Integration of Metabolism

1. INTEGRATION OF METABOLISM
Ashok Katta

5. Energy
containing
nutrients
Carbohydrates
Fats
Proteins
Energy
Depleted
End products
CO2
H2O
NH3
Cell
macromolecules
Proteins
Polysaccharides
Lipids
Nucleic acids
Precursor
molecules
Amino acids
Sugars
Fatty acids
Nitrogenous bases
Catabolism
Anabolism
ATP + Pi
NADH+H+
NADPH+H+
FADH2
ADP + Pi
NAD+
NADP+
FAD

7. Regulation of metabolic reactions
1. Allosteric interaction
2. Covalent modification
3. Adjustment of enzyme levels
4. Compartmentation
5. Metabolic specializations of organs

8. • Metabolism is a continuous process, with thousands of
reactions, simultaneously occurring in the living cell.
• Though metabolism of each of major food nutrients, viz.
– Carbohydrates,
– Lipids and
– Proteins
o have been considered separately for the sake of
convenience, it actually takes place simultaneously in
the intact animal and are closely interrelated to one
another.
• The metabolic processes involving these three major food
nutrients and their interrelationship can be broadly
divided into three stages

9. Three Stages of Metabolism
Stage 1
Stage of
hydrolysis
Polysaccharides,
are broken down to
glucose
Lipids (TG) is hydrolysed
to FFA and glycerol.
Proteins are hydrolysed to
amino acids.

10. Foods
GLYCOLYSIS
CarbohydratesProteins Lipids
Amino acids Fatty acid &
glycerol
NADH + H+
NADH + H+
FADH2
O2
H2O
Glucose
Pyruvate
Acetyl CoA
CO2
CO2
PDH COMPLEX
Waste products
NH3
Preparatory stage
Conversion of subunits to
acetyl CoA and production of
small amount of energy ATP &
NADH.
Oxidative stage
In presence of O2, acetyl CoA is
oxidised to CO2 and H2O by
common final pathway TCA cycle.
Considerable ATP is produced in
this process.
Stage 3
CO2
NADH + H+
KREBS CYCLE
e-
e-
e-
ETC

11. INTEGRATION OF METABOLISM
Definition-
• The co-ordination between three metabolites
(carbohydrates, lipids and proteins) called
Integration Of Metabolism.

12. Cellular level
Tissue or Organ
level
The integration of
metabolism is must be
studied at two levels

13. Significance of Integration of metabolism
• It ensures a supply of suitable fuel for all
tissues, at all the time (from the fully fed state
to the totally starved state)
• Under positive caloric balance,
– A significant proportion of the food energy intake is
stored as either glycogen or fat
• Under negative caloric balance,
– Fatty acids are oxidised in preference to glucose, to
spare glucose for those tissues (Brain & RBCs) that
require it under all conditions.

14. Major Metabolic Pathways and their
Control Sites
Glycolysis
Gluconeogenesis
Citric Acid Cycle
Pentose Phosphate Pathway
Glycogen Synthesis and Degradation
Fatty Acid Synthesis and Degradation

15. Glucose
Glucose 6-phosphate
Fructose 6- phosphate
Fructose 1,6- bisphosphate
G 3-pDHAP
1,3-Bisphosphoglycerate
3-Phosphoglycerate
2-Phosphoglycerate
Phosphoenol pyruvate
pyruvate
Takes place in the cytosol.
Degrades glucose for…
ATP production and
Carbon skeletons for biosynthesis.
Phosphofructokinase catalyzes 1st
committed step.
It is the “valve” controlling the rate
of glycolysis.
Phosphofructokinase
Inhibitors: ATP, citrate
Activators: AMP, F-2,6-BP

16. Occurs mainly in the liver and kidneys.
Pruvate is carboxylated in the mitochondria. The other reactions
occur in the cytosol.
Glycolysis and gluconeogenesis are reciprocally regulated.

17. Takes place inside mitochondria
The rate of the TCA cycle matches the
need for ATP.
High ATP levels decrease the activities
of 2 enzymes:
Citrate synthase
Isocitrate dehydrogenase
High NADH inhibits
Citrate synthase,
Isocitrate dehydrogenase, and
a-ketoglutarate dehydrogenase.
Ensures that the rate of the citric acid
cycle matches the need for ATP.

18. Takes place in the cytosol in two stages:
Oxidative decarboxylation of G-6-Phosphate
Non-oxidative, reversible metabolism of 5C phosphosugars into
phospharylated 3C and 6C glycolitic intermediates
First committed step is catalysed by glucose-6-phosphate
dehydrogenase.
Glucose 6-phosphate
6-phosphogluconolactone
6-phosphogluconate
Glucose 6-phosphate
dehydrogenase
Gluconolactone
hydrolase
NADP+
NADPH+H+
Mg+
H2O
High NADP+

19. Glycogen metabolism is regulated by controlling the
activities of two critical enzymes…
Glycogen phosphorylase and
Glycogen synthase.
1. Hormonal regulation through reversible phosphorylation.
2. Allosteric regulation
Phosphorylation
Activates phosphorylase
Inactivates glycogen synthase

20. Insulin
+
Glycogen
Glucose 1-P
cAMP+Glycogen Phosphorylase Glycogen Synthase
Glucagon, Epinephrine
-
-
+
Glucose 6-phoshate
+
Ca, AMP
-
Glucose 6-
phosphate
ATP
Reciprocal
regulation

21. Fatty acids are made in the cytosol.
2C units are added to a growing chain on an acyl carrier protein.
Acetyl groups are carried from mitochondria to the cytosol as
CITRATE
Citrate increases the activity of acetyl CoA carboxylase which
increases fatty acid synthesis

22. Insulin
phosphatase
Acetyl CoA
carboxylase
(inactive)
Acetyl CoA
carboxylase
(active)
Protein
kinase
Glucagon, Epinephrine
ATPADP
P
-
+
Malonyl-CoA
Acetyl-CoA
Glucose
Citrate
palmitate
Palmitoyl CoA
NADPH
Pentose phosphate
pathway
-
-
+
G6PD
Covalent modification Allosteric regulation

23. Occurs in the mitochondria where fatty acids are degraded to acetyl
CoA which then enter the citric acid cycle if the supply of
oxaloacetate is adequate.
Acylcarnitine formation is important
ATP need is important
If there is too much malonyl CoA, fatty acid degradation is inhibited.

24. Key
Junctions

25. Glucose 6
phosphate
Pyruvate AcetylCoA
Key junctions

26. Glucose is phosphorylated
after it enters cells and it
cannot be reconverted to
glucose by most cells.
ATP abundant:
Glycogen synthesis
favored.
ATP is low:
Glycolysis is favored.
NADPH is low:
Pentose phosphate
pathway favored

28. Integration of metabolism
at Cellular level
• It includes the flow of key metabolites (e.g. glucose, fatty
acids, glycerol and amino acids) between different
metabolic pathways at cellular level.
• The major fuel depots in animals are…
– Glycogen in liver and muscle;
– Triacylglycerols in adipose tissue; and
– Protein, mostly in skeletal muscle
• The usual order of preference for use of these is…
glycogen
fat
protein

29. Inter-conversion Between 3 Principal Components
 Conversion of carbohydrates into fats and fats
into carbohydrates
 Conversion of carbohydrates into proteins and
proteins into carbohydrates
 Conversion of proteins into fats and fats into
proteins.

30. Conversion of Carbohydrates into Fats
Glucose 6-phosphate
Pyruvate
Glycolysis
Glucose
Acetyl CoA Fatty acid Triglycerides
Glyceraldehyde 3 P

31. Conversion of Fatty Acids to Carbohydrate
 There is no net conversion of fatty acids to glucose or
glycogen take place.
 Only a Odd chain fatty acids are glucogenic as it forms a
molecule of propionyl-CoA upon β-oxidation.
 Propionyl-CoA can be converted to succinyl-CoA, an
intermediate of citric acid cycle, which can be converted to
glucose by gluconeogenesis.
Odd chain fatty acid propionyl CoA succinyl CoA
Glucose
β-oxidation

32. Conversion of Carbohydrates into
Proteins and
Proteins into Carbohydrates

33. Conversion of Fats into Proteins &
Proteins into Fats

34. Integration of Metabolism at Tissue or
Organ Level
 Integration of metabolism at tissue or organ level
includes the inter-relationship of different tissues and
organs to meet metabolic demands for the whole body.
 Role of Liver
 Role of Skeletal Muscle
 Role of Adipose Tissue
 Role of Heart Muscle
 Role of Brain

35. Metabolic Profile of Organs

36. Role of Liver
• Major metabolic processing
center, (except TGL)
• After absorption, most of
nutrients pass through the portal
vein to the liver for processing
and distribution.

37. Major roles of the liver include the following:
Maintenance of blood glucose levels.
During the fed state,
Converts and stores excess glucose as glycogen.
Converts it to fatty acids.
During the fasting state,
provides glucose for the body by…
glycogenolysis and
gluconeogenesis.
During starvation,
It synthesizes ketone bodies and supplies to the peripheral
tissues as a source of energy.
It serves as the major site of fatty acid synthesis.

38. Carbohydrate Metabolism
 Glucose 6-phosphate is
the key intermediate in
liver.
 It may be …
– polymerized into
glycogen,
– dephosphorylated to
blood glucose, or
– converted to fatty acids
via acetyl-CoA.
– It may undergo oxidation
by glycolysis, the citric
acid cycle, and
respiratory chain to
yield ATP.
– or enter the HMP Shunt
to yield pentoses and
NADPH.
Protein Metabolism
 Amino acids are used
to..
 synthesize liver &
plasma proteins,
 their carbon skeletons
are converted to
glucose and
glycogen by
gluconeogenesis;
 the ammonia formed
by deamination is
converted to urea.
Lipid Metabolism
 The liver converts fatty
acids to…
 TGLs,
 Phospholipids, or
 Cholesterol and its
esters, for transport as
plasma lipoproteins to
adipose tissue for
storage.
 Fatty acids can also be
oxidized to yield ATP or
 To form ketone bodies.

39. Role of Skeletal Muscle
Skeletal muscle maintains large stores of glycogen,
which provide energy during exercise.
During starvation, free fatty acids and ketone bodies
supplied by liver are oxidized in preference to glucose in
muscle.
The protein present in muscle may be used as a fuel
source, if no other fuel is available.
Pyruvate, the product of glycolysis in the skeletal
muscle, may be converted to either lactate or alanine

40.  Amorphous tissue widely distributed
about the body
 Triacylglycerols are stored in tissue
(enormous reservoir of metabolic fuel)
 continuous synthesis and breakdown of
triacylglycerols, controlled by hormone-
sensitive lipase
 Needs glucose to synthesis TAG;
 Glucose level determines if fatty acids
are released into blood
Role of Adipose Tissue

41. Role of Heart Muscle
• The activity of heart muscle is
constant and rhythmic
• The heart functions as a completely
aerobic organ and is very rich in
mitochondria Prefers fatty acid as
fuel
• Continually nourished with oxygen
and free fatty acid, glucose, or
ketone bodies as fuel.

42. Role of Brain
Brain has two remarkable metabolic
features
1. very high respiratory metabolism
20 % of oxygen consumed is used by
the brain.
2. but no fuel reserves Uses only
glucose as a fuel and is dependent on
the blood for a continuous incoming
supply (120g per day)
In fasting conditions, brain can use -
hydroxybutyrate, converting it to
acetyl-CoA for the energy
production via TCA cycle
Generate ATP to maintain the membrane
potentials essential for transmission
of nerve impulses
Glucose is fuel for brain -> consumes 120g/day -> 60-70 % of utilization of glucose
in starvation -> ketone bodies can replace glucose

43. Metabolism in Absorptive
(fed) state

44. Absorptive (fed) state
Overview of the absorptive (fed) state
• The absorptive state is the 2 – 4 hours period after ingestion of meal.
• During this interval, transient increase in plasma glucose, amino acids &
triacylglycerols (main nutrients) occur.
• As a result of elevated glucose & amino acids, insulin secretion is
increased from the pancreas & glucagon secretion is decreased.
• Elevated insulin/glucagon ratio & ready availability of circulating
substrates cause increased synthesis of TGL & glycogen to be stored.
• During the absorptive period, all tissues use glucose as a fuel.
• During absorptive period, metabolic responses of the body is dominated
by alterations of the metabolism of 4 organs, liver, adipose tissue,
muscle & brain.

45. Enzyme changes in the fed state
Flow of intermediates through metabolic pathways is controlled by:
1) Availability of substrates (within minutes)
2) Allosteric regulation of enzymes (within minutes)
3) Covalent modification of enzymes (within minutes to hrs.)
4) Induction-repression of enzyme synthesis (within hrs. to days)
Each mechanism operates on a different time-scale
(response occurs within minutes, minutes to hours or hours to days)
In fed state, these regulatory mechanisms ensure that available
nutrients (in abundance) are directed to be stored as glycogen,
triacylglycerol & protein

46. Liver: nutrient distribution center
• Venous drainage of gut passes through the hepatic portal vein
(to liver cells) before entry into the general circulation.
Thus, after a meal, liver receives blood containing absorbed
nutrients (mainly glucose, amino acids & fatty acids) &
elevated levels of insulin secreted by the pancreas
• During the absorptive period, the liver takes up nutrients which
are carbohydrates, lipids & most amino acids.
These nutrients are…
• Metabolized or
• Stored or
• Routed to other tissues

47. After a meal containing carbohydrate, liver consumes about 60% of
glucose from portal circulation.
Increased entry of glucose is not insulin dependent: as GLUT-2 of liver is
not influenced by insulin.
Liver metabolism of glucose is increased by:
1- Increased phosphorylation of glucose (i.e. glucose 6-phosphate by glukokinase)
2- Increased glycolysis of glucose (with production of acetyl CoA fatty acids)
3- Increased glycogen synthesis glucose stored or energy
4- Increased activity of pentose phosphate pathway of glucose (to provide NADPH)
5-Decreased gluconeogenesis (synthesis of glucose from non-carbohydrate sources)
Carbohydrate Metabolism
Liver: nutrient distribution center

48. 1- Increased fatty acid synthesis:
Favored by :
- Availability of substrates (acetyl CoA & NADPH from glucose metabolism)
- Activation of acetyl CoA carboxylase (rate-limiting step in fatty acid
synthesis)
2- Increased triacylglycerol (TAG) synthesis:
Favored by:
- Fatty acid is provided from de novo synthesis from acetyl CoA &
chylomicron remnants taken by the liver.
- Glycerol 3-phosphate is provided by glucose metabolism (glycolysis).
Liver packages TAG into VLDL that are secreted into blood for use by
extrahepatic tissues (particularly adipose & muscle).
Fat metabolism
Liver: nutrient distribution center

49. 1- Increased protein synthesis:
To replace any degraded proteins during fast period.
No storage of extra protein or amino acids.
2- Increased amino acid degradation:
In the absorptive state, more amino acids are present than the liver
can use for synthesis of proteins.
Excess amino acids are not stored in any form BUT,
They are released to blood to other tissues for protein synthesis or,
deaminated in liver into carbon skeleton & ammonia
Carbon skeleton can be catabolized for energy production or used for
fatty acid synthesis.
Liver can synthesize proteins from abundant diet amino acids to a certain limit
after which excess amino acids are either released to other tissues or
degraded.
Amino acid metabolism
Liver: nutrient distribution center

50. Liver: nutrient distribution center
Liver
in the absorptive
state

51. Adipose tissue: energy storage depot
Carbohydrate metabolism:
1- Increased glucose transport:
GLUT-4 of adipocytes are insulin-sensitive.
In the absorptive state, insulin conc. is elevated resulting in increased
influx of glucose into adipocytes.
2- Increased glycolysis:
due to increased intracellular levels of glucose
Glycolysis provides glycerol 3-phosphate for triacylglycerol synthesis.
3- Increased activity of pentose phosphate pathway (PPP)
Increased PPP results in increased formation of NADPH essential for
fatty acid synthesis.

52. Fat metabolism:
1- Increased synthesis of fatty acids (NOT A MAJOR PATHWAY):
Fatty acid synthesis in adipose tissue is not a major pathway.
Instead, most fatty acids added to adipose tissues are provided by diet
fat (in chylomicrons) with a lesser amount supplied by VLDL of liver.
2- Increased triacylglycerol synthesis:
Exogenous fatty acids (from diet fat: chylomicrons & liver fat: VLDL)
& glycerol 3 phosphate (from glycolysis of glucose) are used for
synthesis of triacylglycerol in adipose tissue.
Thus, in well-fed state (absorptive state),
storage of triacylglycerol (fat) in adipose tissue is favored
Adipose tissue: energy storage depot

53. Adipose tissue: energy storage depot
Adipose tissue
in the
absorptive
state

54. Overview:
• Skeletal muscle is able to respond to changes in demand for ATP that
accompanies muscle contraction.
• At rest, muscle account for about 30% of oxygen consumption of the body
During vigorous exercise, muscles account for up to 90% of total oxygen
consumption.
• Skeletal muscle depends on aerobic & anaerobic glycolysis metabolism for
getting energy (while heart muscle depends on aerobic metabolism only).
• Skeletal muscles have stores for energy in the form of glycogen,
(while heart muscle does not have these stores).
Resting skeletal muscle

55. Resting skeletal muscle
Carbohydrate metabolism:
1- Increased glucose transport:
GLUT-4 of skeletal muscles cells are insulin-sensitive.
In the absorptive state (after a carbohydrate rich meal), insulin conc. is elevated
resulting in increased influx of glucose into skeletal muscle cells.
Glucose provides energy to muscles during the fed state (in contrast to the
fasting state in which ketone bodies & fatty acids are the major fuels of resting
muscles.
1- Increased glycogen synthesis:
During absorptive period, glucose (which is abundant after a carbohydrate rich
meal), is stored in the form of glycogen in skeletal muscles.

56. Amino acid metabolism:
1- Increased protein synthesis:
During the absorptive period, amino acid uptake & protein synthesis is increased
to replace degraded protein since the previous meal.
2- Increased uptake of branched-chain amino acids (leucine, isoleucine & valine)
These amino acids escape metabolism by the liver & are taken up by muscle.
Resting skeletal muscle

57. Resting skeletal muscle
Skeletal muscles in the
absorptive state

58. Overview:
• Brain accounts for 20% of basal oxygen consumption of body at rest (although it is
only 2% of adult weight).
• Brain uses energy at a constant rate.
• Brain is vital for proper functioning of all organs of the body & so, special priority is
given to its energy needs.
• Glucose normally serves as the primary fuel as the concentration of ketone bodies
in the fed state is too low to serve as an alternate energy source.
• If blood glucose falls to below 30 mg/100 ml (Normal: 70 – 110 mg/100 ml),
cerebral functions are impaired.
If hypoglycemia occurs for even a short time, severe & irreversible brain damage may
occur.
N.B. During fast, ketone bodies play a significant roles.
Brain

59. Carbohydrate metabolism:
In the fed (absorptive) state, the brain uses glucose exclusively as a fuel.
(140 grams/day is oxidized to carbon dioxide & water)
Excess glucose is not stored (no glycogen stores). Accordingly, the brain is
completely dependant on availability of blood glucose.
Brain

60. Organ map during the absorptive state
showing intertissue relationship

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Ashok Katta
Dept. of Biochemistry,
Dhanalakshmi Srinivasan Medical College,
Perambalur
Thankyou