METABOLISM

Thousands of chemical reactions are taking place inside a cell in an organized, well coordinated
and purposeful manner; all these reactions are collectively called as METABOLISM

Types of metabolic pathway

Catabolic pathway è Energy rich complex macromolecules are degraded into smaller
molecules. Energy is released during this process is trapped as ATP.

Anabolic pathway è The cells synthesize complex molecules from simple precursors. It requires
energy

Amphibolic pathway è In this pathway catabolism & anabolism are linked.

Stages of metabolism

Primary metabolism è Macromolecules are converted into smaller one by digestion

Secondary metabolism è Smaller components are absorbed & catabolized & oxidized to CO2 &
reducing equivalents 9NADH / FADH2)

Tertiary metabolism è These reduced equivalents enter into ETC & converted into ATP.

CARBOHYDRATE METABOLISM

Major source of energy for living cells

Digestion of Carbohydrates

Diet contain Polysaccharides & disaccharides

In duodenum Maltose, Iomaltose, dextrin,

(Pancreatic Amylase) Branched & unbranched oligosaccharides

Enzymes in brush border of intestine Monosaccharides

(Sucrase, Maltase, Isomaltase, Lactase)

Absorbed into intestinal cells

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Absorption of Glucose

By specific transmembrane proteins called

Glucose Transporters

Transporters Present in Properties

GluT1 RBC, brain, kidney, colon, retina, Transport glucose in most of cells
Placenta
GluT2 Serosal surface of intestinal cells, liver, Non rate limiting glucose
beta cells of pancrease transporters
GluT3 Neurons, brain Transport glucose into brain cells

GluT4 Skeletal, heart muscle, adipose tissue Insulin mediated glucose

transporter
GluT5 Small intestine, testis, sperms, kidney Transport fructose

GluT7 Liver endoplasmic reticulam Glucose from ER to cytoplasm

SGluT Intestine, kidney Transport glucose from lumen into

intestinal cell

Absorption of Glucose

Transport from Lumen to Intestinal cell by

SGluT 1 à Sodium dependent cotransport mechanism

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Transport from intestinal cell to Blood by

GluT 2 à Uniport, facilitated diffusion

Transport via GluT 2

Uniport, facilitated diffusion.

Glucose binds to the transporter on the one side of the membrane, which causes
change of configuration of the transporter. This leads to closure of first binding site. At the same time,
the binding site is now exposed on the inner side of this membrane & releasing the glucose.

The process is called PING-PONG mechanism.

Transport via GluT 4

Insulin mediated glucose transporter. Major glucose transporter in Skeletal muscle & Adipose
tissue

Clinical application

In Type 2 Diabetes mellitus, due to insulin resistance in muscle & fat cells, membrane GluT4 is
reduced. So in diabetes entry of glucose in muscle is only half of the normal cells

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MAJOR PATHWAY OF CARBOHYDRATE METABOLISM

1. GLYCOLYSIS è Oxidation of glucose to pyruvate & lactate

2. CITRIC ACID CYCLE è Oxidation of Acetyl CoA to CO2

3. GLUCONEOGENESIS è Synthesis of glucose from non carbohydrate precursors

4. GLYCOGENESIS è Formation of Glycogen from Glucose

5. GLYCOGENOLYSIS è The breakdown of Glycogen to Glucose

6. HEXOSE MONOPHOSPHATE SHUNT è Oxidation of glucose to Co2 & H2O

7. URONIC ACID PAHWAY è Oxidation of glucose to glucuronicacid & Pentoses

8. GALACTOSE METABOLISM è Conversion of galactose to Glucose

9. FRUCTOSE METABOLISM è Oxidation of fructose topyruvate

10. AMINO SUGAR & MUCOPOLYSACCHARIDE METABOLISM è Synthesis of amino sugars and
other sugars for the formation of mucopolysaccharides & glycoproteins.

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GLYCOLYSIS

( EMBDEN – MEYERHOF PATHWAY)

DEFINITION

Oxidation of glucose to pyruvate (aerobic condition) or lactate (Anaerobic condition) with the
production of ATP.

SITE OF METABOLISM

Cytoplasm

PHASES OF GLYCOLYSIS

Energy investment phase (1, 2, 3)

Splitting phase (4)

Energy generation phase (5 – 9)

SIGNIFICANCE OF GLYCOLYSIS

1. Only pathway that is taking place in all cells

2. Only source of energy in erythrocytes & Brain

3. During strenuous exercise, Anaerobic glycolysis is the major source of energy for muscles

4. This pathway is the preliminary step for complete oxidation of food stuffs

5. It provides carbon skeleton for synthesis of non essential aminoacids & glycerol part of fat

6. Most of the reactions of the glycolytic pathway are reversible, which are also used for
gluconeogenesis.

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In Anaerobic Glycolysis , Total No of ATPs formed are = 2

In Aerobic Glycolysis, Total No of ATPs formed are = 7

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FATE OF PYRUVATE

I N AEROBIC CONDITION

IN ANAEROBIC CONDITION

SUMMARY OF GLYCOLYSIS

1st , 3rd , & 9th steps are IRREVERSIBLE

Enzymes involved in those reactions are called key regulatory enzymes

5th , 6th , & 9th steps are ENERGY PRODUCING STEPS

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SIGNIFICANCE OF LACTATE PRODUCTION

The availability of coenzymes inside a cell is limited. For 5th step 2 molecules of NAD are
required. In aerobic conditions, NADH is converted into NAD by oxidative phosphorylation. But during
exercise, there is lack of oxygen. So this reconversion is not possible.

For smooth operation of this pathway, regeneration of the NAD is essential in cytoplasm itself.
Hence pyruvate is reduced to lactate by Lactate dehydrogenase.

In RBC, there are no mitochondria. So end product of glucose is lactate in RBC.

LACTIC ACID CYCLE / CORI’S CYCLE

It is a process in which glucose is converted to lactate in the muscle; and in the liver this lactate
is reconverted into glucose.

During active exercise, excessive lactate is produced. Accumalation of these lactate cause
muscle cramps. To prevent this lactate accumalation body utilizes Cori’s cycle.

SIGNIFICANCE OF CORI’S CYCLE

Lactate is efficiently reutilized

Glucose formation from the lactate is energy consuming process, which cause increased
metabolism. This lead to increased oxygen consumption. This is the cause for oxygen dept after vigorous
exercise

PASTEUR EFFECT

Inhibition of glycolysis by Oxygen is known as PASTEUR EFFECT. It is due to inhibitory effect of

citrate & ATP on Phosphofructokinase.

WARBURG HYPOTHESIS

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 Cancer cells utilize energy from glycolysis & if cancer cells grow very fast, the blood vessels are
unable to supply adequate oxygen. So hypoxia exists. So lactic acid production is increased. This lactic
acid is utilized for gluconeogenesis, which is energy consuming process, which cause Cancer Cachexia.

RAPAPORT – LEUBERING CYCLE

Supplementary pathway to glycolysis, operated in Erythrocytes.

In RBC, 1,3 bisphosphoglycerate is converted into 2,3 bisphosphoglycerate by 2,3

bisphosphoglycerate mutase.

SIGNIFICANCE OF 2,3 –BPG

2,3-BPG combines with haemoglobin & reduces the affinity towards oxygen. So oxygen can
unload easily into the tissues.

In hypoxic conditions the 2,3-BPG concentration in RBCs increase, thus favoring the release of
Oxygen to the tissues even in low PO2

No ATP is generated in this pathway

CITRIC ACID CYCLE /TRICARBOXYLIC ACID CYCLE /KREBS CYCLE

TCA CYCLE

Final common oxidative pathway of food stuffs

Oxidizes acetyl CoA to CO2 & H2O

Source of Reduced Coenzymes (NADH, FADH2)

Acts as link between Anabolic & catabolic pathway

SITE OF TCA CYCLE

MITOCHONDRIAL MATRIX

TCA CYCLE – AN OVER VIEW

2 carbon Acetyl CoA combines with 4 Carbon Oxaloacetate to produce 6 carbon Tricarboxylic
acid (Citrate)

2 carbons are oxidized to CO2

Oxaloacetate is regenerated & recycled

So Oxaloacetate is play a catalytic role in TCA cycle

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 2.5

1.5
ETC

2.5
2.5
1 4

Total ATP synthesis in TCA cycle è 10 ATPs.

SIGNIFICANCE OF TCA CYCLE

1. Acetyl CoA is completely oxidized during one cycle

2. 10 ATPs are generated

2. Final common oxidative pathway of all food stuffs

4. Integration of major metabolic pathways

5. Fat is burned on the wick of carbohydrates

6. Excess carbohydrates are converted as neutral fat

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 7. No net synthesis of carbohydrates from fats

8. Carbon skeletons of aminoacids finally enter into this cycle

9. Amphibolic pathway

10. Anaplerotic role

AMPHIBOLIC PATHWAY

Glycolysis & Betaoxidation of fats are catabolic pathway,

Glycogen synthesis, fatty acid synthesis, cholesterol synthesis are Anabolic pathway. But TCA cycle is
truly Amphibolic pathway ( Both Catabolic & Anabolic ) in nature. There is continuous influx & efflux of 4
carbon units from the TCA cycle.

ANAPLEROTIC ROLE OF TCA CYCLE

TCA cycle acts as sources of precursor of biosynthetic pathways. Eg :- Heme is synthesized

from succinyl coA & Aspartate is synthesized from oxaloacetate. To counterbalance such losses & to
keep the concentrations of the 4 carbon units in the cell ,anaplerotic reactions are essential. Anaplerotic
reactions are filling up reactions, which supply 4-carbon units to the TCA cycle. This is called anaplerotic
role of TCA cycle.

Important Anaplerotic reactions

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 Pyruvate à Oxaloacetate (Pyruvate carboxylase)

Glutamate à α-Keto glutarate (Transaminases)

Aspartate à Oxaloacetate (Transaminases)

Pyruvate à Malate (Malic enzyme)

ENERGETICS

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 GLUCONEOGENESIS
DEFINITION

It is a process by which glucose molecules are produced from non carbohydrate precursors.

Several enzymes of glycolysis involved in gluconeogenesis, But Gluconeogenesis is not reversal

of glycolysis.

SITE OF GLUCONEOGENESIS

Mainly in LIVER

Lesser extent in KIDNEY

Pathway è Partly Mitochondrial & Partly Cytoplasmic

SUBSTRATES FOR GLUCONEOGENESIS

[Link]

[Link] aminoacids (Alanine, glutamic acid, Aspartic acid)

[Link]

[Link] CoA

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14
KEY GLUCONEOGENIC ENZYMES

1. Pyruvate carboxylase

2. Phosphoenol Pyruvate

3. Fructose 1-6 bisphosphatase

4. Glucose-6-Phosphatase

SIGNIFICANCE OF GLUCONEOGENESIS

Only liver can replenish blood glucose through gluconeogenesis, because glucose-6-phosphatase
is present mainly in liver

During starvation, gluconeogenesis maintains the blood glucose level. The stored glycogen is
depleted within first 12 – 18 hours of the fasting.

ENERGY REQUIREMENT OF GLUCONEOGENESIS

2xPyruvate à 2xoxaloacetate è -2 ATPs

2x Oxaloacetate à 2xphosphoenol pyruvate è -2 ATPs

2x3 Phosphoglycerate à 2x1,3 bisphosphoglycerate è -2ATPs

Total è -6 ATPs

6ATPs are utilized for one Glucose molecule synthesis

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GLYCOGEN METABOLISM

• GLYCOGENESIS è SYNTHESIS OF GLYCOGEN

• GLYCOGENOLYSIS è DEGRADATION OF GLYCOGEN

GLYCOGENESIS
DEFINITION è Biosynthesis of glycogen from glucose

SITE è Liver & Muscles (major)

Brain & Kidney (Minor extent)

SITE OF REACTIONS è Cytoplasm

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GLYCOGEN / GLYCOGEN PRIMER

The primer is made up of a protein carbohydrate complex. It is a dimeric protein, having a two
identical monomers. An oligosaccharide chain of 7 glucose units is added to each monomer.

Branching Enzyme

Glycogen synthase add glucose units only in alpha 1,4 linkages. To create alpha 1,6 linkage,
Branching enzyme is required.

When the chain is lengthened to 11 – 12 glucose residues, the branching enzyme will transfer a
block of 6 – 8 glucose residues from this chain to another site on the growing molecule. The branching
enzyme forms this alpha 1,6 linkages.

To this newly created branch, further glucose units can be added in alpha 1,4 linkage by
glycogen synthase.

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GLYCOGENOLYSIS è breakdown of glycogen
Storage form of carbohydrates in the human body.

Stored in the muscle & Liver

Major function of liver glycogen is to provide glucose during fasting. (10gram/100gram of Liver
tissue)

Glycogen content in skeletal muscle is 1 – 2 gr/100gr

SITE OF GLYCOGENOLYSIS è Cytoplasm

REACTIONS

Glycogen phosphorylase removes glucose as glucose-1-phosphate from glycogen. This enzyme

contains PLP (Pyridoxal phosphate) as prosthetic group. It removes one unit at one time. It sequentially
hydrolyses alpha 1,4 glycosidic linkage, till it reaches 3 – 4 glucose residue away from branch point.

Then a block of 3 glucose residues (trisaccharide unit) are transferred from the branching point
to another branch by the Transferase enzyme

Now branch point is free. So α-1,6 glucosidase hydrolyses the α-1,6 linkage at the branch point
& release the free glucose. Ratio of Glu-1-Phosphate to free glucose is 8:1.

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 GLYCOGENOLYSIS

Phosphorylase
r
Glu-1-Phosphate in live Glucose
y
Phospho gluco Mutase Onl
Glycolysis
Glu -6-phosphate
Muscle 2 ATPs
GLYCOLYSIS 3 ATPs

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 GLYCOGEN STORAGE DISORDERS

TYPE ENZYME DEFECT ORGANS SYMPTOMS

INVOLVED

I – Von Glucose 6 Liver, Kidney, Glycogen accumulates in hepatocytes

gierke’s phosphatase Intestine & renal cells. Enlarge liver & kidney.
disease Fasting hypoglycemia, lactic acidemia,
hyperlipidemia, ketosis, gouty arthritis.
II – Pompe’s Lysosomal α-1,4 All organs Glycogen accumulates in lysosome of
disease glucosidase all cell cause enlarged liver & heart.
Death due to heart failure. Affection of
nervous system
III- Cori’s Amylo α-1,6 Liver, muscle, Branched chain glycogen accumulates,
disease glucosidase heart, leucocytes liver enlargement. Symptoms like
vongierke’s disease, but in milder form.
IV – Glucosyl 4,6 Most tissues Glycogen with only few branches
Anderson’s transferase accumulates. Cirrhosis of liver &
disease impairment of liver function.

V – McArdle’s Muscle glycogen Skeletal muscle Muscle glycogen stores very high.
disease phosphorylase Not available during exercise, so
persons cannot do strenous
exercise. So suffer from muscle
cramps, & muscle may get
damaged due to inadequate
energy supply. Blood lactate &
pyruvate level is normal
VI –Her’s Liver glycogen Liver Liver glycogen cannot form
disease phosphorylase glucose. Hepatomegaly, mild
hypoglycemia, ketosis seen.

Vii- Tarui’s Phosphofructokinase Skeletal muscles, Muscle cramps, hemolysis occur.

disease erythrocytes

VIII, IX, X & XI have been identified. They are due to deficient in liver phosphorylase enzyme

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