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Carbohydrate Metabolism
Carbohydrate Metabolism
Carbohydrate metabolism is a fundamental biochemical process that
ensures a constant supply of energy to living cells. The most important
carbohydrate is glucose, which can be broken down via glycolysis, enter
into the Kreb's cycle and oxidative phosphorylation to generate ATP.
 Oxidative phosphorylation is a combination of two simultaneous
processes; the electron transport chain and chemiosmotic coupling. The
electron transport chain (also known as the respiratory chain) comprises 4
complexes located in the inner mitochondrial membrane. NADH and
FADH2, produced from glycolysis and the Krebs cycle, release electrons at
certain points in the chain, which are passed from one electron acceptor to
the next. Each time an electron is passed from one complex to the next, it
loses energy.
 Chemiosmotic coupling harnesses the energy from the electron transport
chain and uses it to transport H+ across the inner mitochondrial membrane,
establishing a concentration gradient. ATP synthase is found in the inner
mitochondrial membrane and this enzyme uses the energy from H+ ion flux
to synthesize ATP. Three ATP molecules can be made from each pair of
electrons from NADH and two ATP molecules are made from a pair of
electrons from FADH2.
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Further important pathways in carbohydrate metabolism include, pentose
phosphate pathway (conversion of hexose sugars into pentoses)
Glycogenesis (conversion of excess glucose into glycogen, stimulated by
insulin)
Glycogenolysis (conversion of glycogen polymers into glucose, stimulated
by glucagon)
Gluconeogenesis (de novo glucose synthesis). Amino acids and Glycerol
can be used to produce glucose (liver)
More glucose is produced via gluconeogenesis than glycogenolysis.
Glycolysis is the breakdown of glucose into pyruvic acid
There are multiple diseases that arise from improper carbohydrate
metabolism,
Diabetes Mellitusis caused by a lack of, or a resistance to, insulin leading
to hypo- or hyperglycemia.
Lactose intolerance is a common allergy in adults and results from a lack
of the enzyme lactase, which converts lactose disaccharides (found in
dairy products) into glucose monosaccharides.
Much rarer diseases such as galactosemia and von Gierke's diseases are
caused by congenital mutations in enzymes involved in glucose metabolic
pathways.
Metabolism
Anabolism:
 Food supplies raw materials for synthesis reactions.
 Synthesize:
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DNA and RNA.
Proteins.
Triglycerides.
Glycogen.
Catabolism:
 Hydrolysis (break down monomers down to CO2 and H2O):
 Hydrolysis reactions and cellular respiration.
 Gluconeogenesis.
 Glycogenolysis.
 Lipolysis.
Amphibolism: Acts as link between the anabolic and catabolic
pathways. (e. g) TCA Cycle
Balance Between Anabolism and Catabolism
 The rate of deposit
and withdrawal of
energy
substrates,
and the conversion of
1 type of energy
substrate
into
another;
are
regulated
by
hormones.
 Antagonistic effects
of insulin, glucagon,
GH, T3 and cortisol
balance
anabolism
and catabolism.
Insert fig. 19.4
How do we use food components in catabolic and anabolic
pathways?
Involves specific chemical reactions:
- Each reaction is catalyzed by a specific enzyme.
- Other compounds, besides those being directly metabolized, are
required as intermediates or catalysts in metabolic reactions
- adenosine triphosphate (ATP)
- nicotinamide adenine dinucleotide (NAD+)
- flavin adenine dinucleotide (FAD+)
- Coenzyme A
ATP
 ATP is the energy currency of the cell
 The structure of ATP is similar to that of nucleic acids
 The energy in ATP is “carried” in the phosphate groups
- to convert ADP into ATP requires energy
- the energy is stored as potential energy in the phosphate
group bond
- removal of the third phosphate releases that energy
NADH, FADH2
 NAD+ can accept a hydrogen ion and become reduced to NADH:
NAD+ + 2[H+] + 2e-  NADH + H+
 The added hydrogen ion (and electrons) can be carried to and used in
other reactions in the body.
 FAD+ is similarly reduced to FADH2.
 NADH and FADH carry hydrogen ions and electrons to the enzymes
in the electron transport chain of the mitochondria, allowing ATP
production there.
Coenzyme- A
 The enzyme coenzyme A converts acetyl groups (2-carbon
structures) into acetyl CoA, which can then be used in metabolic
reactions
 During the course of acetyl CoA production, energy is released and
is used to convert NAD+ to NADH
Cellular Respiration
 Generating ATP from food requires glycolysis, the Krebs Cycle and
electron transport chain.
 Overall reaction:
C6H12O6 + 6 O2----> 6 CO2 + 6 H2O + 38 ATP + heat
 The Main point: the break down of glucose releases LOTS of
energy:
- about 40% in usable form (ATP)
- about 60% as heat
Glycolysis
 Glycolysis is the breakdown of glucose into pyruvic acid
 Two main steps are involved, occurring in the cytoplasm of cells
(no organelles involved).
The two main steps of glycolysis
Step one:
glucose
glucose 6-phosphate
ATP
ATP
fructose 1,6diphosphate
Step two:
fructose 1,6diphosphate
2 pyruvic acid
2 NADH 2 ATP
2 ATP
What happens to pyruvic acid?
 In aerobic respiration (oxygen present):
- pyruvic acid moves from cytoplasm to mitochondria
- pyruvic acid (3 carbons) is converted to acetyl group (2
carbons), producing CO2 in the process
- acetyl group is converted to acetyl CoA by coenzyme A
- acetyl CoA is used in the Krebs cycle.
Kreb’s Cycle / TCA cycle / Citric acid cycle
 Acetyl CoA combines with oxaloacetic acid, forming citric acid
 A series of reactions then occurs resulting in:
- one ATP produced
- three NADH and one FADH2 produced (go to electron
transport chain)
- two CO2 molecules produced
Electron-transport Chain
 The main point: NADH and FADH2 carry H+ ions to the electrontransport chain, resulting in production of ATP
 To do this, the H+ ions are moved along the transport chain,
eventually accumulating in the outer mitochondrial compartment
 The H+ ions move back into the inner mitochondrial compartment
via hydrogen channels, which are coupled to ATP production.
 At the end of the transport chain, four hydrogen ions join with two
oxygen molecules to form water:
4 H+ + O2 ----> 2 H2O
 In the absence of oxygen, the transport chain stalls (no ATP
production)
Net Result of Glycolysis, Citric Acid Cycle, and Electron Transport
Chain:
 Production of ATP (stored, potential energy for chemical reactions
in the body; 40% of energy released).
 Production of heat (maintains body temperature; 60% of energy
released).
 Also, production of CO2 and H2O.
Storage and Utilization of Glycogen
 Excess glucose can be stored as glycogen.
glucose
glucose
6-phosphate
glucose
1-phosphate
glycogen
 Stored glycogen can be utilized, by glycogenolysis.
 Glycogenolysis:
-glycogen is broken down into glucose 6phosphate
- liver transforms glucose 6-phosphate
glucose, maintaining blood glucose levels
to
Diabetes mellitus is a metabolic condition characterized by an
inability to regulate blood glucose levels. It is caused by either
defects in insulin production and secretion (Type I) or defects in
insulin signaling (Type II)
Type I Diabetes or insulin-dependent or juvenile diabetes
 It is usually due to autoimmune attack of β-islet cells in the pancreas.
It can also be idiopathic and there is increasing evidence of a viral
etiology. The normal function of β-islet cells is to produce insulin in
response to elevated blood glucose, which in turn promotes the
conversion of glucose into glycogen for storage. Destruction of βislet cells prevents insulin production and subsequently manifests as
hyperglycemia.
 Genetic susceptibility genes for type I diabetes have been identified
and include IDDM1, which codes for a MCH II complex that is
displayed on the surface of β-islet cells. Certain polymorphisms of
this gene result in the display of improper antigens on the surface of
β-cells, leading to their targeting for destruction by T-cells.
Type II Diabetes or non-insulin-dependent or obesity-related diabetes
 It is characterized by insulin resistance and a loss of insulin sensitivity.
Insulin levels may be increased (hyperinsulinemia) or decreased
(hypoinsulinemia). Other factors that contribute include decreased activity
of glucose transporters, increased hepatic glucose production and delayed
β-cell sensitivity to hyperglycemia. The etiology of type II diabetes is
unknown, but it is associated with obesity (particularly central obesity),
sedentary lifestyle, high sugar diet, total body irradiation (a cancer
treatment), hypertension and increasing age.
Pharmacological Interventions
 First line treatment for type I diabetes is insulin replacement therapy. Type
II diabetes is initially treated by attempts to maintain glycemic control with
diet modifications. Pharmacological interventions, such as metformin, are
used later. Diabetic complications are prevalent and uncontrolled, so there
is intense interest in developing pharmacological agents that allow better
management of this condition. Novel antidiabetic treatments include
fibroblast growth factor-21 analogs, renal sodium-glucose transporter
inhibitors, free fatty acid receptor ligands, dipeptidyl peptidase IV (DPPIV) inhibitors and more
 Blood glucose
are :
carbohydrate metabolism exist
1. Glycolysis
2. Glycogenesis
3. HMP Shunt
4. Oxidation of Pyruvate
5. Kreb’s Cycle / TCA cycle / Citric acid cycle
6. Change to lipids
 Fasting
blood glucose
carbohydrate
metabolism :
1. Glycogenolysis
2. Gluconeogenesis
GLYCOLYSIS (Total ATP formed is 7)
 Glycolysis
oxidation of glucose
energy
 It can function either aerobically or anaerobically
pyruvate
 Occurs in the cytosol of all cell
 AEROBICALLY GLYCOLYSIS :
Pyruvate
Mitochondria
CoA
Kreb’s Cycle
lactate
oxidized to Acetyl
CO2 + H2O + ATP
Glycolysis
CH2O
C
6
CH2OH
5
H
H
H
Dihydroxyacetone
phosphate
1
H
OH
3
OH
2 NAD+ + 2 P
6
2 NADH + 2H+
CH2O
P
HCOH
ADP
C
O
P
O
OH2C
O
H
H
H
OH
2
Glucose 6-phosphate
HCOH
3-Phosphoglyceric acid
(2 molecules)
COOH
2
ATP
P
CH2O
OH
OH
1, 3-Bisphosphoglyceric acid
(2 molecules)
2 ADP
7
H
OH
P
Glyceraldehyde
3-phosphate
5
Glucose (1 molecule)
1
HO
CH2O
OH
ATP
H
HCOH
2
H
P
O
CH2OH
O
4
HO
H
C O
P
8
P
OH2C
6
O
1
5
H
CH2OH
CH2OH
HCO
2
H
HO
4
Phosphofructokinase
H
3
Fructose 6-phosphate
ATP
OH2C
H
H
4
O
P
COOH
CH2O
HO
OH
CH2
Phosphoenolpyruvic acid
(2 molecules)
2 ADP
O
H
9
C
ADP
P
2-Phosphoglyceric acid
(2 molecules)
COOH
OH
3
OH
P
P
OH
Fructose 1, 6-bisphosphate
10
2
ATP
CH3
C O
COOH
Pyruvic acid
(2 molecules)
OXIDATION OF PYRUVATE
 Occur in mitochondria
 Oxidation of 1 mol Pyruvate
+ 3 mol ATP
1 mol Acetyl-CoA
 CH3COCOOH + HSCoA + NAD+
CH3CO-SCoA + NADH
(Acetyl-CoA)
(Pyruvate)
 Catalyzed by Pyruvate dehydrogenase enzyme
 This enzyme need CoA as coenzyme
 In Thiamin deficiency, oxidation of pyruvate is
impaired
lactic and pyruvic acid
GLYCOGENESIS
 Synthesis of Glycogen from glucose
 Occurs mainly in muscle and liver cell
 The reaction :

Glucose
Glucose-6-P
Hexokinase / Glucokinase
 Glucose-6-P
Glucose-1-P
Phosphoglucomutase
 Glucose-1-P + UTP
UDPG + Pyrophosphate
UDPG Pyrophosphorylase
GLYCOGENESIS
 Glycogen synthase catalyzes the formation of α-
1,4-glucosidic linkage in glycogen
 Branching enzyme catalyzes the formation of α1,6-glucosidic linkage in glycogen
 Finally
the branches grow by further additions
of 1 → 4-glucosyl units and further branching
(like tree!)
GLYCOGENOLYSIS
 The breakdown of glycogen
 Glycogen phosphorylase catalyzes cleavage of the
1→4 linkages of glycogen to yield glucose-1phosphate
 α(1→4)→α(1→4) glucan transferase transfer a
trisaccharides unit from one branch to the other
 Debranching enzyme hydrolysis of the 1→6
linkages
 The combined action of these enzyme leads to
the complete breakdown of glycogen.
GLYCOGENOLYSIS
Phosphoglucomutase
 Glucose-1-P
Glucose-6-P
Glucose-6-phosphatase
 Glucose-6-P
Glucose
 Glucose-6-phosphatase enzyme
a specific
enzyme in liver and kidney, but not in muscle
 Glycogenolysis in liver yielding glucose export to
blood
to increase the blood glucose
concentration
 In muscle
glucose-6-P
glycolysis
Glycogenesis and Glycogenolysis
GLUCONEOGENESIS
 Pathways that responsible for converting
noncarbohydrate precursors to glucose or glycogen
 In mammals
occurs in liver and kidney
 Major substrate :
1. Lactic acid
from muscle, erythrocyte
2. Glycerol
from TG hydrolysis
3.Glucogenic amino acid
 Gluconeogenesis meets the needs of the body for
glucose when carbohydrate is not available from
the diet or from glycogenolysis
 A supply of glucose is necessary especially for
nervous system and erythrocytes.
 The enzymes :
1. Pyruvate carboxylase
2. Phosphoenolpyruvate karboxikinase
3. Fructose 1,6-biphosphatase
4. Glucose-6-phosphatase
HMP SHUNT/HEXOSE MONO PHOSPHATE SHUNT /
PENTOSE PHOSPHATE PATHWAY / Phosphogluconate pathway
 An alternative route for the metabolism of glucose /
glycolysis
 It does not generate ATP but has two major function :
1. The formation of NADPH synthesis of fatty acid
and steroids (Oxidative non-reversible phase)
2. The synthesis of ribose / erythrose
nucleotide
and nucleic acid formation as well as aromatic
aminoacid synthesis (Non-Oxidative reversible phase)
• It’s primary role is anabolic rather than catabolic
• It takes place in the cytosol
HMP SHUNT
 Active in : liver, adipose tissue, adrenal cortex,
thyroid, erythrocytes, testis and lactating
mammary gland
 Its activity is low in muscle
 In erythrocytes :
 HMP Shunt provides NADPH for the reduction of
oxidized glutathione by glutathione reductase
reduced glutathione removes H2O2
glutathione peroxidase
HMP SHUNT
Glutathione reductase
 G-S-S-G
2-G-SH
(oxidized glutathione)
(reduced glutathione)
Glutathione peroxidase
 2-G-SH + H2O2
G-S-S-G + 2H2O
 This reaction is important
accumulation of
H2O2 may decrease the life span of the erythrocyte
damage to the membrane cell
hemolysis
HMP SHUNT
Regulation of HMP shunt pathway
Glucose 6-phosphate DH is the regulatory enzyme.
NADPH is a potent competitive inhibitor of the enzyme.
Usually the ratio NADPH/NADP+ is high so the enzyme is inhibited.
But, with increased demand for NADPH, the ratio decreases and
enzyme activity is stimulated.
The reactions of the non-oxidative portion of the pentose pathway are
readily reversible.
The concentrations of the products and reactants can shift depending
on the metabolic needs of a particular cell or tissue.
Increase in ATP: a putative inhibitor of these steps
BLOOD GLUCOSE
 Blood glucose is derived from the :
1. Diet the digestible dietary carbohydrate yield
glucose blood
2. Gluconeogenesis
3. Glycogenolysis in liver
 Insulin play a central role in regulating blood
glucose
blood glucose
 Glucagon
blood glucose
 Growth hormone inhibit insulin activity
 Epinephrine
stress
blood glucose
The Krebs cycle (Total ATP formed is 34)
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Also known as citric acid cycle TCA cycle
Occurs in matrix of mitochondria
Series of redox reactions
2 decarboxylation reactions release CO2
Reduced coenzymes (NADH and FADH2) are the most
important outcome
One molecule of ATP generated by substrate-level
phosphorylation
Final pathway for the oxidation of carbohydrtaes.
The Krebs Cycle
CO2
CH3
CoA
C O
COOH
C O
CH3
NADH + H+
+
Pyruvic NAD
acid
Acetyl
coenzyme A
To electron
transport chain
Oxaloacetic acid
NADH + H+
CH2
COOH
NAD+
COOH
HCOH
To electron
transport
chain
H2C COOH
HOC COOH
1
H2O
H2C COOH Citric acid
8
CH2
COOH
Malic acid
H2O
Fumaric acid
CoA
COOH
C O
2
7
H2C COOH
COOH
CH
HC
HC COOH
COOH
FADH2
HOC COOH
KREBS
CYCLE
H Isocitric acid
3
6
FAD
NAD+
H2C COOH
CO2
H2C COOH CoA
Succinic acid
GTP
H2C COOH
GDP
ADP
NADH + H+
5
CO2
CH2
O C S CoA
ATP
Succinyl CoA
H2C COOH
HCH
4
O C COOH
Alpha-ketoglutaric acid
NAD+
NADH + H+
To electron
transport chain
Enzymes and Energetics in TCA Cycle
1. Citrate synthase
2. Aconitase
3. Isocitrate dehydrogenase
4. α-Ketoglutarate dehydrogenase
5. Succinate thiokinase
6. Succinate dehydrogenase
7. Fumarase
8. Malate dehydrogenase
In TCA cycle, 4 mol. of NADH (approx. equal to 2.5 ATP) and 1 mol. of
FADH2 (approx. equal to 1.5 ATP) are produced / each mol. of acetylCoA catabolized in one turn of the cycle.
In addition, 2 ATP is formed by substrate level phosphorylation catalyzed by
succinate thiokinase.
Glyoxylate Pathway
The glyoxylate cycle, a variation of the TCA cycle, is an anabolic
pathway occurring in plants, bacteria and fungi.
In microorganisms, the glyoxylate cycle allows cells to utilize simple
carbon compounds as a carbon source when complex sources such
as glucose are not available.
The glyoxylate cycle utilizes three of the five enzymes associated
with the TCA cycle and shares many of its intermediate steps. The
two cycles vary when, in the glyoxylate cycle, IsoCitrateLyase
enzyme converts isocitrate into glyoxylate and succinate instead of
α-ketoglutarate as seen in the TCA cycle.
The glyoxylate cycle then continues on, using glyoxylate and acetylCoA to produce malate.
Glyoxylate Pathway
Electron transport chain
Electron transport chain
4.
Series of electron carriers in inner mitochondrial
membrane reduced and oxidized
As electrons pass through chain, exergonic reactions
release energy used to form ATP

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

Chemiosmosis
Final electron acceptor is oxygen to form water
Chemiosmosis
 Carriers act as proton pumps to expel H+ from
mitochondrial matrix
 Creates H+ electrochemical gradient – concentration
gradient and electrical gradient
 Gradient has potential energy – proton motive force
 As H+ flows back into matrix through membrane, generates
ATP using ATP synthase
Summary of cellular respiration
Uronic acid Pathway of Glucose
Importance in humans:
 Provides UDP-glucuronic acid for conjugation [conjugation of
bilirubin, steroids etc] and synthesis of glycosaminoglycans.
 In lower animals (not in primates- deficiency of enzyme L-
gulonolactone oxidase), this pathway leads to synthesis of Vit C.
 Essential Pentosuria: one of Garrod’s tetrad [alkaptonuria,
albinism, pentosuria, cystinuria- inborn error of metabolism]:
*1 in 2500 births due to deficiency of xylitol dehydrogenase →
L-xylulose excreted in urine gives + benedict’s test-not harmful.
*Diffentiated from DM by + Bials test [orcinol in HCL-Bial’s
reagent]
by pentose sugars.
URONIC ACID PATHWAY
G-6-P
Phosphoglucomutase
G-1-P
+ UTP [UDPG Phosphorylase]
UDP- Glucose
enters Uronic acid pathway
Aldose reductase- Glucose to Sorbitol [glucitol]:
Lens, retina, Schwann cell of peripheral nerves, kidney, placenta,
RBC, cells of ovaries and seminal vesicles.
Sorbitol dehydrogenase- Sorbitol to Fructose
Glucoe to Sorbitol to Fructose: in seminal vesicles for sperm cell
[fructose is preferred carbohydrate energy source]
Hyperglycemia: Uncontrolled DM-large amt Glucose enters
Lens, Retina,Nerve, Kidney – with action of aldose reductase
→↑Sorbitol, cannot pass through cell memb, so trapped inside
cell.
Sorbitol dehydrogenase is absent in Lens, retina, kidney and
nerve cell →↑sorbitol accumulates →Osmotic effects →cell
swelling and water retention:
cause of cataract formation, peripheral neuropathy, vascular
problems leading to nephropathy and retinopathy