Integrated Metabolism
OR
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Intermediary MetabolismOR
Interrelationship Between
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Various Metabolic Pathways
OR
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Interdependence Of MetabolicPathways
To Better Understand Metabolism Of
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Various Biomolecules
? Metabolism of each chief
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biochemical was studiedindividual 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 andreproduction.
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 ModificationsMetabolism 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 FedCondition 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 ofFatty 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 isutilized 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 OfTCA Cycle
TCA Cycle
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Is anExcellent 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 Hemebiosynthesis 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 Ureacycle 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 acidsIV. 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 theTCA 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 ofnon Essential amino acids.
vPyruvate to Alanine
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vOAA to AspartatevKetoglutarate 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 offatty 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 excessin emergency conditions.
Remember
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Fatty acids
cannot be converted
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to Glucose In HumanBody
? Acetyl-CoA obtained from Beta-
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oxidation of fatty acids cannot bereversibly 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 intoSuccinyl-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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forPurine 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 humanbody.
?Amino acid Glycine is
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connected to Hemebiosynthesis.
? 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 acidpathway 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 drugmetabolism.
?Glucuronic acid is involved
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in Mucopolysaccharidebiosynthesis.
? 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 mechanismIV. Biosynthetic Reactions
V. Activation Reactions
Crossroads Of Metabolism
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v Important Metabolites in humanbody 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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OfAcetyl CoA
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Formation And Fates Of OxaloacetateOR
Formation And Fates Of Succinyl-CoA
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Metabolites FormingNon essential Amino acids
In Human Body
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Phosphoenolpyruvate
Phenylalanine Tyrosine Tryptophan
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TyrosineRibose 5-phosphate
Histidine
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PyruvateAlanine Valine Leucine
a-Ketoglutarate
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Glutamate
Glutamine Proline Arginine
3-Phosphoglycerate
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Serine
Glycine
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CysteineOxaloacetate
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 OrgansAnd Their
Interrelationships
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Metabolic Profile of Organs
75
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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 Liverstores excess free Glucose as
Glycogen.
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?In emergency condition In Liver
Glycogen is degraded via
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Glycogenolysis andbiosynthesizes Glucose via
Gluconeogenesis.
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?Liver biosynthesizes
endogenous Lipids and
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mobilize out it as VLDLfor extra hepatic use.
Muscles
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? In a normal metabolic statemuscle 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 severeexercise 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 viaGluconeogenesis(Cori cycle).
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?In resting Muscle fattyacids 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 andunlimitedly 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 bybrain 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 isby 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 gglucose daily.
Erythrocytes
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? Erythrocytes uses obligatorily
Glucose for its activity.
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? It lacks Mitochondria hencethe 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 anstorage 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 PrevailsChemical Unity In Diversity
? Intermediates/End Products of one metabolic
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pathway may be connected to anothermetabolic 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 ofCarbohydrate.
? 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 MetabolismPurine
Uric acids
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Glycogen
Ribose-5-P
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monophosphatePRPP
Pyrimidine
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G-6-P
monophosphate
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GlycineSerine
G-3-P
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Malonyl CoA
Fatty acids
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b-OxidationPEP
Acetoacetyl CoA
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Cholesterol
Acetyl CoA
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OtherPyruvate
amino
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Triacylglycerols
Oxaloacetate
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acidsAlanine
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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OtherGlutamate acids
Cycle
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amino
Glutamine
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acidsWhy Metabolic Pathways are
Integrated?
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ORWhat 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 intermediarymetabolites 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 biochemicalenvironment 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 OfKnowledge 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 relatedcomplexities.
? 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 Knowledgeof 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 ofCarbohydrates".
?Which metabolic pathway
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is an excellent example ofintegrated 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. Explainwith 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 withUrea 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 tissuesTHANK YOU
Biochemistry Department
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