1. The document discusses carbohydrate metabolism, including glycolysis, the citric acid cycle (TCA cycle), gluconeogenesis, glycogenesis, and glycogenolysis. 2. Glycolysis converts glucose to pyruvate, producing ATP and NADH. The TCA cycle further oxidizes pyruvate, producing more ATP, NADH, and FADH2. 3. Gluconeogenesis produces glucose from non-carbohydrate sources. Glycogenesis and glycogenolysis involve the synthesis and breakdown of glycogen for glucose storage and mobilization.

1. Biochemistry-
Central metabolism
SONY PETER
MINISTRY OF EDUCATION
MIZAN-TEPI UNIVERSITY
ETHIOPIA

2. Definition
Carbohydrate Metabolism
a. Glycolysis & TCA Cycle
b. Gluconeogenesis
c. Glycogenesis & Glycogenolysis
d. Glucose Homeostasis
 Normal values
 Supply of glucose to blood
 Removal of glucose from blood
e. Clinical correlates
 Glycogen storage disorders
 Fasting storage disorders
 Fasting hyperglycemia
 Fasting hypoglycemia

3. Definition- Carbohydrate metabolism denotes the
various biochemical processes responsible for
the formation, breakdown, and interconversion
of carbohydrates in living organisms. Digestion breaks
down complex carbohydrates into a few
simple monomers for metabolism: glucose, fructose,
and galactose.
-Glucose constitutes about 80% of the products, and is the
primary structure that is distributed to cells in the tissues,
where it is broken down or stored as glycogen.

4. -In aerobic respiration, the main form of cellular respiration
used by humans, glucose and oxygen are metabolized to
release energy, with carbon dioxide and water as
byproducts. Most of the fructose and galactose travel to the
liver, where they can be converted to glucose.

6. Glycolysis & TCA Cycle
What is Glycolysis?
Glycolysis is the metabolic pathway that
converts glucose C6H12O6 , into pyruvate, CH3COCOO− + H+.
The free energy released in this process is used to form the
high-energy molecules ATP (adenosine triphosphate) and
NADH (reduced nicotinamide adenine dinucleotide).

8. Glycolysis produces 2 ATP, 2 NADH, and 2 pyruvate
molecules: Glycolysis, or the aerobic catabolic breakdown of
glucose, produces energy in the form of ATP, NADH, and
pyruvate, which itself enters the citric acid cycle to produce
more energy.
Four total molecules of ATP are formed
during glycolysis. Two, however, are used during
the glycolysis reactions. So the net gain is 2.

9. The sequence of glycolysis reaction is separated into two
phases
1. The preparatory phase
2. The pay-off phase

10. Preparatory Phase
Preparatory phase is the stage in which there is consumption
of ATP and is also known as the investment phase. The pay-
off phase is where ATP is produced. The first five steps of the
glycolysis reaction is known as the preparatory or
investment phase. This stage consumes energy to convert the
glucose molecule into two molecules three carbon sugar
molecule.

11. Step 1
The step one in glycolysis is phosphorylation. This step
glucose is phosphorylated by the enzyme hexokinases. In this
process, ATP molecule is consumed. A phosphate group from
the ATP is transferred to the glucose molecules to produce
glucose-6- phosphate.
Glucose + Hexokinase + ATP → Glucose-6-phosphate + ADP
(C6H12O6) (C6H11O6P1)

12. Step 1

13. Step 2
The second stage of glycolysis is an isomerization reaction.
In this reaction the glucose-6-phosphate is rearranged into
fructose-6-phosphate by the enzyme glucose phosphate
isomerase. This is a reversible reaction under normal
conditions of the cell.
Glucose-6-phosphate + Phosphoglucoisomerase → Fructose-6-phosphate
(C6H11O6P1) (C6H11O6P1)

14. Step 2

15. Step 3
In the third step of glycolysis is a phosphorylation reaction.
In this step the enzyme phosphofructokinase is transfers
phosphate group to form fructose 1,6-bisphosphate. Another
ATP molecule is used in this step.
Fructose 6-phosphate + phosphofructokinase + ATP
(C6H11O6P1)
→ Fructose 1,6-bisphosphate + ADP
(C6H10O6P2)

16. Step 3

17. Step 4
This step in glycolysis is a destabilization step, where a the
action of the enzyme aldolase splits fructose 1,6-
bisphosphate into two sugars. These sugars are isomers of
each other, they are dihydroxyacetone phosphate and
glyceraldehyde phosphate.
Fructose 1,6-bisphosphate + aldolase
(C6H10O6P2)
→Dihydroxyacetone phosphate +Glyceraldehyde phosphate
(C3H5O3P1) (C3H5O3P1)

18. Step 4

19. Step 5
Step 5 of glycolysis is an interconversion reaction. Here, the
enzyme triose phosphate isomerase interconverts the
molecules dihydroxyacetone phosphate and glyceraldehyde
phosphate.
Dihydroxyacetone phosphate→ Glyceraldehyde phosphate
(C3H5O3P1) (C3H5O3P1)

20. Step 5
This step marks the end of the preparatory or the investment
phase of glycolysis. So at the end here, the 6-carbon glucose
molecule is split into two three-carbon molecules with the
expense of twp ATP molecules.

22. Pay-off Phase
The second phase of glycolysis is known as the pay-off
phase of glycolysis. This phase is characterized by gain of
the energy-rich molecules ATP and NADH.

23. Step 6
This step of glycolysis is a dehydrogenation step. The
enzyme triose phosphate dehydrogenase, dehydrogenates
glyceraldehyde 3-phosphate and adds an inorganic
phosphate to form 1,3-bisphosphoglycerate. Firstly, the
enzyme action transfers a H-(hydrogen) from
glyceraldehyde phosphate to the NAD+ which is an
oxidizing agent to form NADH. The enzyme also adds a
inorganic phosphate from the cytosol to the glyceraldehyde
phosphate to form 1,3-bisphosphoglycerate. This reaction
occurs with both the molecules produced in the previous step.

24. 2 Glyceraldehyde phosphate + Triose
(C3H5O3P1)
phosphate dehydrogenase + 2H- + 2P + 2NAD+
→ two 1,3-Bisphosphoglycerate + 2NADH + 2H+
(C3H4O4P2)

25. Step 6

26. Step 7
Step 7 of glycolysis is a substrate-level phosphorylation
step, where the enzyme phosphoglycerokinase transfers a
phosphate group from 1,3-bisphosphoglycerate. The
phosphate is transferred to ADP to form ATP. This process
yields two molecules of 3-phosphoglycerate molecules and
two molecules of ATP. There are two molecules of ATP
synthesized in this step of glycolysis.
2 molecules of 1,3 bisphophoglycerate (C3H4O4P2)+
phosphoglycerokinase + 2 ADP →2 molecules of 3-
phosphoglycerate (C3H5O4P1) + 2 ATP

27. Step 7

28. Step 8
This step of glycolysis is a mutase step, occurs in the
presence of the enzyme phosphoglycerate mutase. This
enzyme relocates the phosphate from the 3-
phosphoglycerate molecular third carbon position to the
second carbon position, this results in the formation of 2-
phosphoglycerates.
2 molecules of 3-phsophoglycerate (C3H5O4P1) +
phsosphoglyceromutase → 2 molecules of 2
Phosphoglycerate (C3H5O4P1)

29. Step 8

30. Step 9
This step of glycolysis is a lyase reaction, which occurs in
the presence of enolase enzyme. In this reaction the
enzyme removes a molecule of water from 2-
phosphoglycerate to form phosphoenolpyruvic acid (PEP).
2 molecules of 2-phosphoglycerate (C3H5O4P1) + enolase
→ 2 molecules of phosphoenolpyruvic acid (PEP)
(C3H3O3P1) + H2O

31. Step 9

32. Step 10
This is the final stage of glycolysis which is a substrate-
level phsophorylation step. In the presence of the enzyme
pyruvate kinase, there is transfer of a inorganic phosphate
molecule from phosphoenol pyruvate molecule to ADP to
form pyruvic acid and ATP. This reaction yields 2 molecules
of pyruvic acid and two molecules of ATP.
2 molecules of PEP (C3H3O3P1) + pyruvate kinase + 2 ADP →
2 molecules of pyruvic acid (C3H4O3) + 2 ATP
This reaction marks the end of glycolysis, hereby producing
two ATP molecules per glucose molecule.

33. Step 10

36. Glycolysis Pathway

37. TCA Cycle

39. The citric acid cycle (CAC) – also known as the tricarboxylic
acid (TCA) cycle or the Krebs cycle is a series of chemical
reactions used by all aerobic organisms to release stored
energy through the oxidation of acetyl-CoA derived
from carbohydrates, fats, and proteins into carbon
dioxide and chemical energy in the form of adenosine
triphosphate (ATP).

40. TCA
Cycle
ATP
CO2

41. The tricarboxylic acid cycle (TCA cycle, also called the Krebs
cycle or the citric acid cycle) plays several roles in metabolism.
It is the final pathway where the oxidative metabolism of
carbohydrates, amino acids, and fatty acids converge, their
carbon skeletons being converted to CO2. This oxidation
provides energy for the production of the majority of ATP in
most animals. The cycle occurs totally in the mitochondria and
is, therefore, in close proximity to the reactions of electron
transport, which oxidize the reduced coenzymes produced by
the cycle. The TCA cycle is an aerobic pathway, because O2 is
required as the final electron acceptor. Most of the body's
catabolic pathways converge on the TCA cycle.

42. The citric acid cycle also supplies intermediates for a number
of important synthetic reactions. For example, the cycle
functions in the formation of glucose from the carbon skeletons
of some amino acids, and it provides building blocks for the
synthesis of some amino acids and heme.
Aerobic metabolism of carbohydrate is carried out in two
phases.
a) Pyruvate produced by glycolysis is first oxidatively
decarboxylated to Acetyl-coA by pyruvate dehydrogenase.
b) Acetyl-coA is then oxidized in the TCA cycle.

44.  The acetyl-CoA, has been oxidized to two molecules of
carbon dioxide.
 Three molecules of NAD were reduced to NADH.
 One molecule of FAD was reduced to FADH2.
 One molecule of GTP (the equivalent of ATP) was
produced.
 Keep in mind that a reduction is really a gain of electrons.
In other words, NADH and FADH2 molecules act as
electron carriers and are used to generate ATP in the next
stage of glucose metabolism, oxidative phosphorylation.

45. It is the formation of glucose from non-carbohydrate materials
in liver and renal cortex. Lactate and pyruvate are quantitatively
the largest source of glucose in gluconeogenesis, particularly in
intense exercise. Next comes the glucogenic amino acids such as
glycine and alanine, during starvation, gluconeogenesis takes
place mainly from amino acids.

47. Regulation of gluconeogenesis
The regulation of gluconeogenesis and glycolysis involves
the enzymes unique to each pathway, and not the
common ones.
While the major control points of glycolysis are the
reactions catalyzed by PFK-1 and pyruvate kinase, the
major control points of gluconeogenesis are the reactions
catalyzed by fructose 1,6-
bisphosphatase and Pyruvate carboxylase.

48. • The other two enzymes unique to gluconeogenesis,
glucose-6-phosphatase and PEP carboxykinase, are
regulated at transcriptional level.

49. Glycogen Metabolism
GLYCOGENESIS
Glycogenesis is the synthesis of glycogen from glucose in the cytosol. Mainly the liver and
muscles and to lesser extent, many other tissues, except mature erythrocytes, brain and
kidneys, carry out glycogenesis.
Glucose (1) glucose 6 -phosphate (2) glucose 1-phosphate (3)
UDP-glucose (4) glycogen amylose (5) glycogen
(1) Hexokinase or glucokinase
(2) Phospho glucomutase
(3) UDP-glucose pyrophosphorylase
(4) Glycogen synthase
(5) Branching enzyme

50.  The enzyme glycogenin is needed to create initial short
glycogen chains, which are then lengthened and branched
by the other enzymes of glycogenesis. Glycogenin, a
homodimer, has a tyrosine residue on each subunit that
serves as the anchor for the reducing end of glycogen.
Initially, about eight UDP-glucose molecules are added to
each tyrosine residue by glycogenin, forming α(1→4)
bonds.

51. • Once a chain of eight glucose monomers is
formed, glycogen synthase binds to the growing glycogen
chain and adds UDP-glucose to the 4-hydroxyl group of
the glucosyl residue on the non-reducing end of the
glycogen chain, forming more α(1→4) bonds in the
process.
• Branches are made by glycogen branching enzyme (also
known as amylo-α(1:4)→α(1:6)transglycosylase), which
transfers the end of the chain onto an earlier part via α-1:6
glycosidic bond, forming branches, which further grow by
addition of more α-1:4 glycosidic units.

54. Glycogenolysis
• Glycogenolysis is a catabolic process; the breakdown of glycogen to
glucose units.
• Glycogen is principally stored in the cytosol granules of -
• Liver
• Muscle

55. Glycogen Function
• In liver – The synthesis and breakdown of glycogen is
regulated to maintain blood glucose levels.
• In muscle - The synthesis and breakdown of glycogen is
regulated to meet the energy requirements of the muscle cell.

56. Glycogenolysis
glycogen(n residues) + Pi ⇌ glycogen(n-1 residues) + glucose-1-
phosphate
• Here, glycogen phosphorylase cleaves the bond linking a terminal
glucose residue to a glycogen branch by substitution of
a phosphoryl group for the α[1→4] linkage. Glucose-1-phosphate is
converted to glucose-6-phosphate by the
enzyme phosphoglucomutase. Glucose residues are phosphorolysed
from branches of glycogen until four residues before a glucose that
is branched with a α[1→6] linkage.

57. • Glycogen debranching enzyme then transfers three of the
remaining four glucose units to the end of another
glycogen branch. This exposes the α[1→6] branching
point, which is hydrolysed by α[1→6] glucosidase,
removing the final glucose residue of the branch as a
molecule of glucose and eliminating the branch. This is the
only case in which a glycogen metabolite is not glucose-1-
phosphate. The glucose is subsequently phosphorylated to
glucose-6-phosphate by hexokinase.

59. • The process is caused by the hormones glucagon and
epinephrine which stimulate glycogenolysis and which
are produced in response to low blood glucose levels. It
takes place in the muscle and liver tissue which is where
glycogen is stored.

60. Control and regulations
 Glycogenesis responds to hormonal control. One of the
main forms of control is the varied phosphorylation of
glycogen synthase and glycogen phosphorylase. This is
regulated by enzymes under the control of hormonal
activity, which is in turn regulated by many factors. As
such, there are many different possible effectors when
compared to allosteric systems of regulation.

61. • Epinephrine not only activates glycogen
phosphorylase but also inhibits glycogen synthase. This
amplifies the effect of activating glycogen phosphorylase.
This inhibition is achieved by a similar mechanism, as
protein kinase A acts to phosphorylate the enzyme, which
lowers activity. This is known as co-ordinate reciprocal
control.

62. • Insulin has an antagonistic effect to epinephrine signaling
via the beta-adrenergic receptor (G-Protein coupled
receptor). When insulin binds to its receptor (insulin
receptor), it results in the activation (phosphorylation) of
Akt gene which in turn activates Phosphodiesterase (PDE).
PDE then will inhibit cyclic AMP (cAMP) action and cause
inactivation of PKA which will cause Hormone Sensitive
Lipase (HSL) to be dephosphorylated and inactive so that
lipolysis and lipogenesis is not occurring simultaneously.

63. • Calcium ions or cyclic AMP (cAMP) act as secondary
messengers. This is an example of negative control. The
calcium ions activate phosphorylase kinase. This activates
glycogen phosphorylase and inhibits glycogen synthase.

64. • Carbohydrate Homeostasis
Brain and other nervous tissues,
except in long-term fasting use glucose as the sole energy source;
even in long-term fasting they require significant amounts of
glucose. Red blood cells can obtain energy only by anaerobic
glycolysis. Skeletal muscle at rest uses predominantly fatty acids,
but in heavy exercise it also draws on muscle glycogen and blood
glucose. Because brain and red blood cells depend on glucose for
energy, glucose must always be available.

65. • Glucose occurs in plasma and interstitial fluid at a concentration
of approximately 80 mg/dL. Approximately 180 g of glucose is
oxidized per day. The body must therefore replenish the total
blood glucose concentration about nine times a day;
nevertheless, the concentration in blood remains remarkably
constant. The glucose level following an overnight fast is
approximately 80 mg/dL. Following a meal, such as breakfast,
the level rapidly rises by 30-50 mg/dL, but within 2 hours it
returns to the previous level where it remains until the next
meal when the pattern is repeated. The remarkable stability of
the blood glucose level is an indication of the balance between
supply and utilization.

66. • Carbohydrate as a Food
• Carbohydrate is essential for the survival of some tissues and as
a structural constituent of nucleic acids, glycoproteins,
proteoglycans, and glycolipids. The normal adult can synthesize
all the needed carbohydrate from non-carbohydrate sources,
namely, amino acids and glycerol. Thus, humans can exist with
little or no dietary carbohydrate intake.
• Our normal diet generally consists of approximately 45%
carbohydrate, 43% lipid, and 10% protein. Of the carbohydrate,
about 60% is starch, 30% sucrose, and most of the remainder
lactose.

67. • Blood sugar regulation is the process by which the levels
of blood sugar, primarily glucose, are maintained by the
body within a narrow range. This tight regulation is
referred to as glucose homeostasis. Insulin, which lowers
blood sugar, and glucagon, which raises it, are the most
well known of the hormones involved, but more recent
discoveries of other glucoregulatory hormones have
expanded the understanding of this process.

68. Glucagon
If the blood glucose level falls to dangerous levels (as during
very heavy exercise or lack of food for extended periods),
the alpha cells of the pancreas release glucagon,
a hormone whose effects on liver cells act to increase blood
glucose levels. They convert glycogen into glucose (this
process is called glycogenolysis). The glucose is released into
the bloodstream, increasing blood sugar.

69. • GLUCAGON: Secretion of glucagon is stimulated by fall in
blood sugar level. Glucagon is antagonistic to insulin and
increases the blood sugar, lower the liver glycogen and may even
produce glucosuria because of its following effects.
(a)Glucagon enhances glycogenolysis in the liver.
(b)It increases hepatic gluconeogenesis.
(c)It decreases hepatic glycogenesis and thus reduces the removal
of blood glucose by the liver.

70. Hypoglycemia, the state of having low blood sugar, is treated
by restoring the blood glucose level to normal by the
ingestion or administration of dextrose or
carbohydrate foods. It is often self-diagnosed and self-
medicated orally by the ingestion of balanced meals. In more
severe circumstances, it is treated by injection or infusion of
glucagon.

71. Insulin
When levels of blood sugar rise, whether as a result
of glycogen conversion, or from digestion of a meal, a
different hormone is released from beta cells found in
the Islets of Langerhans in the pancreas. This
hormone, insulin, causes the liver to convert more glucose
into glycogen (this process is called glycogenesis), and to
force about 2/3 of body cells (primarily muscle and fat tissue
cells) to take up glucose from the blood through
the GLUT4 transporter, thus decreasing blood sugar.

72. When insulin binds to the receptors on the cell surface,
vesicles containing the GLUT4 transporters come to the
plasma membrane and fuse together by the process of
endocytosis, thus enabling a facilitated diffusion of glucose
into the cell. As soon as the glucose enters the cell, it is
phosphorylated into Glucose-6-Phosphate in order to
preserve the concentration gradient so glucose will continue
to enter the cell. Insulin also provides signals to several other
body systems, and is the chief regulator of metabolic control
in humans.

73. • A rise in blood sugar level stimulates insulin secretion. Insulin
lowers the blood sugar in several ways.
(a)It increases glucose uptake by muscles, adipocytes and other
extrahepatic tissues.
(b)It enhances utilization of glucose by promoting glycolysis and
aerobic metabolism of pyruvate in tissues and also by
stimulating lipogenesis from glucose in adipocytes.
(c)It decreases both glycogenolysis and gluconeogenesis in the liver
and there by decreases the addition of glucose to the blood.
(d)It stimulates glycogenesis in the liver to enhance the storage of
carbohydrates as liver glycogen.

74. There are also several other causes for an increase in blood
sugar levels. Among them are the 'stress' hormones such
as epinephrine (also known as adrenaline), several of the
steroids, infections, trauma, and of course, the ingestion of
food.

75. Diabetes mellitus type 1 is caused by insufficient or non-
existent production of insulin, while type 2 is primarily due
to a decreased response to insulin in the tissues of the body
(insulin resistance). Both types of diabetes, if untreated,
result in too much glucose remaining in the blood
(hyperglycemia) and many of the same complications. Also,
too much insulin and/or exercise without enough
corresponding food intake in diabetics can result in low
blood sugar (hypoglycemia).

77. Clinical Correlates
A Glycogen storage disease (GSD,
also glycogenosis and dextrinosis) is a metabolic
disorder caused by enzyme deficiencies affecting
either glycogen synthesis, glycogen breakdown
or glycolysis (glucose breakdown), typically
within muscles and/or liver cells.

78. • GSD has two classes of cause: genetic and acquired.
Genetic GSD is caused by any inborn error of
metabolism(genetically defective enzymes) involved in
these processes. In livestock, acquired GSD is caused
by intoxication with the alkaloid castanospermine.

81. • This inability to maintain adequate blood glucose levels
during fasting results from the combined impairment of
both glycogenolysis and gluconeogenesis.
• Fasting hypoglycemia is often the most significant
problem in GSD I, and typically the problem that leads to
the diagnosis.

82. • Fasting hyperglycemia is defined as when you don't eat
for at least eight hours. Recommended range without
diabetes is 70 to 130mg/dL. (The standard for measuring
blood glucose is "mg/dL" which means milligrams per
deciliter.) If your blood glucose level is above 130mg/dL,
that's fasting hyperglycemia.
• Because fasting can elevate cortisol levels. One of
cortisol's effects is that it raises blood sugar. So, in
someone with blood sugar regulation issues, fasting can
actually make them worse.

83. • Hypoglycemia is the condition when your blood glucose
(sugar) levels are too low. It happens to people with
diabetes when they have a mismatch of medicine, food,
and/or exercise.Reactive hypoglycemia, which happens
within a few hours of eating a meal. Fasting
hypoglycemia, which may be related to a disease