Download MBBS Biochemistry PPT 51 Integrated Metabolism Lecture Notes

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Integrated Metabolism

OR

Intermediary Metabolism

OR

Interrelationship Between

Various Metabolic Pathways

OR

Interdependence Of Metabolic

Pathways

To Better Understand Metabolism Of

Various Biomolecules

? Metabolism of each chief

biochemical was studied

individual y and separately.
? This was just for convenience

and better understanding of

? Various metabolic pathways

associated with each

biochemical constituent.

What is Integrated Metabolism?
? Various metabolic reactions, pathways and

processes of important biochemical moieties of

human body viz:

? Carbohydrates
? Lipids
? Proteins
? Nucleic acids
? Hemoglobin

? Takes place in different cells and cellular

compartments of specific tissues and organs.

? For maintaining normal health ,growth and

reproduction.

The Metabolic Pathways Of Cel s

Takes Place

? Synergistical y
? Closely Interrelated/Integrated
? With Interdependence
? In a Regulated manner
? With good coordination
? In the cellular compartments

of the body

? Various metabolic pathways

related to different metabolic

moieties

?Takes place synergistical y, as

per the cellular conditions.

Factors Regulating Metabolism

? Hormones are the key regulators of

Enzymes

? Regulatory Enzymes are stimulated or

inhibited by specific hormones

? Enzymes are regulated by:

?Al osteric Regulation
?Covalent Modifications
Metabolism Is Regulated By

? Availability of Substrates Regulate

Metabolism :

?Ratio of ATP and AMP
?Citrate levels
?Fructose 2,6 Bisphosphate levels

? Low and high levels of ATP stimulate and

inhibit the regulatory enzymes of Glycolysis

and TCA.

? Increased levels of Citrate stimulates

enzyme Acetyl CoA Carboxylase of De Novo

biosynthesis of Fatty acid.

? Increased Fructose 1,6 Bisphosphatase is

? Al osteric stimulator of PFK of Glycolysis
? Al osteric inhibitor of Fru1,6Bis Phosphatase

of Gluconeogenesis.


Evidences Of

Metabolic Interrelationships
Interrelationships

Of

Carbohydrate with Lipid Metabolism

Free Excess Glucose In Wel Fed

Condition Is a Source For Lipogenesis
? Pyruvate end product of Glycolysis is

oxidatively decarboxylated to Acetyl-

coA

? Acetyl-coA is then utilized via TCA

cycle

? Acetyl-coA of Glucose when excess is

diverted and used for biosynthesis of

Fatty acids and Cholesterol.

? Glyceraldehyde-3-phosphate an

intermediate of Glycolysis of Glucose

, is a source for Glycerol production.

? Glycerol obtained from Glucose is

utilized during Lipogenesis ,for

biosynthesis of Triacylglycerol and

Phospholipid biosynthesis.


? When Carbohydrates taken in

excess can be converted to

TAG which is


? Stored as reserve source of

energy in Adiposecytes

Interrelationships Of

TCA Cycle
TCA Cycle

Is an

Excellent example

of

Integrated Metabolism

? The TCA cycle intermediates are

very significant

? These intermediates are

influxed and effluxed as per the

cellular need and maintain

biochemical Homeostasis.


Efflux of TCA Intermediates

? Citrate ? Denovo Biosynthesis of Fatty

acids.

? OAA is reversibly transaminated to

Aspartate.

? Ketoglutarate reversibly transaminated

to Glutamate.

? Succinyl CoA is effluxed for Heme

biosynthesis and Ketolysis.


Influx of TCA Cycle Intermediates

? Ketoglutarate is added by Glutamate by

it's Glutamate Dehydrogenase activity.

? Succinyl -CoA is obtained from Propionyl-

CoA which is a source from B-oxidation of

odd chain fatty acid

? Catabolism of Valine, Isoleucine &

Methionine (VIM) amino acids forms

Succinyl-CoA.


? Fumarate is influxed through

Phenylalanine & Tyrosine

metabolism

? Fumarate also through Urea

cycle by Argininosuccinase

activity.
Points To Remember

? TCA intermediates are used for

the biosynthesis of:

I. Glucose

I . Amino acids

I I. Fatty acids

IV. Heme

Interrelationship Of

TCA with Urea Cycle


Interrelationship Of

Lipid and Carbohydrate

Metabolism
? Fat burns under the Flame of

Carbohydrates

? For complete oxidation of Fatty

acids

? Their needs presence of

sufficient amount of cel ular

Glucose.

?In a wel fed

conditions


?The major source of

OAA is Glucose.
?Oxaloacetate is an

essential initiating

metabolite for the

TCA cycle.

?OAA serve as a flame

for oxidation of

Acetyl CoA via TCA

cycle.
? Cel ular deprivation of Glucose

leads to incomplete oxidation of

Fatty acids.

? Accumulates Acetyl-CoA in

Mitochondrial matrix.

? Impermeable Acetyl-CoA is then

transformed to permeable ketone

bodies via ketogenesis.

Interrelationship

Of

Carbohydrates

And

Protein Metabolism
? Intermediates of Carbohydrate

metabolism can be a source of

? Carbon skeleton for biosynthesis of

non Essential amino acids.

vPyruvate to Alanine
vOAA to Aspartate
vKetoglutarate to Glutamate

-oxidation of Fatty acid and it's

Interrelationship
? The reduced coenzymes FADH2

& NADH+H+ generated during

it's pathway are

? Integrated with ETC /oxidative

phosphorylation to generate

ATP.

?Acetyl-CoA formed as an end

product of oxidation of

fatty acids

?Is integrated with TCA cycle

for it's complete oxidation.
? Acetyl-coA can be a source for

Ketone bodies production via

Ketogenesis.

? To smal extent in normal

metabolic conditions and excess

in emergency conditions.

Remember

Fatty acids

cannot be converted

to Glucose In Human

Body
? Acetyl-CoA obtained from Beta-

oxidation of fatty acids cannot be

reversibly converted to Pyruvate

? Since PDH complex is irreversible in

action.

? Thus there is no net conversion of

Fatty acids (Fat) to Glucose

(Carbohydrates).

? However Propionyl-CoA end product

of oxidation of odd chain fatty acid

? Serve as a source for Glucose

production after conversion into

Succinyl-CoA (intermediate of TCA

cycle)

? Succinyl-CoA in turn can be a source

for Heme synthesis and Ketolysis.
?Fatty acids are also not

a source for Amino

acids Biosynthesis in

human body .

Interrelationship With ETC

? Reduced coenzyme NADH+H+

generated in Glycolysis

? By action of Glyceraldehyde? 3 ?

Phosphate Dehydrogenase

? Enter in ETC for its reoxidation

and ATP generation.
HMP Shunt and It's lnterrelationships

? Glucose is alternatively oxidized

through HMP shunt to generate:

? NADPH+H+ (reducing equivalents)

? Ribose-5- phosphate
? NADPH+H+ are integrated to:
*Biosynthesis of Fatty acids
*Biosynthesis of Cholesterol
*Drug metabolism

? The Ribose-5-phosphate

(pentose sugar) of HMP

shunt is integrated for

?Biosynthesis of Purine &

Pyrimidine Nucleotides.
Amino acids are interrelated

for

Purine and Pyrimidine

biosynthesis

?Gly , Asp, Gln for Purine Biosynthesis
?Asp and Gln for Pyrimidine Synthesis
Amino acids are Source

For Glucose In Human Body

? Glucogenic amino acids are source

for production of Glucose via

Gluconeogenesis.

? 100 gm of Proteins can produce

approx 60 gm of Glucose in human

body.
?Amino acid Glycine is

connected to Heme

biosynthesis.

? Glycerol released during

lipolysis of TAG is integrated

? With Gluconeogenesis to

produce Glucose.
Interrelationships of

Uronic acid pathway

? Glucuronic acid of Uronic acid

pathway is integrated with Phase

I conjugation reactions of

detoxification process.

?Glucuronic acid is involved in

Bilirubin and other drug

metabolism.
?Glucuronic acid is involved

in Mucopolysaccharide

biosynthesis.

? ATP produced during oxidative

phosphorylation are connected to:

I. Nerve impulse conduction
I . Muscular activity
I I. Active transport mechanism
IV. Biosynthetic Reactions
V. Activation Reactions
Crossroads Of Metabolism

v Important Metabolites in human

body who function as crossroads of

metabolism :

1. Pyruvate
2. Acetyl-CoA
3. OAA
4. Succinyl-CoA


Formation And Fates

Of

Pyruvate

Formation And Fates

Of

Acetyl CoA


Formation And Fates Of Oxaloacetate

OR

Formation And Fates Of Succinyl-CoA
Metabolites Forming

Non essential Amino acids

In Human Body

Phosphoenolpyruvate

Phenylalanine Tyrosine Tryptophan

Tyrosine

Ribose 5-phosphate

Histidine
Pyruvate

Alanine Valine Leucine

a-Ketoglutarate

Glutamate

Glutamine Proline Arginine
3-Phosphoglycerate

Serine

Glycine

Cysteine

Oxaloacetate

Aspartate

Asparagine Methionine Threonine Lysine

Isoleucine
Metabolic Profile

And

Interrelationship Among Organs

Important Metabolic Organs

And Their

Interrelationships


Metabolic Profile of Organs

75

Liver

? Biochemical Factory of Human body
? Metabolical y very active in all

states (well fed and fasting).

? Has good coordination with other

body organs.
? Liver is a Glucostatic organ regulates

blood Glucose in al conditions.

?In a wel fed condition Liver

stores excess free Glucose as

Glycogen.

?In emergency condition In Liver

Glycogen is degraded via

Glycogenolysis and

biosynthesizes Glucose via

Gluconeogenesis.

?Liver biosynthesizes

endogenous Lipids and

mobilize out it as VLDL

for extra hepatic use.
Muscles

? In a normal metabolic state

muscle uses Glucose and Fatty

acids as main sources of energy.

? In a well fed state muscles has

large stores of Glycogen (3/4th)

? In contracting muscles during severe

exercise in anaerobic condition

Glycolysis ends as Lactate.

? Later Lactate is metabolized by

converting it into Glucose after carried

through blood in Liver via

Gluconeogenesis(Cori cycle).


?In resting Muscle fatty

acids are the major source

of energy

?This use spare Glucose to

be used by Brain and

Erythrocytes.

Metabolic cooperation between

the skeletal muscle and liver.

The Cori Cycle


Metabolic Profile of Muscles

83

Adipose Tissue

? TAG can be abundantly and

unlimitedly stored in adipocytes

? TAG serve as a reserve store of

energy during well fed condition.

? TAG is the major fuel for this

tissue.


Metabolic Profile of Adipose Tissue

? Needs Glucose for biosynthesis of TAG

? Glucose level determines to release

Fatty acids into blood

? Hormone sensitive Lipase is activated

when Insulin/Glucagon ratio is low
Brain

? Glucose is the main fuel of Brain

(120 gm/day)

? Fatty acids cannot be utilized by

brain as they are bound to Albumin

and cannot cross blood brain

barrier.

Metabolic Profile of Brain

60-70 % of bodies utilization of Glucose is

by Brain.

In starvation -> Ketone bodies can

replace Glucose


Brain is a major

Glucose consumer

Fatty acids do not serve as a fuel!

Consumes about 120 g

glucose daily.

Erythrocytes

? Erythrocytes uses obligatorily

Glucose for its activity.

? It lacks Mitochondria hence

the Glycolysis ends in Lactate.


Metabolic Profile of Kidney

? Filtration of Blood- Plasma Ultra Filtrate
? Reabsorption ,Secretion of Substances
? From Plasma Ultra filtrate -> Water , Glucose

important absorbable metabolites reabsorbed as

per the threshold values.

? Production of Urine -> Secretion of waste products

? During Starvation -> Important site of

Gluconeogenesis (1/2 of blood Glucose)

91




The wel -fed state:

Insulin stimulates glucose consumption and

Stimulated by an

storage in muscle and liver.

increase in blood

glucose level.

Stored as glycogen

or triacyglycerol.


In Human Body

There Prevails

Chemical Unity In Diversity
? Intermediates/End Products of one metabolic

pathway may be connected to another

metabolic pathway of same or another

metabolite.

? An end product of one metabolic

pathway of Carbohydrate is connected to

another metabolic pathway of

Carbohydrate.

? Intermediate of Carbohydrate metabolic

pathway is interrelated to a metabolic

pathway of Lipid or Nucleic acid.

Integration of Fuel Metabolism

Purine

Uric acids

Glycogen

Ribose-5-P

monophosphate

PRPP

Pyrimidine

G-6-P

monophosphate

Glycine

Serine

G-3-P

Malonyl CoA

Fatty acids

b-Oxidation

PEP

Acetoacetyl CoA

Cholesterol

Acetyl CoA

Other

Pyruvate

amino

Triacylglycerols

Oxaloacetate

acids

Alanine

TCA

Aspartate

Cycle a

Other

-ketoglutarate

Urea

amino

Urea

Other

Glutamate acids

Cycle

amino

Glutamine

acids
Why Metabolic Pathways are

Integrated?

OR

What Is the Significance Of

Integrated Metabolism

To Human Body?
Integrated Metabolism Occurs To

1. To Interconvert biochemical metabolites

as per the cel ular need.

2. To meet the bodies fuel demand.

3. To regulate the levels of intermediary

metabolites and maintain their

equilibrium.

4. To coordinate with the various cel s,

tissues and organs for existence.

5. To impart normal biochemical

environment and maintain health.

?A well coordinated and

regulated integrated

metabolism of human

body

?Protects from metabolic

catastrophes.
Significance Of

Knowledge Of Integrated Metabolism

To Doctors

? Doctors are responsible for confirm diagnosis and

treatment of biochemical alterations of a

disordered patients.

? Study of integrated metabolism with their

interrelationships in a normal healthy conditions

helps a doctor :

? To better understand various deranged

metabolic conditions and the related

complexities.

? Rule out the right biochemical underlying cause

of metabolic disorders and pathogenesis.

? Try correct the altered metabolism in treatment.
? Prerequisite to Become A Good

Doctor Is to

?Acquire Profound Knowledge of

Integrated Metabolism

?With Good Concepts And its

Understanding.

A good Doctor is one

Who has An

Understanding Knowledge

of Biochemistry
Questions

? Long Essays.

? Q.1.Describe the common metabolic pathway.

OR

? Why TCA cycle is called as common metabolic

pathway? Explain with reactions.

? Q.2.Explain "Fat burns under the flame of

Carbohydrates".
?Which metabolic pathway

is an excellent example of

integrated metabolism?

Justify it.

? Q.3.How Carbohydrate, Lipid & Protein

metabolic pathways are integrated &

interrelated with each other. Explain

with the help of flow diagram.

? Q.4.Explain the three stages in the

intermediary metabolism of

Carbohydrate, Lipid & Protein.


?Influx & Efflux of TCA

intermediates.

?Integration of TCA with

Urea cycle.

?Formation and Fates of

? Pyruvate
?Acetyl-CoA
?Succinyl-CoA
?Oxaloacetate
?-Ketoglutarate
? Q.5.Describe the role of

fol owing organs during

wel fed condition.

?Liver
?Brain
?Muscles
?Adipose tissues

THANK YOU

Biochemistry Department

This post was last modified on 05 April 2022