Download MBBS Biochemistry PPT 51 Integrated Metabolism Lecture Notes

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Intermediary Metabolism

OR

Interrelationship Between

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Various Metabolic Pathways

OR

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Interdependence Of Metabolic

Pathways

To Better Understand Metabolism Of

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Various Biomolecules

? Metabolism of each chief

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biochemical was studied

individual y and separately.
? This was just for convenience

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and better understanding of

? Various metabolic pathways

associated with each

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biochemical constituent.

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

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processes of important biochemical moieties of

human body viz:

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? Carbohydrates
? Lipids
? Proteins
? Nucleic acids
? Hemoglobin

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? Takes place in different cells and cellular

compartments of specific tissues and organs.

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? For maintaining normal health ,growth and

reproduction.

The Metabolic Pathways Of Cel s

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Takes Place

? Synergistical y
? Closely Interrelated/Integrated

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? With Interdependence
? In a Regulated manner
? With good coordination
? In the cellular compartments

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of the body

? Various metabolic pathways

related to different metabolic

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moieties

?Takes place synergistical y, as

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per the cellular conditions.

Factors Regulating Metabolism

? Hormones are the 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 ATP and AMP
?Citrate levels
?Fructose 2,6 Bisphosphate levels

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? Low and high levels of ATP stimulate and

inhibit the regulatory enzymes of Glycolysis

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and TCA.

? Increased levels of Citrate stimulates

enzyme Acetyl CoA Carboxylase of De Novo

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biosynthesis of Fatty acid.

? Increased Fructose 1,6 Bisphosphatase is

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

of Gluconeogenesis.

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Evidences Of

Metabolic Interrelationships
Interrelationships

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Of

Carbohydrate with Lipid Metabolism

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Free Excess Glucose In Wel Fed

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

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oxidatively decarboxylated to Acetyl-

coA

? Acetyl-coA is then utilized via TCA

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cycle

? Acetyl-coA of Glucose when excess is

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diverted and used for biosynthesis of

Fatty acids and Cholesterol.

? Glyceraldehyde-3-phosphate an

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intermediate of Glycolysis of Glucose

, is a source for Glycerol production.

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? Glycerol obtained from Glucose is

utilized during Lipogenesis ,for

biosynthesis of Triacylglycerol and

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Phospholipid biosynthesis.


? When Carbohydrates taken in

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excess can be converted to

TAG which is

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? Stored as reserve source of

energy in Adiposecytes

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Interrelationships Of

TCA Cycle
TCA Cycle

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Is an

Excellent example

of

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Integrated Metabolism

? The TCA cycle intermediates are

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very significant

? These intermediates are

influxed and effluxed as per the

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cellular need and maintain

biochemical Homeostasis.

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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.

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Influx of TCA Cycle Intermediates

? Ketoglutarate is added by Glutamate by

it's Glutamate Dehydrogenase activity.

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? Succinyl -CoA is obtained from Propionyl-

CoA which is a source from B-oxidation of

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odd chain fatty acid

? Catabolism of Valine, Isoleucine &

Methionine (VIM) amino acids forms

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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

? TCA intermediates are used for

the biosynthesis of:

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I. Glucose

I . Amino acids

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I I. Fatty acids

IV. Heme

Interrelationship Of

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TCA with Urea Cycle


Interrelationship Of

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Lipid and Carbohydrate

Metabolism
? 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.

?In a wel fed

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conditions


?The major source of

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OAA is Glucose.
?Oxaloacetate is an

essential initiating

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metabolite for the

TCA cycle.

?OAA serve as a flame

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for oxidation of

Acetyl CoA via TCA

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cycle.
? Cel ular deprivation of Glucose

leads to incomplete oxidation of

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Fatty acids.

? Accumulates Acetyl-CoA in

Mitochondrial matrix.

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? Impermeable Acetyl-CoA is then

transformed to permeable ketone

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bodies via ketogenesis.

Interrelationship

Of

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Carbohydrates

And

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Protein Metabolism
? Intermediates of Carbohydrate

metabolism can be a source of

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? Carbon skeleton for biosynthesis of

non Essential amino acids.

vPyruvate to Alanine

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vOAA to Aspartate
vKetoglutarate to Glutamate

-oxidation of Fatty acid and it's

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Interrelationship
? The reduced coenzymes FADH2

& NADH+H+ generated during

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it's pathway are

? Integrated with ETC /oxidative

phosphorylation to generate

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ATP.

?Acetyl-CoA formed as an end

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product of oxidation of

fatty acids

?Is integrated with TCA cycle

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

Ketone bodies production via

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Ketogenesis.

? To smal extent in normal

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metabolic conditions and excess

in emergency conditions.

Remember

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Fatty acids

cannot be converted

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to Glucose In Human

Body
? Acetyl-CoA obtained from Beta-

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oxidation of fatty acids cannot be

reversibly converted to Pyruvate

? Since PDH complex is irreversible in

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action.

? Thus there is no net conversion of

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Fatty acids (Fat) to Glucose

(Carbohydrates).

? However Propionyl-CoA end product

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of oxidation of odd chain fatty acid

? Serve as a source for Glucose

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production after conversion into

Succinyl-CoA (intermediate of TCA

cycle)

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? Succinyl-CoA in turn can be a source

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

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a source for Amino

acids Biosynthesis in

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human body .

Interrelationship With ETC

? Reduced coenzyme NADH+H+

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generated in Glycolysis

? By action of Glyceraldehyde? 3 ?

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Phosphate Dehydrogenase

? Enter in ETC for its reoxidation

and ATP generation.

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HMP Shunt and It's lnterrelationships

? Glucose is alternatively oxidized

through HMP shunt to generate:

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? NADPH+H+ (reducing equivalents)

? Ribose-5- phosphate
? NADPH+H+ are integrated to:

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*Biosynthesis of Fatty acids
*Biosynthesis of Cholesterol
*Drug metabolism

? The Ribose-5-phosphate

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(pentose sugar) of HMP

shunt is integrated for

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?Biosynthesis of Purine &

Pyrimidine Nucleotides.
Amino acids are interrelated

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for

Purine and Pyrimidine

biosynthesis

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

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For Glucose In Human Body

? Glucogenic amino acids are source

for production of Glucose via

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Gluconeogenesis.

? 100 gm of Proteins can produce

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approx 60 gm of Glucose in human

body.
?Amino acid Glycine is

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connected to Heme

biosynthesis.

? Glycerol released during

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lipolysis of TAG is integrated

? With Gluconeogenesis to

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produce Glucose.
Interrelationships of

Uronic acid pathway

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? Glucuronic acid of Uronic acid

pathway is integrated with Phase

I conjugation reactions of

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detoxification process.

?Glucuronic acid is involved in

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Bilirubin and other drug

metabolism.
?Glucuronic acid is involved

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in Mucopolysaccharide

biosynthesis.

? ATP produced during oxidative

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phosphorylation are connected to:

I. Nerve impulse conduction
I . Muscular activity

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I I. Active transport mechanism
IV. Biosynthetic Reactions
V. Activation Reactions
Crossroads Of Metabolism

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v Important Metabolites in human

body who function as crossroads of

metabolism :

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

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Formation And Fates

Of

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Pyruvate

Formation And Fates

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Of

Acetyl CoA

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Formation And Fates Of Oxaloacetate

OR

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

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Liver

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

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states (well fed and fasting).

? Has good coordination with other

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body organs.
? Liver is a Glucostatic organ regulates

blood Glucose in al conditions.

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?In a wel fed condition Liver

stores excess free Glucose as

Glycogen.

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?In emergency condition In Liver

Glycogen is degraded via

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Glycogenolysis and

biosynthesizes Glucose via

Gluconeogenesis.

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?Liver biosynthesizes

endogenous Lipids and

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mobilize out it as VLDL

for extra hepatic use.
Muscles

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? In a normal metabolic state

muscle uses Glucose and Fatty

acids as main sources of energy.

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? In a well fed state muscles has

large stores of Glycogen (3/4th)

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? In contracting muscles during severe

exercise in anaerobic condition

Glycolysis ends as Lactate.

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? Later Lactate is metabolized by

converting it into Glucose after carried

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through blood in Liver via

Gluconeogenesis(Cori cycle).

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?In resting Muscle fatty

acids are the major source

of energy

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?This use spare Glucose to

be used by Brain and

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Erythrocytes.

Metabolic cooperation between

the skeletal muscle and liver.

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The Cori Cycle


Metabolic Profile of Muscles

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83

Adipose Tissue

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? TAG can be abundantly and

unlimitedly stored in adipocytes

? TAG serve as a reserve store of

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energy during well fed condition.

? TAG is the major fuel for this

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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
Brain

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? 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

and cannot cross blood brain

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barrier.

Metabolic Profile of Brain

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60-70 % of bodies utilization of Glucose is

by Brain.

In starvation -> Ketone bodies can

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replace Glucose


Brain is a major

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Glucose consumer

Fatty acids do not serve as a fuel!

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Consumes about 120 g

glucose daily.

Erythrocytes

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? Erythrocytes uses obligatorily

Glucose for its activity.

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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
? From Plasma Ultra filtrate -> Water , Glucose

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important absorbable metabolites reabsorbed as

per the threshold values.

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? Production of Urine -> Secretion of waste products

? During Starvation -> Important site of

Gluconeogenesis (1/2 of blood Glucose)

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91

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The wel -fed state:

Insulin stimulates glucose consumption and

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Stimulated by an

storage in muscle and liver.

increase in blood

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glucose level.

Stored as glycogen

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or triacyglycerol.


In Human Body

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There Prevails

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

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pathway may be connected to another

metabolic pathway of same or another

metabolite.

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? An end product of one metabolic

pathway of Carbohydrate is connected to

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another metabolic pathway of

Carbohydrate.

? Intermediate of Carbohydrate metabolic

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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
Why Metabolic Pathways are

Integrated?

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OR

What Is the Significance Of

Integrated Metabolism

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To Human Body?
Integrated Metabolism Occurs To

1. To Interconvert biochemical metabolites

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as per the cel ular need.

2. To meet the bodies fuel demand.

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3. To regulate the levels of intermediary

metabolites and maintain their

equilibrium.

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4. To coordinate with the 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

To Doctors

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? Doctors are responsible for confirm diagnosis and

treatment of 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 the related

complexities.

? Rule out the right biochemical underlying cause

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of metabolic disorders and pathogenesis.

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

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Doctor Is to

?Acquire Profound Knowledge of

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Integrated Metabolism

?With Good Concepts And its

Understanding.

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A good Doctor is one

Who has An

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Understanding Knowledge

of Biochemistry
Questions

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? Long Essays.

? Q.1.Describe the common metabolic pathway.

OR

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? Why TCA cycle is called as common metabolic

pathway? Explain with reactions.

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

Carbohydrates".
?Which metabolic pathway

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is an excellent example of

integrated metabolism?

Justify it.

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? Q.3.How Carbohydrate, Lipid & Protein

metabolic pathways are integrated &

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interrelated with each other. Explain

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.

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?Integration of TCA with

Urea cycle.

?Formation and Fates of

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

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?-Ketoglutarate
? Q.5.Describe the role of

fol owing organs during

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wel fed condition.

?Liver
?Brain
?Muscles

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?Adipose tissues

THANK YOU

Biochemistry Department

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