carbohydrate metabolism

1. BioCHEMISTRY
b.Pharma 2nd semester unit-2nd
Carbohydrate Metabolism
Mr. Bulet Kumar Gupta
Assistant Professor
Sai College of Pharmacy, Mau

2. Krebs Cycle
Introduction
The Krebs cycle or TCA cycle (tricarboxylic acid cycle) or Citric acid
cycle is a series of enzyme catalysed reactions occurring in the
mitochondrial matrix, where acetyl-CoA is oxidised to form carbon
dioxide and coenzymes are reduced, which generate ATP in the electron
transport chain.
Krebs Cycle is a part of Cellular Respiration
Cellular respiration is a four-stage process. In the process, glucose is
oxidised to carbon dioxide and oxygen is reduced to water. The energy
released in the process is stored in the form of ATPs.
36 to 38 ATPs are formed from each glucose molecule.

3. The four stages are:
1) Glycolysis
2) Formation of Acetyl Co-A
Note-This is linked reaction because it links Glycolysis with Krebs
cycle.
3) Krebs cycle
4) Electron Transport Chain (ETC)

5. Krebs Cycle Steps
It is an eight-step process. Krebs cycle or TCA cycle takes place in the
matrix of mitochondria under aerobic condition.
Step 1: The first step is the condensation of acetyl CoA with 4-carbon
compound oxaloacetate to form 6C citrate, coenzyme A is released. The
reaction is catalysed by citrate synthase.
Step 2: Citrate is converted to its isomer, isocitrate. The
enzyme aconitase catalyses this reaction.
Step 3: Isocitrate undergoes dehydrogenation and decarboxylation to
form 5C 𝝰-ketoglutarate. A molecular form of CO2 is released. Isocitrate
dehydrogenase catalyses the reaction. It is an NAD+ dependent enzyme.
NAD+ is converted to NADH.

6. Step 4: 𝝰-ketoglutarate undergoes oxidative decarboxylation to form
succinyl CoA, a 4C compound. The reaction is catalyzed by the 𝝰-
ketoglutarate dehydrogenase enzyme complex. One molecule of CO2 is
released and NAD+ is converted to NADH.
Step 5: Succinyl CoA forms succinate. The enzyme succinyl CoA
synthetase catalyses the reaction. This is coupled with substrate-level
phosphorylation of GDP to get GTP. GTP transfers its phosphate to ADP
forming ATP.
Step 6: Succinate is oxidised by the enzyme succinate dehydrogenase to
fumarate. In the process, FAD is converted to FADH2.
Step 7: Fumarate gets converted to malate by the addition of one H2O.
The enzyme catalysing this reaction is fumarase.

7. Step 8: Malate is dehydrogenated to form oxaloacetate, which combines
with another molecule of acetyl CoA and starts the new cycle.
Hydrogens removed, get transferred to NAD+ forming NADH. Malate
dehydrogenase catalyses the reaction.
Location: Krebs cycle occurs in the mitochondrial matrix.
Note that 2 molecules of Acetyl Co-A are produced from oxidative
Decarboxylation of 2 Pyruvates so two cycles are required per glucose
molecule.
To summarize, for complete oxidation of a glucose molecule, Krebs
cycle yields 4 CO2, 6NADH, 2 FADH2 and 2 ATPs.

8. Significance of Krebs Cycle
1) Krebs cycle or Citric acid cycle is the final pathway of oxidation of glucose, fats
and amino acids
2) Many animals are dependent on nutrients other than glucose as an energy source.
3) Amino acids (metabolic product of proteins) are deaminated and get converted to
pyruvate and other intermediates of the Krebs cycle.
4) Fatty acids undergo 𝞫-oxidation to form acetyl CoA, which enters the Krebs cycle.
5) It is the major source of ATP production in the cells.
6) It plays an important role in gluconeogenesis and lipogenesis and interconversion
of amino acids
7) Many intermediate compounds are used in the synthesis of amino acids &
nucleotides.
8) The genetic defects of the Krebs cycle enzymes are associated with neural damage.

9. Energetic of Aerobic Respiration
Glycolysis Produced -------- 8 ATP
Oxidation of Pyruvic Acid -------- 6 ATP
Krebs Cycle -------- 24 ATP
Total -------- 38 ATP
Note-
1 FADH (Flavin adenine dinucleotide) =2 ATP
1 NADP (Nicotinamide adenine dinucleotide) = 3 ATP

10. GLUCONEOGENESIS
The synthesis of glucose from non-carbohydrate compounds is known as
Gluconeogenesis.
The major substrates/precursors for Gluconeogenesis are lactate, Pyruvate, Glucogenic
amino acids, propionate and glycerol.
Location of Gluconeogenesis- Gluconeogenesis occurs mainly in the Cytosol
Gluconeogenesis works in the opposite direction of glycolysis, which creates glucose
from pyruvate, lactate, and glucogenic amino acids.
It’s also known as Neoglucogenesis. It’s a universal pathway found in humans,
animals, plants, fungus, and other living species.
Gluconeogenesis Functions
Human systems create glucose to keep blood sugar levels in check.
Because cells use glucose to create the energy component adenosine triphosphate, blood
glucose levels must be maintained (ATP).

11. When a person hasn’t eaten in a while, such as during a starvation,
gluconeogenesis takes place.

12. Importance of Gluconeogenesis
1) During deprivation, the gluconeogenesis cycle is important for blood
glucose regulation.
2) Many cells and tissues, including RBCs, neurons, skeletal muscle,
the medulla of the kidney, and embryonic tissue, rely on glucose to
meet their energy needs.
3) The Neoglucogenesis cycle removes metabolites such as lactate
(produced by muscles and RBCs) and glycerol from the bloodstream
(produced from adipose tissue).

13. Glycogen Metabolism
Glycogenolysis is a metabolic process that converts glycogen from the
muscles and liver to its monosaccharide form, glucose.
Animals store glucose as glycogen, which is broken down in a process
called Glycogenolysis.
Glycogen is a glucose polysaccharide stored in the muscles and liver.
The body utilises this to produce ATP (adenosine triphosphate), an
organic substance that provides energy to drive various activities in
living cells.
Low levels of ATP within live cells trigger the glycogenolysis process.
When the cells detect a low level of ATP, the liver and muscles liberate
glycogen and break it down into glucose or simple sugar.

14. Which are then used to produce ATP.
Location
Glycogenolysis occurs in the cytoplasm of cells in the liver, muscles, and
adipose tissue.
The liver breaks down the glycogen to maintain the glucose level in the
blood. The muscle cells break down the glycogen to conserve the energy
required for the contraction of muscles.

15. Functions and Significance
1) The liver and muscle tissue cells undergo glycogenolysis in response
to neurological and hormonal impulses. Glycogenolysis, in particular,
is crucial for controlling blood glucose levels and the fight-or-flight
response.
2) Glycogen breakdown in the muscle cells (myocytes) serves as an
instant resource of glucose-6-phosphate for the process of glycolysis,
which produces energy for muscle contraction.
3) The process of glycogenolysis differs in liver cells or hepatocytes.
The liver does not immediately utilize the glucose that is created
during glycogenolysis in the liver.
4) Glycogen is a form of energy storage in animals similar to starch.

16. Glycogen storage disease (GSD)
Glycogen storage disease (GSD) is a rare metabolic disorder where the
body is not able to properly store or break down glycogen, a form of
sugar or glucose.
GSD affects the liver, muscles and other areas of the body, depending on
the specific type.
Children with GSD are missing one of the several enzymes that break
down glycogen, and glycogen can build up in the liver, causing problems
in the liver, muscles or other parts of the body.
When the enzyme deficiency affects the liver, it leads to low blood
glucose levels (also called Hypoglycemia) during periods of fasting.
GSD is hereditary, meaning it is passed down from parents to children.

19. The most common types of GSD include:-
1. Glycogen storage disease type I (GSD I), also known as Von
Gierke disease, accounts for about 25 percent of all children with
GSD. Symptoms typically appear when an infant is 3 to 4 months of
age and may include hypoglycemia (low blood sugar, which can
cause fatigue, constant hunger.
The liver and sometimes the kidneys swell due to built-up glycogen.
1. Glycogen storage disease type III (GSD III), also known as Cori
disease or Forbes disease, causes glycogen to build up in the liver
and muscles. Symptoms typically appear within the first year of life.
Children with this type of GSD may have a swollen belly, delayed
growth, and weak muscles.

20. 3. Glycogen storage disease type IV (GSD IV), also known as
Andersen disease, is one of the most serious types of GSD.
Symptoms typically appear in a child’s first month of life and include
failure to gain weight or grow at an expected rate.
This type of GSD often leads to cirrhosis of the liver and can affect
the heart and other organs as well.

21. Hexose Monophosphate (HMP) Shunt
The Hexose Monophosphate (HMP) shunt, also known as the pentose
phosphate pathway or Phosphogluconate pathway, is a metabolic
pathway that runs parallel to Glycolysis.
This pathway produces NADPH and intermediates required for the
synthesis of nucleic acids and amino acids.
Features of the HMP Shunt
•It is an anabolic pathway that takes place in the cytosol for most
organisms.
•The pathway takes place in two distinct phases: oxidative and non-
oxidative phases.
•The reactions of this pathway are enzyme catalysed.

22. •The products obtained from the pathway include NADPH, which is
used in biosynthesis in cells, ribose-5-phosphate, which is used in the
synthesis of nucleic acid and nucleotides, and erythrose-4-phosphate,
which is used for the synthesis of aromatic amino acids.
•The HMP shunt is a tightly controlled metabolic pathway that is
connected with other pathways, such as glycolysis and Gluconeogenesis,
depending upon the metabolic needs of the body.
•The pathway takes place in two distinct phases: oxidative and non-
oxidative phases.

23. Phases of the HMP Shunt
Oxidative Phase
In this phase, NADPH is produced by the reduction of two molecules of
NADP+. The energy for this production is utilised by the conversion of
glucose-6-phosphate to ribulose-5-phosphate. The three steps of the
oxidative phase of the HMP shunt are:
Non-Oxidative Phase
The non-oxidative phase can be summarised in five steps:

25. Significance of HMP Shunt
The HMP shunt pathway is significant because it provides NADPH and
important intermediated products for the synthesis of biomolecules.
Some of the points of significance are:
NADPH performs several functions in the body, such as:
It takes part in the synthesis of steroids and fatty acids.
It is an important component within phagolysosomes in the immune
response.
Glutathione is reduced by NADPH in the presence of glutathione
reductase.
The glyceraldehyde 3-phosphate and fructose 6-phosphate produced in
the pathway are intermediates for glycolysis and gluconeogenesis.

26. Clinical Significance of HMP Shunt
Deficiency of Glucose-6-Phosphate Dehydrogenase: The deficiency of
this enzyme which is required in the initial steps for the production of
NADPH, affects the red blood cells.
Conversely, this deficiency can provide resistance to the malarial
parasite Plasmodium falciparum. This is possible because the cell
membranes of the RBCs are weakened, and the parasite cannot
continue its life cycle.
Diagnosis of Thiamine Deficiency: It is diagnosed by administering
thiamine to suspected patients and observing the activity of
transketolase enzymes in the RBCs. If the enzyme shows high activity,
the deficiency of thiamine (vitamin B1) is confirmed.

27. Hormonal regulation of blood glucose level and Diabetes mellitus.
Diabetes mellitus is a disorder related to carbohydrate metabolism
caused due to deficient secretion or utilization of insulin and is
characterized by many symptoms collectively called Syndrome X.
The pancreas secretes insulin and glucagon. Both hormones work in
balance to play a vital role in regulating blood sugar levels. If the level of
one hormone is higher or lower than the ideal range, blood sugar levels
may spike or drop.
The secreted insulin then activates the enzyme glycogen synthase which
proceeds to form Glycogen, the polymer of glucose -------> Blood
Glucose level falls.

29. •Once blood glucose levels start following the Alpha cells of islets of
Langerhans of Pancreas start secreting the “Glucagon” which has
inhibitory effect on glycogenesis and also causes breakdown of the
Glycogen (Glycogenolysis) stored in liver hence increasing the blood
sugar levels.
•Delta cells of islets of Langerhans of Pancreas secrete “Somatostatin”
which is a local hormone and controls secretion of other hormones of
Pancreas.
•Together, insulin and glucagon help maintain a state called homeostasis
in which conditions inside the body remain steady. When blood sugar is
too high, the pancreas secretes more insulin. When blood sugar levels
drop, the pancreas releases glucagon to raise them.

30. Complications of Diabetes mellitus:
The symptoms of high blood sugar include:
•Frequent urination.
•Excessive thirst (Polydipsia)
•Feeling excessively hungry.
•unexplained weight loss
•slow healing
•itchy, dry skin
•increased likelihood of infections
•headaches
•fatigue

31. Electron transport chain
An electron transport chain (ETC) is a series of protein complexes and
other molecules that transfer electrons from electron donors to electron
acceptors via redox reactions (both reduction and oxidation occurring
simultaneously) and couples this electron transfer with the transfer
of protons (H+ ions) across a membrane.
The electrons that transferred from NADH and FADH2 to the ETC
involves four multi-subunit large enzymes complexes and two mobile
electron carriers. Many of the enzymes in the electron transport chain
are membrane-bound.
Electron Transport Chain is a series of compounds where it makes use of
electrons from electron carrier to develop a chemical gradient.

32. Large amounts of ATP could be produced through a highly efficient
method termed oxidative Phosphorylation.
ATP is a fundamental unit of metabolic process. The electrons are
transferred from electron donor to the electron acceptor leading to the
production of ATP.
It is one of the vital phases in the electron transport chain. Compared to
any other part of cellular respiration the large amount of ATP is
produced in this phase.
When electrons are passed from one component to another until the
end of the chain the electrons reduce molecular oxygen thus producing
water.

34. Electron Transport Chain in Mitochondria
Complex 1- It comprises enzymes consisting of iron-sulfur and FMN.
Here two electrons are carried out to the first complex aboard NADH.
FMN is derived from vitamin B2.
Complex 2- FADH2 that is not passed through complex 1 is received
directly from complex 2. The first and the second complexes are
connected to a third complex through compound ubiquinone (Q). The Q
molecule is soluble in water and moves freely in the hydrophobic core of
the membrane. In this phase, an electron is delivered directly to the
electron protein chain. The number of ATP obtained at this stage is
directly proportional to the number of protons that are pumped across
the inner membrane of the mitochondria.

35. Complex 3- The third complex is comprised of Fe-S protein, Cytochrome
b, and Cytochrome c proteins. Cytochrome proteins consist of the heme
group. Complex 3 is responsible for pumping protons across the
membrane. It also passes electrons to the cytochrome c where it is
transported to the 4th complex of enzymes and proteins. Here, Q is the
electron donor and Cytochrome C is the electron acceptor.
Complex 4- The 4th complex is comprised of cytochrome c, a and a3.
There are two heme groups where each of them is present in
cytochromes c and a3. The cytochromes are responsible for holding
oxygen molecule between copper and iron until the oxygen content is
reduced completely. In this phase, the reduced oxygen picks two
hydrogen ions from the surrounding environment to make water.

36. Oxidative Phosphorylation
Oxidative Phosphorylation is the process of ATP formation, when
electrons are transferred by electron carriers from NADH or FADH2 to
oxygen.
Oxidative phosphorylation is the final step in cellular respiration. It
occurs in the mitochondria. It is linked to a process known as electron
transport chain. The electron transport system is located in the inner
mitochondrial membrane. The electrons are transferred from one
member of the transport chain to another through a series of redox
reactions.

38. Substrate Level Phosphorylation
Phosphorylation involves the transfer of phosphate group from one
compound to other. Substrate level Phosphorylation is a direct
Phosphorylation of ADP with a Phosphatase group by using the energy
obtain from a coupled reaction.
Occurs in cytoplasm (Glycolysis - due to aerobic and anaerobic
condition) and in mitochondrial matrix (Krebs cycle).

39. Inhibitors of Elecron transport chain
•Retinone
•Piericidin-A
•Barbiturates
•Antimycins
•Dimercaprol
•Cyanides
•Azide
•Hydrogen sulphide
•Carbon mono-oxide

40. Inhibitors of Oxidative Phosphorylation
•Oligomycin
•Rutamycin
•Atractylate