Download MBBS Biochemistry PPT 63 Integrated Metabolism Lecture Notes

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HUMAN INTER-RELATIONSHIPS


WORLD OF BIOMOLECULES

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And

INTER-RELATIONSHIPS

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ANY GUESSES FOR TODAYS TOPIC ?
Integrated Metabolism

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OR

Intermediary Metabolism

OR

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Interrelationship Between

Various Metabolic Pathways

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OR

Interdependence Of Metabolic

Pathways

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What Is an Essence of

Normal, Health, Growth and Reproduction

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of Human Body?
Normal Metabolism of Biomolecules

Metabolism and Types

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Important Factors Of Metabolism

?Metabolites

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?Hormones
?Enzymes
?Cofactors
?Coenzymes
?Water

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?Oxygen

? Various metabolic reactions, pathways and

processes of important biomolecules of human

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body viz:

? Carbohydrates
? Lipids

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? Proteins
? Nucleic acids
? Hemoglobin

? Taking place in different cells and cellular

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compartments of specific tissues and organs.


Significance To Study

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Individual Metabolic Pathways

Of Various Biomolecules

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? Metabolism of each chief

biomolecule was studied

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individual y and separately.

? For convenience and clear

understandings of metabolic

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reactions associated to it.


Features of

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Normal Metabolic Pathways
1. Well Planned
2. Compartmentalized
3. Well Organized/ More Systematic

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4. Require Specific Conditions
5. Synergistic/Simultaneous
6. Flexible/Adapt/Change for good survival
7. Induced as per condition
8. Regular in its operation

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9. Regulated/Control ed/Balanced
10. Good cooperation and coordination

Hormones Regulate Metabolism
? Hormones are key regulators of

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Enzymes

? Regulatory Enzymes are stimulated or

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inhibited by specific hormones

? Enzymes are regulated by:

?Al osteric Regulation

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?Covalent Modifications

Metabolism Is Regulated By

? Availability of Substrates Regulate

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Metabolism :

?Ratio of Insulin/Glucagon
?Ratio of ATP and AMP

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?NADH/NAD
?Citrate levels
?Fructose 2,6 Bisphosphate levels
? Low and high levels of ATP stimulate and

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inhibit regulatory enzymes of Glycolysis and

TCA.

? Increased levels of Acetyl-CoA and Citrate

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stimulates enzyme Acetyl CoA Carboxylase

of De Novo biosynthesis of Fatty acid.

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? Increased Fructose 1,6 Bisphosphatase is

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

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of Gluconeogenesis.

What is an Integrated Metabolism?
? Metabolic pathways are Closely

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Interrelated/Integrated

/Interdependent

?Not total y dependent nor total y

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independent

OR

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?But partial dependence and partial

independence

Stages Of Integrated Metabolism

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Evidences Of

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Metabolic Interrelationships

Interrelationships

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Of

Carbohydrates with Lipid Metabolism

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Free Excess of Glucose

In Wel Fed Condition

Is a Source For Lipogenesis

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Acetyl-CoA Obtained from

Glucose Metabolism

Is Precursor for

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Lipid Metabolism

(Fatty acids and Cholesterol)

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? Pyruvate (3C Keto acid) an end product

of Glycolysis is oxidatively

decarboxylated to Acetyl-CoA

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? Acetyl-CoA is then utilized via TCA

cycle

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? Acetyl-CoA obtained from Glucose

when excess is diverted and used for

biosynthesis of Fatty acids and

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Cholesterol.
Glyceraldehyde Of Glycolysis

Integrated as Glycerol

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of

TAG and Glycerophospholipid

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? Glyceraldehyde-3-phosphate an

intermediate of Glycolysis of Glucose ,

is a source for Glycerol production.

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? Glycerol obtained from Glucose is

utilized during Lipogenesis ,for

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biosynthesis of Triacylglycerol and

Phospholipid biosynthesis.

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? Thus when Carbohydrates

ingested in excess can be

transformed to TAG which is

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? Stored as reserve source of

energy in Adiposecytes

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Interrelationships

Of

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TCA Cycle
TCA Cycle

Is an

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Excellent Example

of

Integrated Metabolism

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? TCA cycle intermediates are very

significant

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? These intermediates are influxed

and effluxed as per the cel ular

need and maintain biochemical

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Homeostasis. (Anaplerotic

Reactions)

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Efflux of TCA Intermediates

? Citrate ? Denovo Biosynthesis of Fatty

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acids.

? OAA is reversibly transaminated to

Aspartate.

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? Ketoglutarate reversibly transaminated

to Glutamate.

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? Succinyl CoA is effluxed for Heme

biosynthesis and Ketolysis.
Influx of TCA Cycle Intermediates

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? Ketoglutarate is added by Glutamate by it's

Glutamate Dehydrogenase activity.

? Succinyl -CoA is obtained from Propionyl-CoA

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which is a source from B-oxidation of odd chain

fatty acid

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? Catabolism of Valine, Isoleucine & Methionine

(VIM) amino acids forms Succinyl-CoA.

? Fumarate is influxed through

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Phenylalanine & Tyrosine

metabolism

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? Fumarate also through Urea

cycle by Argininosuccinase

activity.

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Points To Remember

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? TCA intermediates are involved

for biosynthesis of:

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I. Glucose

I . Amino acids

I I. Fatty acids And Cholesterol

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IV. Heme


Interrelationship Of

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TCA with Urea Cycle

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Interrelationships Of

Lipid With Carbohydrate

Metabolism

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Fat Burns Under Flame of

Carbohydrates

? Fat burns under the Flame of

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Carbohydrates

? For complete oxidation of Fatty

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acids

? Their needs presence of

sufficient amount of cel ular

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Glucose.


Oxaloacetate Serves Flame for Complete

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Oxidation Of Fatty acid

? In a well fed condition
? Major source for OAA is

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Glucose

? By Pyruvate Carboxylase

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activity
?Oxaloacetate is an

essential initiating

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metabolite for TCA cycle

?Oxaloacetate (OAA)

serve as a flame for

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oxidation of Acetyl

CoA via TCA cycle.
? Cel ular deprivation of Glucose

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lowers OAA leads to incomplete

oxidation of Fatty acids.

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? Accumulates Acetyl-CoA in

Mitochondrial matrix.

? Impermeable Acetyl-CoA is then

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transformed to permeable ketone

bodies via ketogenesis.

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-oxidation of Fatty acid and it's

Interrelationship
? Reduced coenzymes FADH2 &

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NADH+H+ generated during it's

pathway are

? Integrated with ETC /oxidative

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phosphorylation to generate

ATP.

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?Acetyl-CoA formed as an end

product of oxidation of

fatty acids

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?Is integrated with TCA cycle

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

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Ketone bodies production via

Ketogenesis.

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? To smal extent in normal

metabolic conditions and excess

in emergency conditions.

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Remember

Fatty acids

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cannot be converted

to Glucose In Human

Body

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? Acetyl-CoA obtained from Beta-

oxidation of fatty acids cannot be

reversibly converted to Pyruvate

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? Since PDH complex is irreversible in

action.

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? Thus there is no net conversion of

Fatty acids (Fat) to Glucose

(Carbohydrates).

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? However Propionyl-CoA an end

product of oxidation of odd chain

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fatty acid

? Serve as a source for Glucose

production after conversion into

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Succinyl-CoA (intermediate of TCA

cycle)

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? Succinyl-CoA in turn can be a source

for Heme synthesis and Ketolysis.
Interrelationship

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Of

Carbohydrates

And

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Protein Metabolism

? Intermediates of Glucose

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metabolism can be a source of

? Carbon skeleton for biosynthesis of

non Essential amino acids.

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vPyruvate to Alanine
vOAA to Aspartate
vKetoglutarate to Glutamate

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Amino Acids And Its Interrelationships
Amino acids are interrelated

for

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Purine and Pyrimidine

biosynthesis

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

For Glucose In Human Body

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? Glucogenic amino acids are source

for production of Glucose via

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Gluconeogenesis.

? 100 gm of Proteins can produce

approx 60 gm of Glucose in human

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body.
?Amino acid Glycine is

connected to Heme

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biosynthesis.

? Glycerol released during

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lipolysis of TAG is integrated

? With Gluconeogenesis to

produce Glucose.

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HMP Shunt and It's lnterrelationships

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? Glucose is alternatively oxidized

through HMP shunt to generate:

? NADPH+H+ (reducing equivalents)

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? Ribose-5- phosphate


? NADPH+H+ are integrated to:

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*Biosynthesis of Fatty acids
*Biosynthesis of Cholesterol
*Drug metabolism
? Ribose-5-phosphate

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(pentose sugar) of HMP

shunt is integrated for

?Biosynthesis of Purine &

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Pyrimidine Nucleotides.

Interrelationships of

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Uronic acid pathway


?Glucuronic acid is involved

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in Mucopolysaccharide

biosynthesis.
? Glucuronic acid of Uronic acid

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pathway is integrated with Phase

I conjugation reactions of

detoxification process.

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?Glucuronic acid is involved in:
?Bilirubin metabolism
?Drug metabolism

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Interrelationship Of ETC

? Reduced coenzyme NADH+H+

generated in Glycolysis

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? By action of Glyceraldehyde? 3 ?

Phosphate Dehydrogenase

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? Enter in ETC for its reoxidation

and ATP generation.

ATP and Its Interrelationships

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? ATP produced during oxidative

phosphorylation are connected to:

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

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Crossroads Of Metabolism

OR

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Metabolites of Cross Roads


v Four Important Metabolites in

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human body who function as

crossroads of metabolism :

1. Glucose-6-Phosphate

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2. Pyruvate
3. Acetyl-CoA
4. Oxaloacetate (OAA)
5. Succinyl-CoA

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Formation And Fates

Of

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Pyruvate

Formation And Fates

Of

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Acetyl CoA

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Formation And Fates Of Oxaloacetate

And

Formation And Fates Of Succinyl-CoA

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Metabolites Forming

Non essential Amino acids

In Human Body

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Phosphoenolpyruvate

Phenylalanine Tyrosine Tryptophan

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Tyrosine

Ribose 5-phosphate

Histidine

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Pyruvate

Alanine Valine Leucine

a-Ketoglutarate

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Glutamate

Glutamine Proline Arginine
3-Phosphoglycerate

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Serine

Glycine

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Cysteine

Oxaloacetate

Aspartate

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Asparagine Methionine Threonine Lysine

Isoleucine
Metabolic Profile

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And

Interrelationship Among Organs

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Important Metabolic Organs

And Their

Interrelationships

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Metabolic Profile of Organs

121

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Liver

? Biochemical Factory of Human body

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? Metabolical y very active in all states

(well fed and fasting)

? Most Cooperative and Coordinated

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organ/Understands responsibility and

does its work (Dutiful/Pious Organ)

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Liver is a Glucostatic Organ

Regulates Blood Glucose

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in al conditions


The wel -fed state:

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Insulin stimulates glucose consumption and

Stimulated by an

storage in muscle and liver.

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increase in blood

glucose level.

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Stored as glycogen

or triacyglycerol.

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?In a wel fed condition Liver stores

excess free Glucose as Glycogen

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(Glycogenesis)

?In emergency condition In Liver

Glycogen is degraded via

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Glycogenolysis and biosynthesizes

Glucose via Gluconeogenesis.
?Liver biosynthesizes

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endogenous Lipids and

mobilizes out it as VLDL

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for extra hepatic use.

?Liver Centre of Ammonia

Detoxification

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Muscles

? In a normal metabolic state

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muscle uses Glucose and Fatty

acids as main sources of energy.

? In a well fed state muscles has

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large stores of Glycogen (3/4th)
? In contracting muscles during severe

exercise in anaerobic condition

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Glycolysis ends as Lactate.

? Later Lactate is metabolized by

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converting it into Glucose after carried

through blood in Liver via

Gluconeogenesis (Cori cycle).

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?In resting Muscle fatty

acids are the major source

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of energy

?This use spare Glucose to

be used by Brain and

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Erythrocytes.


Metabolic cooperation between

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the skeletal muscle and liver.

The Cori Cycle

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Metabolic Profile of Muscles

136

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Adipose Tissue

? TAG can be abundantly and

unlimitedly stored in adipocytes

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? TAG serve as a reserve store of

energy during well fed condition.

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? TAG is the major fuel for this

tissue.
Metabolic Profile of Adipose Tissue

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? Needs Glucose for biosynthesis of TAG

? Glucose level determines to release

Fatty acids into blood

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? Hormone sensitive Lipase is activated

when Insulin/Glucagon ratio is low

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Brain

? Glucose is the main fuel of Brain

(120 gm/day)

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? Fatty acids cannot be utilized by

brain as they are bound to Albumin

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and cannot cross blood brain

barrier.

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Metabolic Profile of Brain

60-70 % of bodies utilization of Glucose is

by Brain.

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In starvation -> Ketone bodies can

replace Glucose

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Brain is a major

Glucose consumer

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Fatty acids do not serve as a fuel!

Consumes about 120 g

glucose daily.

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Erythrocytes

? Erythrocytes uses obligatorily Glucose as

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a source of energy for its activity.

? Erythrocytes cannot use Fatty acids and

Ketone bodies as source of energy.

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? It lacks Mitochondria hence the

Glycolysis ends in Lactate.

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Metabolic Profile of Kidney

? Filtration of Blood- Plasma Ultra Filtrate
? Reabsorption ,Secretion of Substances

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? From Plasma Ultra filtrate -> Water , Glucose important

absorbable metabolites reabsorbed as per the threshold

values.

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? Production of Urine -> Secretion of waste products
? Important role in water, electrolyte ,acid base balance.

? During Starvation -> Important site of Gluconeogenesis

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(1/2 of blood Glucose)

145

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In Human Body

There Prevails

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Chemical Unity In Diversity

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? Intermediates/End Products of one metabolic

pathway may be connected to another

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metabolic pathway of same or another.

? An end product of one metabolic

pathway of Carbohydrate is connected to

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another metabolic pathway of

Carbohydrate.

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? Intermediate of Carbohydrate metabolic

pathway is interrelated to a metabolic

pathway of Lipid or Nucleic acid.

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Integration of Fuel Metabolism

Purine

Uric acids

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Glycogen

Ribose-5-P

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monophosphate

PRPP

Pyrimidine

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G-6-P

monophosphate

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Glycine

Serine

G-3-P

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Malonyl CoA

Fatty acids

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b-Oxidation

PEP

Acetoacetyl CoA

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Cholesterol

Acetyl CoA

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Other

Pyruvate

amino

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Triacylglycerols

Oxaloacetate

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acids

Alanine

TCA

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Aspartate

Cycle a

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Other

-ketoglutarate

Urea

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amino

Urea

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Other

Glutamate acids

Cycle

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amino

Glutamine

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acids

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Why Metabolic Pathways are

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Integrated?

OR

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What Is the Significance Of

Integrated Metabolism

To Human Body?

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Integrated Metabolism Occurs To

1. To Interconvert biochemical metabolites as

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per the cel ular need

2. To meet the bodies fuel demand
3. To regulate levels of intermediary

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metabolites and maintain their equilibrium

4. To coordinate with various cel s, tissues

and organs for existence

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5. To impart normal biochemical

environment and maintain health
?A well coordinated and

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regulated integrated

metabolism of human

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body

?Protects from metabolic

catastrophes.

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Significance Of

Knowledge Of Integrated Metabolism

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To Doctors
? Prerequisite to Become A Good

Doctor Is to:

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?Acquire Profound Knowledge of

Integrated Metabolism

?With Good Understanding

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Biochemical Concepts And its

Interrelationships

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Doctors Responsibility

Health Professionalist

? To Heal and Relieve Pain of Patients

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? To Understand Sign Symptoms
? Correlate with Biochemical basis
? Depict Biochemical Alteration
? Confirm diagnosis
? Control, treat biochemical alterations of a

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disordered patients
? Study of integrated metabolism with their

interrelationships in a normal healthy conditions

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helps a doctor :

? To better understand various deranged

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metabolic conditions and related complexities

? Rule out right biochemical underlying cause of

metabolic disorders and pathogenesis

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? Try correct an altered metabolism in treatment

Take Home Messages

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Interrelationship Of Human

Biochemical System

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A good Doctor is one

Who has An

Understanding Knowledge of

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Intermediary Metabolism
Questions

? Long Essays.

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? Q.1.Describe the common metabolic pathway.

OR

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? Why TCA cycle is called as common metabolic

pathway? Explain with reactions.

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

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Carbohydrates".
?Which metabolic pathway

is an excellent example of

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integrated metabolism?

Justify it.

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? Q.3.How Carbohydrate, Lipid & Protein

metabolic pathways are integrated &

interrelated with each other. Explain

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with the help of flow diagram.

? Q.4.Explain the three stages in the

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intermediary metabolism of

Carbohydrate, Lipid & Protein.

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?Influx & Efflux of TCA

intermediates.

?Integration of TCA with

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Urea cycle.

?Formation and Fates of

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? Pyruvate
?Acetyl-CoA
?Succinyl-CoA
?Oxaloacetate
?-Ketoglutarate

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? Q.5.Describe the role of

fol owing organs during

wel fed condition.

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?Liver
?Brain
?Muscles
?Adipose tissues

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THANK YOU

Dr Anissa Atif Mirza

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Biochemistry Department

AI MS Rishikesh

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Important Tips For

4/4/2022

183

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Three Gifts For Human Beings

On Which Health And Success Depend Upon

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How Best they are Utilized

For Significant/Good Long Term Outcome

?Body- Sense

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?Time
?Energy
Factors For Quality Of Health

Normal State Of Biomolecules and Metabolism

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? Intentions and Actions= Behavior (Sleep Cycle)

? Nutrition (Food Cycle)

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? Environment (Companionship)

Health Factors

Il Health Factors

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Positive Behavior- Sensibly

Negative Behavior- Carefree

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,thoughtful ,rightful care of body ,Uncontrolled, dysregulated

by Controlled ,Regulated with

activities with disobedience rigid

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obedient implementation's of Do's non implementations of Do's and

of Health and Avoid Don'ts of

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high implementations of Don'ts

Health
Balanced Diet- Simple and Natural Imbalanced Diet with more

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Appropriate Quality and Quantity processed and refined with poor

of all essential nutrients

quality and improper quantity of

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nutrients

Proper Sleep- Time 7-8 Hrs

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Improper Sleep with low time in

(Early To Bed and Early To Rise)

night and more time in day

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Environment- Natural Unpolluted Environment ?

Companionship with ?

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Polluted with physical, chemical

Good ,Positive, Helpers

and biological pollutants

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Companions with ?

Bad,Negative,Distractors
Biomolecules And Their Processes Responsible For Health

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Similar Features Implemented In Practical Human Life wil

impart Success

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1. Focused and Specific

2. Implement rules and regulations/orders of

metabolism (Obedient)

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3. Interdependence -Communicate and

Cooperate

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4. Disciplined and Dutiful-Responsible/Sensible

5. No two works at a time- For maintaining ful

Concentration

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6. Complete one priority work and start Next

priority -

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7. Not much multitasking/Very few multitasking as per

need

8. Do Not get overloaded at one time

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9. Understand situation and work accordingly (Adapt as

per condition)

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10. Sparing actions, Distribute (Charity, Share and Care)

11. Work with good pace in regularity

12. Proof Read -No Chance of Mistakes/Less errors

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13. Defined and Refined- Limitations

14. Homeostasize to be in limit and do not cross limits

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15. Productive/Significant-Non Futile (Economical

,Reutilizes ,No wastage)
Tips To Ensure Good ,Healthy Life

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? Live Life

? Thoughtful y,Righteously,Carefuly,Actively,Alertly

? Eat Balanced

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? Proportionate Quantity and Appropriate Quality

? Drink and Breathe

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? Unpol uted Water and Air

? Cultivate Cheerfulness

? Love,Share,Care,

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? Thankfulness,Politeness,Selflessness

? Avoid Synthetic, Chemical Interactions

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? Chemical, Inhibitions leads to Disorders

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Live a Thoughtful, Rightful and Lawful

Life

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? Life is Journey of Realization

? Life is path to bring changes by corrections and

improvements

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? Use Sense , Time and Energy for good significant

long-term outcome

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? Adopt Do's of Health and Success

? Quit/Sacrifice don'ts with steadfastness for

prevention of Il -health and Failures

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Let Al of Us Realize and Clearly Differentiate

? Do's and Don'ts of every human action
? Obedience and Disobedience
? Respect and Disrespect

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? Truth and False
? Mistakes and Corrections
? Success and Failure
? Good and Bad
? Wrong and Right

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? Healthy and Unhealthy
? Hygienic and Unhygienic
? Significant and Insignificant
? Helpful and Harmful

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? Friend and Enemy
? Well wisher and Bad Wisher
? Patience and Impatience
? Gratitude and Thankless
? Blessings and Cursing's

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Factors For Success

? Blessings

1. Selflessness/No Selfishness

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2. Taking care equal y for oneself and

others

3. Obedience for truth and significant acts

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4. Responsible and Dutiful
5. Being Truth and Transparent
6. Not making people wait /Lying

6. Not Cheating for our own benefits

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7. Keeping and Fulfil ing Promises
8. Sharing of al good you have
9. Caring for one who needs
10. Spreading/Not Hiding significant

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/true Knowledge

11. Not Distracting persons who are on

righteous path

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12. Not Irritating one who is righteous
13. Lifting people who needs

14. Guiding for Right acts

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15. Stopping from wrong acts

16. Not Hurting any soul with

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disrespect and disobedience

17. Obeying and implementing true

words

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18. Using best Sense, Energy and

Time for best long term outcome

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S.No

8 Rs To Implement

1

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Realize

2

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Recapitulate

3

Reasoning

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4

Reassess

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5

Respond

6

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Rehearse

7

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Regular and Routine

8 4/4/2022

Rejuvenate

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9 Ps Implement

9 Cs Implement

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Prayers

Concentrate

Priorities

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Communicate

Plan - Protocol

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Cooperate

Practice

Commitment

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Proof Read

Control

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Perseverance

Coordinate

Positivity

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Compensate

Patience

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Companionship

Perfectionist

Cope up & Change

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Best For Human Health

Thoughtfulness and Righteousness

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Eating And Living Style

Natural-Planned ,Organized ,Regular , Disciplined

Simple , Humble, Care and Share

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Yes for Good Stead Fast No For Bad

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198
Implement

Thoughtfulness and Righteousness

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? Everywhere and Anywhere

? Every work and Any work

? Every time and Anytime

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Tips Of Good Success

?Good Hard work
?Good Intentions

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Live An Evidenced Based Life

? Acquire Knowledge- Search/Ask

(Do's and Don'ts of priority actions)

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? Assess/Understand Truth

? Accept

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? Apply/Implement -Truth/Dos

? Appraise/Evaluate its significance

? Spread Truth and Significance

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THANKS