This
occurs during fasting, starvation or high intensity exercise.
6
 The liver regulates blood glucose concentration with the
help of two hormones
 insulin secreted from the beta cells of pancrease
 glucagon secreted from alpha cells of pancrease
7
Role of
 Released when blood glucose concentration is higher than
normal
 Role is to lower glucose concentration to normal levels by
 Stimulating cells to take up glucose for use in energy
production (glycolysis)
 Stimulates liver and muscle to convert glucose to glycogen
(glycogenesis)
 Stimulating liver and adipose tissue to convert glucose to fatty
acids and consequently to triglycerides (lipogenesis)
 Inhibits glucose producing pathways e.g. gluconeogenesis and
glycogenolysis
8
Role of
 Released when blood glucose concentration is lower than
normal (e.g. during starvation, fasting, intense exercise)
 Role is to raise glucose concentration to normal levels by
 Stimulating liver to breakdown stored glycogen to glucose
 Stimulates adipose tissue to release fatty acids (from

triglycerides) for energy production
 Stimulates protein breakdown to produce amino acids which
can be converted into glucose through gluconeogenesis
9
Summary- Hormonal regulation of blood glucose concentration
10
 A laboratory test to check how the body metabolizes glucose,

and how quickly it is cleared from the blood.
 It is one of the tools used to diagnose diabetes
 Patient fasts for >5 hrs

 Blood (to determine fasting levels of glucose) and urine
sample taken at zero time (baseline)
 Patient given 75g of glucose dissolved in 200ml of distilled
water
 Blood and urine samples taken every 30 min (after taking
glucose solution) for three hours 11
Glucose tolerance test (GTT)-
 Normal response
 Initial rise in plasma glucose that does not cross renal
threshold.
 Plasma glucose concentration returns to normal within 1-2hrs.
 Abnormal response
i. Diminished/Impaired glucose tolerance
i. Plasma glucose increase more than normal
ii. Fasting glucose level is high.
iii. Delayed return to normal plasma concentration.
iv. Urine shows glycosuria indicating diabetes or potential diabetes.
12
 Abnormal response
ii. Increased glucose tolerance - flat curve type.
 There is little increase in plasma glucose level and
 no glucosuria.
 Could be as a result of
 adrenal or thyroid hormone hypofunction
 Malabsorption of glucose
13
Hypothyroidism
14
SPECIFIC PATHWAYS OF CARBOHYDRATE METABOLISM
Glycogen metabolism
Glycogenesis
• Is formation of glycogen from glucose.
• Depends on demand for glucose and

ATP (energy).
• Insulin promotes conversion of glucose

into glycogen when glucose & ATP are
present in high amounts
• Glycogen is stored in liver and muscle
15
Glycogen metabolism
Glycogenolysis
16
• Isthe pathway for oxidation of glucose into lactic acid or

pyruvate.
• Takes place in cytoplasm in the presence or absence of oxygen
• Under aerobic conditions, glucose is oxidized to pyruvate
(aerobic glycolysis).
• Pyruvate then oxidatively decarboxylated & converted
to Acetyl-CoA (in the mitochondria).
• Acetyl-CoA then enters the tricarboxylic acid (TCA) cycle
where it under goes a series of reactions to produce energy.
• Under anaerobic conditions, e.g. during vigorous exercise,
glucose is oxidized to lactic acid (Anaerobic glycolysis).
17
1
5
6
10
18
• Consists of 10 enzyme catalyzed reactions

• Can be divided into two separate phases
• Chemical priming phase (reaction 1 to 5 ) requiring energy
in the form of ATP.
• Energy-yielding phase (Reaction 6 to 10): Produces 4 ATPs
and 2 NADH
19
Individual reactions of glycolysis
• Catalyzed by hexokinase (EC 2.7.1.1)

• Involves ATP-dependent phosphorylation of glucose to form
glucose 6-phosphate
20
• Phosphorylation has two goals:

• Converts nonionic glucose into an anion that is trapped in
the cell
• The inert glucose becomes activated into a reactive form
capable of being further oxidized.
21
• Catalyzed by Phosphohexose Isomerase/phosphoglucose

isomerase (EC 5.3.1.9)
• Involves isomerization of glucose 6-phosphate to fructose 6-
phosphate (F6P).
• Reaction is reversible and can be used both for glycolysis and
gluconeogenesis.
• This isomerization
makes C-1 of the
fructose available
for phosphorylation
22
• Catalyzed by Phosphofructokinase (EC 2.7.1.11)- which uses of a 2nd

ATP to convert fructose 6-phosphate to fructose 1,6-bisphosphate.
• The reaction is irreversible
• Phosphofructokinase is the rate-limiting enzyme of glycolysis
23
• Catalyzed by fructose bisphosphate aldolase (EC 4.1.2.13)

• Involves cleavage of fructose 1,6-bisphosphate into two 3-carbon
products: dihydroxyacetone phosphate & glyceraldehyde 3-
phosphate.
• Reaction is reversible, can be utilized for both glycolysis and
gluconeogenesis
24
• Triose Phosphate Isomerase (EC 5.3.1.1) catalyzes interconversion

of glyceraldehyde-3-phosphate & dihydroxyacetone phosphate.
• Only glyceraldehyde-3-phosphate continues with glycolysis.
• This reaction permits both products of the aldolase reaction to
continue in the glycolysis
• The last reaction of first phase of glycolysis
25
• Catalyzed by glyceraldehyde-3-Phosphate Dehydrogenase (1.2.1.12)

• Marks beginning of the second phase of glycolysis.
• In this reaction glyceraldehyde-3-Phosphate is oxidized to 1,3-
bisphosphoglycerate by NAD+ which is in turn reduced to NADH
• The reaction is reversible
1,3-bisphosphoglycerate
26
• Catalyzed by phosphoglycerate Kinase (EC 2.7.2.3)
• The high-energy phosphate of 1,3-bisphosphoglycerate is used
to form ATP and 3-phosphoglycerate (3PG)
• Reaction is reversible under normal cell conditions.
• Substrate level phosphorylation- the phosphate group to make
ATP comes from a substrate molecule
• This is the first ATP-generating step of glycolysis.
3-phosphoglycerate 27
• Catalyzed by phosphoglycerate mutase (5.4.2.1)
• The 3-phosphoglycerate is converted to 2-phosphoglycerate
• Its an isomerization reaction
3-phosphoglycerate 2-phosphoglycerate
28
• Catalyzed by enolase (EC 4.2.1.11)
• 2-phosphoglycerate is dehydrated to phosphoenolpyruvate which is
a high energy intermediate
2-phosphoglycerate
29
• Catalyzed by pyruvate kinase (EC 2.7.1.40)
• It’s a highly exergonic reaction, where the high-energy
phosphate of phosphoenolpyruvate is used to produce ATP.
• It’s a Substrate level phosphorylation reaction
• Pyruvate is also produced in this reaction
• Reaction is irreversible.
Phosphoenolpyruvate
30
Products of glycolysis related to energy production

• 2 ATP
• 2 NADH
• 2 pyruvate
Fate of different products of glycolysis

• The ATP can immediately be used by energy requiring
processes
31
• NADH can be used to produce ATP in electron transport chain
• However, cytosolic NADH cannot enter mitochondria (ETC site)
• The electrons of
cytosolic NADH are
taken to ETC by FADH2
through glycerol 3-
phosphate shuttle
32
• Fate of pyruvate from glycolysis depends on the type of

organism, cell type and the availability of oxygen.
• Under aerobic conditions in humans pyruvate is
oxidatively decarboxylated to acetyl-CoA which then
enters the TCA cycle
• The reaction is catalyzed by the pyruvate dehydrogenase
complex
33
• Under anaerobic conditions (without oxygen), pyruvate has 2

fates
1. Lactic acid fermentation
2. Alcoholic fermentation.
34
Lactic acid fermentation

• Under anaerobic conditions (without oxygen) in humans
pyruvate is reduced to lactate in a reaction catalyzed by
lactate dehydrogenase
35
Lactic acid fermentation

• E.g. during intense exercise
• Oxygen in the muscles is depleted.
• Anaerobic conditions are produced.
• Lactic acid accumulates.
• Muscles get tired and become painful.
36
Alcoholic fermentation
• In anaerobic microorganisms such as yeast pyruvate is converted to
ethanol via acetaldehyde
• Enzyme pyruvate decarboxylase converts pyruvate to acetaldehyde
• Alcohol dehydrogenase converts acetaldehyde to ethanol
• The process is used to produce alcoholic beverages.
37
Regulation of glycolysis
• Glycolysis is regulated though controlling the activity of three key
enzymes
• Hexokinase
• Phosphofructokinase
• Pyruvate kinase
1. Hexokinase
• Catalyzes the first irreversible reaction.
• Allosterically inhibited by glucose 6-phosphate.
38
2. Phosphofructokinase
• Is allosterically inhibited by
• ATP
• Citrate
• H+ due to lactic acid accumulation during anaerobic conditions
• Is allosterically activated by
• AMP
• ADP
• Fructose 2,6-bisphosphate
39
3. Pyruvate kinase
• Regulated by both allosteric and covalent modification.
• Allosterically activated by fructose 1,6-bisphosphate (feed forward
stimulation).
• Allosterically inhibited by high ATP concentration
• Inactivated by phosphorylation (covalent modification)
40
GLUCONEOGENESIS (GNG)
• A pathway for synthesis of glucose from non-carbohydrate
carbon substrates, e.g. lactic acid, glycerol, and glucogenic
amino acids.
• Takes place mainly in the liver (90%) and to a smaller extent
in kidney cortex (10%).
• Occurs during periods of fasting, starvation, or intense
exercise and is highly endergonic (requires energy).
• Gluconeogenesis is a target of chemical therapy for type II
diabetes, such as metformin, which inhibit glucose formation
41
GLUCONEOGENESIS
Individual reactions of gluconeogenesis
• GNG consists of eleven enzyme-catalyzed reactions.
• Seven of the reactions are reversible steps of glycolysis.
• can begin in mitochondria or cytoplasm
• In mitochondria, GNG begins with the formation of
oxaloacetate through carboxylation of pyruvate by puruvate
carboxylase (EC 6.4.1.1)
42
GLUCONEOGENESIS
• 1 ATP is used in this reaction and is catalyzed by pyruvate
carboxylase
• Pyruvate carboxylase is
• stimulated by high levels of acetyl-CoA (from fatty acid
oxidation or due to lack of oxaloacetate)
• inhibited by high levels of ADP (indicates need for
energy).
43
GLUCONEOGENESIS
• The other reactions of gluconeogenesis take place in cytoplasm
• However, oxaloacetate can not cross the mitochondrial
membrane to go to cytoplasm
• Oxaloacetate is then reduced into malate by malate
dehydrogenase (EC 1.1.1.37) using NADH in order to be
transported out of the mitochondria.
• Malate is then transported from mitochondria to cytoplasm
• In the cytoplasm, malate is oxidized back to oxaloacetate using
NAD+
44
Oxaloacetate
GLUCONEOGENESIS
• In the cytoplasm, oxaloacetate is decarboxylated and
phosphorylated by phosphoenolpyruvate carboxykinase (EC
4.1.1.49) to produce phosphoenolpyruvate (PEP)
Oxaloacetate phosphoenolpyruvate
• The next 6 reactions are reversible reactions of glycolysis 45

GLUCONEOGENESIS
• In reaction 9 fructose-1,6-bisphosphatase (EC 3.1.3.11)
catalyzes the irreversible hydrolysis of fructose-1,6-
bisphosphate to fructose-6-phosphate.
• Note: intermediates same as in glycolysis but different enzymes
• Reaction 10 is a reversible reaction of glycolysis

• It involves formation of glucose-6-phosphate from fructose-6-
phosphate in a reaction catalyzed by phosphoglucoisomerase
46
GLUCONEOGENESIS
• In reaction 11 glucose 6-phosphate is hydrolyzed by glucose-6-
phosphatase to produce glucose.
• The glucose is then released into the blood and can then be
transported to various tissues for use in energy production
Glucose 6-
phosphatatse
H2O
47
GLUCONEOGENESIS
Regulation of gluconeogenesis
• Most steps in gluconeogenesis are reversible reactions of glycolysis
• However, to prevent occurrence of a futile cycle, some unique
reactions of gluconeogenesis are not found in glycolysis
• The glycolytic enzymes hexokinase/ glucokinase,
phosphofructokinase, & pyruvate kinase are replaced with glucose-
6-phosphatase, Fructose-1,6-bisphosphatase, &
phosphoenolpyruvate carboxykinase respectively in
gluconeogenesis
• When the unique enzymes of gluconeogenesis are activated,
glycolysis is switched off and vice versa.
• This system of control is called reciprocal regulation & it allows
glycolysis & GNG to inhibit each other & prevent the occurenceof a
futile cycle. 48
GLUCONEOGENESIS
• Fructose-1,6-bisphosphatase is the most important enzyme in
regulation of gluconeogenesis
• The enzyme is regulated by signal transduction by cAMP and its
subsequent phosphorylation after release of hormone glucagon
• Glucagon activates the enzyme adenylate cyclase
• Adenylate cyclase converts ATP to 3’-5-cyclic AMP (cAMP).
• cAMP activates cAMP-dependent protein Kinase
• cAMP-dependent Protein Kinase phosphorylates Fructose-1,6-
bisphosphatase
• Phosphorylation of fructose-1,6-bisphosphatase activates this
enzymes and hence gluconeogenesis
49
GLUCONEOGENESIS
• Fructose-1,6-bisphosphatase is the most important enzyme in
regulation of gluconeogenesis
• Fructose-1,6-bisphosphatase is activated through phosphorylation
which is catalyzed by cAMP dependent protein kinase
• Fructose-1,6-bisphosphatase is also activated by acetyl
CoA and citrate
• Acetyl-CoA & citrate inhibit the activity of pyruvate kinase
(glycolysis)
50
THE CITRIC ACID/ TRICARBOXYLIC ACID(TCA)/ KREBS CYCLE
• It is the third step in carbohydrate metabolism.
• Pyruvate from glycolysis travel into the interior of the
mitochondria.
• Pyruvate is are then converted into acetyl- CoA (oxidative
decarboxylation) by the pyruvate dehydrogenase complex
51
THE TCA CYCLE
52
• Conversion of pyruvate to Acetyl-CoA is not part of TCA
cycle but is a step that prepares pyruvate to enter TCA
cycle.
• Metabolism of lipids and proteins can also contribute to
Acetyl-CoA to join TCA cycle
• TCA cycle consists of eight enzyme catalyzed reactions
• The products of one completed TCA cycle are
• 3 NADH
• 1 FADH2
• 1 GTP
• 2CO2 53
• Two acetyl-CoA molecules are produced from each glucose
molecule
• Therefore two TCA cycles are required per glucose molecule.
• At the end of both cycles, the products are:
• 6 NADH
• 2 GTP
• 2 FADH2
• 4 CO2
NADH, FADH2 and GTP important for energy production
54
• NADH and FADH2 are used in the electron transport chain
to produce ATP
• GTP donates a phosphate group to ADP to form ATP
55
Regulation of citric acid cycle
• TCA cycle regulated through
• Product inhibition
• Substrate availability
• Main product involved in regulation is NADH
• Excess NADH inhibits several enzymes including
• Pyruvate dehydrogenase-preparative step
• Isocitrate dehydrogenase- reaction 3
• α-ketoglutarate dehydrogenase- Reaction4
• citrate synthase -reaction 1
56
Regulation of citric acid cycle
• Other regulators of TCA cycle
• Acetyl-CoA inhibits pyruvate dehydrogenase
• Succinyl-CoA inhibits succinyl-CoA synthetase and
citrate synthase.
• Calcium activates pyruvate dehydrogenase, isocitrate
dehydrogenase and α-ketoglutarate dehydrogenase.
• Citrate is used for feedback inhibition, as it inhibits
phosphofructokinase which then inhibits glycolysis.
57
ELECTRON TRANSPORT CHAIN & OXIDATIVE PHOSPHORYLATION
• Oxidative phosphorylation- Synthesis of ATP from ADP and
inorganic phosphate (pi) in the mitochondria catalyzed by
ATP synthase.
• Oxidative phosphorylation is driven by the electron-
transport chain.
• Also the process by which NADH and FADH2 produced by
nutrient oxidation are oxidized with concurrent formation of
ATP.
58
• The electron transport chain (ETC) is located along the inner
mitochondrial membrane
59
• ETC is made of four protein complexes/redox centres
• NADH: Coenzyme Q oxidoreductase,
• Succinate: Coenzyme Q oxidoreductase,
• Coenzyme Q:Cytochrome c Oxidase
• Cytochrome c Oxidase
60
• Electrons generated by oxidation of NADH and FADH2 are
passed through the four protein complexes until they are
accepted by oxygen to form water
• As electrons move from one complex to another, the energy
released is harnessed to synthesize ATP by ATP synthase .
• 1 NADH=3ATP
• 1FADH2=2ATP
61
Summary of ATP produced from complete oxidation of a glucose
molecule
 Glycolysis
 Substrate level phosphorylation (step 7 and 10 ) 2ATP
 2 NADH X 2 ATP/ cytoplasmic NADH 4 ATP
 Preparative step -2 pyruvates 2 Acetyl CoA molecules
 2 NADH x 3 ATP/NADH 6ATP
 Citric acid cycle (2 cycles/glucose molecule)
 2 GTP x1 ATP/GTP 2 ATP
 6 NADH X 3 ATP/NADH 18 ATP
 2 FADH2 X 2 ATP/ FADH2 4 ATP
Total 36 ATP
62
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METABOLISM OF

 This energy is released when glucose is oxidized

 Glucose oxidation involves a series of enzyme catalyzed reactions

Riboflavin (Vit • Flavin adenine dinucleotide (FAD) Carriers of

 Normal blood glucose concentration-4.0-5.5mmol/L (72-

 Stimulates adipose tissue to release fatty acids (from

 A laboratory test to check how the body metabolizes glucose,

 Patient fasts for >5 hrs

• Depends on demand for glucose and

• Insulin promotes conversion of glucose

• Glycogen is stored in liver and muscle

• Isthe pathway for oxidation of glucose into lactic acid or

• Consists of 10 enzyme catalyzed reactions

• Catalyzed by hexokinase (EC 2.7.1.1)

• Phosphorylation has two goals:

• Catalyzed by Phosphohexose Isomerase/phosphoglucose

• Catalyzed by Phosphofructokinase (EC 2.7.1.11)- which uses of a 2nd

• Catalyzed by fructose bisphosphate aldolase (EC 4.1.2.13)

• Triose Phosphate Isomerase (EC 5.3.1.1) catalyzes interconversion

• Catalyzed by glyceraldehyde-3-Phosphate Dehydrogenase (1.2.1.12)

Products of glycolysis related to energy production

Fate of different products of glycolysis

• Fate of pyruvate from glycolysis depends on the type of

• Under anaerobic conditions (without oxygen), pyruvate has 2

Lactic acid fermentation

Lactic acid fermentation

• The next 6 reactions are reversible reactions of glycolysis 45

• Reaction 10 is a reversible reaction of glycolysis

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