Carbohydrates and carbohdrates metabolism Rajesh Kumar Kushwaha

CARBOHYDRATE
METABOLISM
By :-
Assistant Professor
Mr. Rajesh Kumar Kushwaha
Ph.D(Biochemistry), M.Tech(BT) M.Phil(BT),
M.Sc(Biochemistry), B.Ed(Science) , D.Pharm,
GATE,CSIR NET
Dept. Of Biotechnology Engineering
Goel Institute of Technology and Management Lucknow-
226028
1

CONTENTS
• Introduction
-Nutrition
-Carbohydrates
-Classification of carbohydrates
-Functions of carbohydratesWhat is metabolism?
• Major metabolic pathways of carbohydrates
-Introduction about each pathway
-Step of reactions in every metabolicpathway
-ClinicalAspects
2

CARBOHYDRATE:
4
 Most abundant organic molecule on earth.
Carbohydrates are defined as aldehyde or keto derivatives
of polyhydric alcohols.
 For example: Glycerol on oxidation is converted to
D-glyceraldehyde, which is a carbohydrate derived from the
trihydric alcohol (glycerol).
All carbohydrates have the general formula CnH2nOn [or it
can be re-written as Cn(H2O)n ] .

Carbohydratesarethemostabundantofalltheorganic
compoundsinnature.
 In plants, energy from the Sun is used to convert carbon dioxide and water into the
carbohydrateglucose.
 Many of the glucose molecules are made into long-chain polymers of starch that store
energy.
 About 65%of the foods in our diet consist of carbohydrates.
 Eachday we utilize carbohydrates in foods such asbread, pasta, potatoes, and rice.
 Other carbohydrates called disaccharides include sucrose (table sugar) and lactose in
milk.
 During digestion and cellular metabolism, carbohydrates are converted into glucose,
 which is oxidized further in our cells to provide our bodies with energy and to provide
the cells with carbon atoms for building molecules of protein, lipids, and nucleic acids.
 In plants, a polymer of glucose called cellulose builds the structural framework.
Cellulose hasother importantuses, too.
 The wood in our furniture, the pages in your notebook, and the cotton in our clothing
are made ofcellulose.

4
Functionof Carbohydrates inCells
 Major sourceof energy for the cell
 Major structural component of plant cell
 Immediate energy in the form of GLUCOSE
 Reserveor stored energy in the form of GLYCOGEN

CLASSIFICATION OF
CARBOHYDRATE
CARBOHYDRATE
Monosaccharides
Erythrose ,
Ribose,Glucose
Oligosaccharides
Polysaccharides Starch , cellulose,
dextrin , dextran
Sucrose , lactose
Maltotriose Maltose
7

5
Classification ofCarbohydrates
• Carbohydrates are classifiedaccordingto the
number of subunits that make them up
3Types ofCarbohydrates
 Monosaccharides
 Oligosaccharides Disaccharides
Trisaccharides
Tetrasaccharides
 Polysaccharides

6
Monosaccharides: are simple sugars, or the
compounds which possessafree aldehyde (CHO)or ketone (C=O)
group and two or more hydroxyl (OH) groups. They are the
simplest sugars and cannot be hydrolysed further into smaller
units.
Monosaccharides contain asingle carbon chain and are
classified on the basis of number of carbon atoms they possess,
and asaldoses or ketoses depending upon their groups.

8
D-glucose
“dextrose”
Blood sugar
D-galactose D-fructose
“Levulose”
Fruit sugar
Fructose:
• Thesweetest of all sugars
– (1.5Xsweeterthan
sucrose)
• Occursnaturallyin fruits and
honey “thefruit sugar”
Glucose
 Other names: Dextrose and Blood Sugar.
 Acomponent of each disaccharide.
Monosaccharides Hexoses
• Galactose
 The essential energy source for all body functions. Seldomoccursfreely in nature
 Bindswith glucoseto form sugar
in milk:lactose.
 Onceabsorbedby the body,
galactoseisconvertedto glucose
to provideenergy.

9
Steriochemistry
Optical isomers (= enantiomers) differ from each other in the disposition of the various atoms
or groups of atoms in space around the asymmetric carbon atom. These are, in fact, the mirror
image of each other.These may also be likened to left- and right-handed gloves.
One form in which H atom at carbon 2 is projected to the left side and OH group to the right is
designated as D-form and the other form where H atom is projected to the right side and OH
group to the left is called asL-form (note the useof small capital letters D and L)
For example, the glyceraldehyde has only one asymmetric carbon atom (numbered as2) andit
can, therefore, exist in 2 isomeric forms :

D-Aldoses containing three , four , five and six atoms 10

11
Properties ofmonosaccharides
1. Mutarotation : when a monosaccharide is dissolved in water, the optical rotatory power
of the solution gradually changes until it reaches a constant value. For ex : when D-
glucose is dissolved in water, a specific rotation of +112.2o is obtained, but this slowly
changes , so that at 24h the value has become +52.7o. This gradual change in specific
rotation is known as mutarotation. This phenomenon is shown by number of pentoses,
hexoses and reducingdisaccharides.
2. Glucoside formation : when D-glucose solution is treated with methanol and HCl, two
compounds are formed, these are α – and β-D- glucosides. Thus, formed glucosides are
not reducingsugar and also doesnot show phenomenon of mutarotation
3. Reducing power : Sugars having free orpotentially free aldehyde orketone group have an
ability to reduce the cupriccopper tocuprous
oxidized +2Cu+
Reducing sugar + 2Cu++ 
(cupric) sugar (cuprous)
4. Oxidation /Reduction: Thealcoholic OH, aldehyde (COH) orketo(C=O) group areoxidizedto
carboxyl group with certain oxidizing agents. The oxidation may be brought under mild or
with vigorous oxidizingcondition
i. With mild oxidant like BrH2O : In this group only aldehyde is oxidized to produce
gluconic acid(monocarbonic). Ketoses do not respond tothis reaction.

12
ii. With strongOxidizingagent likeConc HNO3 :Both aldehyde or ketone groups areoxidized
to yield dicarboxylicacids
iii.Oxidation with metal hydroxides: Metal hydroxides likeCu(OH)2,
Ag OH oxidizefreealdehyde orketone group of mutarotatingsugar and reduce themselves
to lower oxides of freemetals
Reduction:The aldehyde orketone group present can bereduced to its respectivealcohol
with sodiumamalgum.
Forex:Fructoseand glucose give the hexahydric alcohol i.e.Sorbitol and Mannitol
Dehydration :Themonosaccharides when treated withConc H2SO4, itget dehydrated to from
5– hydroxyl – methyl furfural derivative
Methylation orEsterification :The glucosidicand alcoholicOH group of mono saccharides and
reducing disaccharides react with acetylating agent like acetic anhydride in pyridine to
from acetate derivatives calledesters.

Carbohydrateswith freecarbonylgroupsorinhemiacetalform givepositive
teststo Benedict’sandFehling’sreagents
without having beenhydrolyzed arereferred as‘reducing’sugars; others
(i.e.,theacetal types)arethen‘non-reducing’sugars

Oligosaccharides
Theseare compound sugarsthat yield 2 to 10molecules of the same or different
monosaccharides on hydrolysis.Accordingly, an oligosaccharideyielding 2 molecules of
monosaccharide on hydrolysis is designated asadisaccharide, and the one yielding 3
moleculesof monosaccharide asatrisaccharide and soon.
Disaccharides –Sucrose, Lactose, Maltose, Cellobiose,Trehalose,Gentiobiose, Melibiose
Trisaccharides –Rhamninose, Gentianose, Raffinose (= Melitose), Rabinose, Melezitose
Tetrasaccharides –Stachyose,Scorodose
Pentasaccharide –Verbascose
The molecular composition of the 3legume oligosaccharides (viz.,raffinose, stachyose and
verbascose) is shown below:
α-Galactose (1–6) α-Glucose (1–2) β-FructoseRaffinose
α-Galactose (1–6) α-Galactose (1–6) α-Glucose (1–2) β-FructoseStachyose
α-Galactose (1–6)α-Galactose (1–6)α-Galactose (1–6)α-Glucose (1–2)β-FructoseVerbascose

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Disaccharides
– Composed of 2monosaccharides
– cellscan make disaccharides by joining two monosaccharides by
biosynthesis.
Glucose +fructose =sucrose
 Tablesugar
 Foundnaturallyin plants:sugarcane,sugarbeets,honey, maplesyrup
 Sucrosemay bepurified from plantsourcesinto Brown, White andPowdered Sugars.
Glucose +galactose =lactose
• Theprimary sugarin milk andmilk products.
• Many people have problemsdigesting largeamounts
of lactose (lactose intolerance)
Glucose +glucose =Maltose
• Produced when starch breaksdown.
• Usednaturallyin fermentation reactions of alcohol and
beermanufacturing.

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Trisaccharides: Composed ofthree monosaccharide ex: Raffinose (Formed by one
mole of each i.e. glu, fruc, galac)
Tetrasaccharides :
ex:Stachyose (composed of two moles of galactose one mole of glu & one mole of fruct)

A great majority of carbohydrates of
nature occur aspolysaccharides
Chemically, the polysaccharidesmay be distinguishedinto
Homopolysaccharides : whichyield, onhydrolysis,asinglemonosaccharideand
Heteropolysaccharides:-which produce amixture of monosaccharideson
hydrolysis. Basedon their functional aspect, the polysaccharides may be grouped
under twoheads:
(a)Nutrient (ordigestible)polysaccharides. Theseactasmetabolicreserve of
monosaccharidesin plantsandanimals,e.g.,starch,glycogenandinulin.
(b)Structural (or indigestible) polysaccharides. Theseserveasrigid mechanical
structures in plantsandanimals,e.g.,cellulose,pectin andchitinand alsohyaluronic
acidandchondroitin.

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Types ofPolysaccharides
1. Starch
– The major digestible polysaccharide in our diet.
– The storage form of carbohydrate in plants.
– Sources: Wheat, rice, corn, rye, barley, potatoes, tubers, yams, etc.
– Two types of plant starch:
1.Amylose
2.Amylopectin

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Amylose: is in the form of straight chain linked together with α- 1-4,
linkages indicating 300 – 5,500 glucose units per molecules, molecular
wt range from 105 to 106. Generally it is water soluble and gives blue
colour with iodine.
Amylopectins: It contain beside straight chain several branched
chains, which are arranged in α—1-4 and β-1-6 linkage units, one
molecule of amylopectin contains 50,000 to 5,00,000 glucose
molecules, molecular wt. range from 107 to 108, it is insoluble in water
and gives purple colour with iodine .

21
2. Cellulose- form cell walls in plant cells
- alsocalledfiber or ruffage
- indigestible byhumans

22
3.Glycogen
The storage form of glucose in the body.
Stored in the liverand muscles.
Found in tinyamounts in meat sources.
Notfound in plants.
Not a significant food source of carbohydrate.

• Glucose is the most important energy source of carbohydrates to the mammals
(except ruminants). The bulk of dietary carbohydrate (starch) is digested and finally
absorbed as glucose into the body.
• Dextrose (glucose in solution in dextrorotatory form) is frequently used in medical
practice.
• Fructose is abundantly found in the semen which is utilized by the sperms for
energy. Several diseases are associated with carbohydrate's e.g., diabetes mellitus,
glycogen storage diseases galactosemia.
• Accumulation of sorbitol and dulcitol in the tissues may cause certain pathological
conditions e.g. cataract, nephropathy.
• The non-digestible carbohydrate cellulose plays a significant role in human
nutrition.
• These include decreasing the intestinal absorption of glucose and cholesterol, and
increasing bulk of feces to avoid constipation.
• The mucopolysaccharide hyaluronic acid serves as lubricant and shock absorbent
in joints.
• The mucopolysaccharide heparin is an anticoagulant( prevents blood clotting).
• The survival of Antarctic fish below -2oC is attributed to the antifreeze
glycoproteins.
• streptomycin is a glycoside employed in the treatment of tuberculosis
Some clinical concepts

FUNCTIONS OF CARBOHYDRATES
 Main source of energy in the body. Energy
production from carbohydrates will be 4 k
calories/g (16 k Joules/g).
 Storage form of energy (starch and glycogen).
 Excess carbohydrate is converted to fat.
 Glycoproteins and glycolipids are components of
cell membranes and receptors.
 Structural basis of many organisms. For example,
cellulose of plants,exoskeleton of insects etc.
27

Biomedical Importance Of Glucose
28
• Glucose is a major carbohydrate
• It is a major fuel of tissues
• It is converted into other carbohydrates
 Glycogen for storage.
 Ribose in nucleic acids.
 Galactose in lactose of milk.
 They form glycoproteins & proteoglycans
 They are present in some lipoproteins (LDL) .
 Present in plasma membrane:glycocalyx.
 Glycophorin is a major intergral membrane glycoprotein
of human erythrocytes.

Metabolism
Thousands of chemical reactionsare
taking place inside a cell in an organized,
well co-ordinated and purposeful
manner; all these reactions are called as
METABOLISM.
TYPES OFMETABOLIC
PATHWAY:
Catabolic Pathway
Anabolic Pathway
Amphibolic Pathway
STAGES AND PHASES OF
METABOLISM:
Primary
Secondary
Tertiary 11

Major Pathways of
Carbohydrate
Metabolism
30

1) Glycolysis
2) Citric Acid Cycle
3) Gluconeogenesis
4) Glycogenesis
5) Glycogenolysis
6) Hexose monophosphate shunt
7) Uronic Acid Pathway
8) Galactose Metabolism
9) Fructose Metabolism
10) Amino sugar metabolism 31

Entry of Glucose into cells
1) Insulin-independent transport system of glucose:
Not dependent on hormone insulin. This is operative
in – hepatocytes, erythrocytes (GLUT-1) and brain.
2) Insulin-dependent transport system: Muscles and
adipose tissue (GLUT-4).
Type 2 diabetes
melitus:
-Due to reduction
in the quantity of
GLUT-4 in insulin
deficiency.
-Insuin resistance
is observed in
tissues. 32

Glycolysis
Embden-Meyerhof pathway
(or)
E.M.Pathway
Definition:
Glycolysis is defined as the sequence of
reactions converting glucose (or glycogen) to
pyruvate or lactate, with the production ofATP
34

Salient features:
35
1) Takes place in all cells of the body.
2) Enzymes present in “cytosomal fraction” of the cell.
3) Lactate – end product – anaerobic condition.
4) Pyruvate(finally oxidized to CO2 & H2O) – end
product of aerobic condition.
5) Tissues lacking mitochondria – major pathway –ATP
synthesis.
6) Very essential for brain – dependent on glucose for
energy.
7) Central metabolic pathway
8) Reversal of glycolysis – results in gluconeogenesis.

Reactions of Glycolysis
1) Energy Investment phase (or)
priming phase
2) Splitting phase
3) Energy generation phase
36

Energy
Investment
Phase
• Glucose is phosphorylated to glucose-6-phosphate by hexokinase (or)glucokinase.
• Glucose-6-phosphate undergoes isomerization to give fructose -6- phosphate in the presenseof
phospho-hexose isomerase and Mg2+
• Fructose-6-phosphate is phoshorylated to fructose 1,6-bisphosphate by phosphofructokinase.
Splitting
Phase
• Fructose 1,6-bisphosphate  glyceraldehyde 3-phosphate + dihydroxyacetone
phosphate.(aldolase enzyme)
• 2 molecules of glyceraldehyde 3-phosphate are obtained from 1 molecule of glucose
Energy
Generation
Phase
• Glyceraldehyde 3-phosphate  1,3-bisphosphoglycerate(glyceraldehyde 3-phosphate hydrogenase )
• 1,3-bisphosphoglycerate  3-phosphoglycerate (phosphoglyceratekinase)
• 3-phosphoglycerate  2-phosphoglycerate (phosphoglycerate mutase)
37
• 2-phosphoglycerate  phosphoenol pyruvate (enolase + Mg2+ &Mn2+)
• Phosphoenol pyruvate  pyruvate [enol] (pyruvate kinase )  pyruvate [keto]  L-Lactate
(lactate dehydrogenase)

Energy production of glycolysis:
ATPproduction = ATPproduced - ATPutilized
ATPproduced ATPutilized Net energy
In absence of oxygen
(anaerobic glycolysis)
4 ATP
(Substrate level
phosphorylation)
2ATP from 1,3 DPG.
2ATP fromphosphoenol
pyruvate
2ATP
From glucose to glucose -
6-p.
From fructose -6-p to
fructose 1,6 p.
2 ATP
In presence of oxygen
(aerobic glycolysis)
4 ATP
(substrate level
phosphorylation)
2ATP from 1,3 BPG.
2ATP from phosphoenol
pyruvate.
2ATP
-From glucose to glucose-
6-p.
From fructose -6-p to
fructose 1,6 p.
8 ATP/
6 ATP (Pyruvate
dehydrogenase
2NADH,ETC,
Oxidative
phosphorylation)
+ 4ATP or 6ATP
(from oxidation of2
NADH + H in
mitochondria).
22

 Pasteur effect : Inhibition of glycolysis by
oxygen (Phosphofructokinase) .
Crabtree effect : The phenomenon of
inhibition of oxygen consumption by the
addition of glucose to tissues having high
aerobic glycolysis.
41

RAPARPORT – LEUBERING CYCLE
• Supplementary pathway/ Shunt pathway to glycolysis .
• Erythrocytes
• Synthesis of 2,3-bisphosphoglycerate (2,3-BPG).
• Without the synthesis of ATP.
• Help to dissipate or waste the energy not needed by RBCs.
• Supply more oxygen to the tissues.
42

CITRIC ACID CYCLE
KREBS CYCLE /
TRICARBOXYLIC ACID/ TCA
CYCLE
Essentially involves the oxidation of acetyl CoA
to CO2 and H2O.
This Cycle utilizes about two-third of total
oxygen consumed by the body.
43

Brief History:
• HansAdolf
Krebs
• 1937
• Studies of
oxygen
consumptiom
in pigeon
breast muscle.
Location of
TCA
• Mitochondrial
matrix
• In close
proximity to
the electronic
transport
chain.
Overview
• 65-70% of the
ATPis
synthesized
• Name : TCA
used because
at the ouset of
the cycle
tricarboxylic
acids
participate.
44

Reactions of citric acid cycle
45
1) Formation of citrate : Condensation of acetyl CoA and
oxaloacetate  catalysed by citrate synthase.
2) & 3) Citrate is isomerized to isocitrate  aconitase (two
steps).
4) & 5) Formation of ᾀ-ketoglutarate : enzyme isocitrate
dehydrogenase.
6) Conversion of ᾀ-ketoglutarate to succinyl CoA :
through oxidative decarboxylation, catalysed by ᾀ-
ketoglutarate dehydrogenase complex.

7)Formation of succinate : enzyme succinate
thiokinase
GTP +ADP ATP+ GDP (nucleoside
diphosphate kinase)
8)Conversion of succinate to fumarase : enzyme
succinate dehydrogenase
9)Formation of malate : enzyme fumarase
10)Conversion of malate to oxaloacetate : enzyme
malate dehydrogenase.
46

• TCA cycle is strictly aerobic in contrast to glycolysis.
• Total of 12 ATPare produced from one acetyl CoA:-
 During the process of oxidation of acetyl CoA via citric
acid cycle  3 NADH2 & 1 FADH2.
 Oxidation of 3 NADH by electron transport chain
coupled with oxidative phosphorylation results in 9
ATP,FADH2  2 ATP.
 One substrate level phosphorylation.
48

• ETC is the transfer of electrons from NADH and FADH2
to oxygen via multiple carriers.
• The electrons derieved from NADH and FADH2 combine
with O2, and the energy released from these oxidation/
reduction reactions is used to derieve the synthesis of ATP
from ADP.
• This transfer of electrons is done by multiple carriers which
constitute the ELECTRON TRASPORT CHAIN.

Complex Name
No. of
Proteins Prosthetic
Groups
Complex I NADH
Dehydrogenase
46 FMN,
9 Fe-S centrs.
Complex II Succinate-
CoQ
Reductase
5 FAD, cyt
b560, 3 Fe-S
centrs.
Complex III CoQ-cyt c
Reductase
11 cyt bH, cyt bL,
cyt c1, Fe
SRieske
Complex IV Cytochrome
Oxidase
13 cyt a, cyt a3,
CuA, CuB

• Mitochondrial ATP synthase consist of two
multisubunit components F0 and F1 which are
linked by a slender stalk.
• F0 is a elecrically drivenmotor that spans the lipid
bilayer foming a channel through which protons can
cross the membrane.
• F0 provides channel forprotons.
• F1 harvest the free energy derieved from proton
movement down the electrochemical gradient by
catalyzing the synthesis of ATP.
• F1 Phosphorylates ADP toATP.

ATP synthase – the three catalytic sites cycle through
three conformational states: O [open], L[loose binding],
T [tight binding]. Proton flux through the synthase
drives this interconversion of states. The essence of this
proposed mechanism is that proton flux lead to the
release of tightly bound ATP.
Binding of ADP and Pi on ATP Synthase

Mitochondrial matrix
Intermembrane space
ADP
+
stationary knob
contains three
catalytic sites that
join inorganic
phosphate to ADP
to make ATP when
the rod is spinning.
A rotor in the
membrane spins
clockwise when H+
flows through it down
the H+ gradient.
A stator anchoredin
the membrane holds
the knob stationary.
As the rotor spins, a
rod connecting the
cylindrical rotor and
knob also spins.
The protruding,

Electron Transport Chain
series of proteins built into
inner mitochondrial membrane
Along cristae
Transport proteins & enzymes
Transport of electrons down ETC linked to pumping of H+ to
create H+ gradient
yields ~36 ATP from 1 glucose.
only in presence of O2 (aerobic respiration)

Mitochondria
(Double Membrane Cell Organelle)
Outer membrane
Inner membrane
a. Highly folded Cristae
b. Enzymes & transport proteins
Intermembrane space
fluid-filled space between
membranes

Glucose
G3P
Glycolysis
2 NADH
Krebs cycle
8NADH
2 FADH2
Remember the Electron Carriers?

NADH
dehydrogenase
Cytochrome
bc1 complex
cytochrome c
oxidase complex
NADH H
NAD+
FADH2
H
FAD
2H+ + 1
2
O2 H2O
e–
C
Inner
mitochondrial
membrane
Intermembrane
space
H+
H+H+
NADH  NAD+ + H
H  e- + H+
p
e
e–
e–
Q
Generation of proton gradient
What powers the proton (H+) pumps?…

Electron carriers pass electrons & H+ to ETC
H cleaved off NADH & FADH2
Electrons stripped from H atoms  H+ (protons)
•Electrons passed from one electron carrier to next in mitochondrial
membrane (ETC)
•Flowing electrons = energy to do work
Transport proteins in membrane pump H+ (protons) across
inner membrane to intermembrane space
Stripping H from Electron Carriers
NAD+
Q
C
NADH H2O
H+
e–
2H+ + O2
H+H+
e–
FADH2
1
2
NADH
dehydrogenase
cytochrome
bc complex
cytochrome c
oxidase complex
FAD
e–
H+
H+
H+
H+
H+ H+
H+H+
H+
ADP
+ Pi
ATP
H+ H+ H+
ATPase/ATP Synthase /Complex 5

But what “pulls” the
electrons down the ETC?
oxidative phosphorylation
electrons
flow downhill
to O2

Electrons move in steps from carrier to carrier downhill to oxygen
Each carrier more electronegative
Controlled oxidation
Controlled release of energy
Electrons flow Downhill
Make ATP
instead of
Fire.

H+
ADP + Pi
H+
H+
H+
H+ H+
H+H+
H+
Set up a H+ gradient
Allow the protons to flow
through ATP synthase
Synthesizes ATP
ADP + Pi  ATP
ATP
“Proton-Motive” force (pmf)

The diffusion of ions across a membrane
Build up of proton gradient just so H+ could flow through
ATP synthase enzyme to build ATP
Chemiosmosis links the
to ATP synthesis
Chemiosmosis

 Proposed Chemiosmotic Hypothesis
 Revolutionary idea at the time
Peter Mitchell
1961 | 1978
proton motive force
1920-1992

Krebs
cycle
Acetyl-CoA
ATP
ATP
H+
H+
4. Protons diffuse back in
down their concentration
gradient, driving the
synthesis of ATP.
3. Oxygen joins with
protons to form
water.
2. Electrons provide
energy
to pump protons
across the
membrane.
1. Electrons are harvested and
carried to the transport
system.
NADH
FADH2
e-
e-
e-
Q
C
H2O
1
2
O2
+
2H+
O2
e-
H+
Electron
Transport
System
Intermembrane
spaceH+
H+
Inner
Mitochondrial
Membrane
Pyruvate from
cytoplasm
Mitochondrial
Matrix
CO2
e-
NADH
ATP
synthase
ADP+Pi

SUMMARY OF ELECTRON TRANSPORT SYSTEM

Cellular respiration
2 ATP + 2 ATP + ~36 ATP

•NADH made in cytosol
•Can’tgetintomatrixofmitochondrion
•2 mechanisms
1. In muscle and brain
Glycerol phosphate shuttle
2. In liver and heart
Malate / aspartate shuttle

 Where did the glucose come from?
 Where did the O2 come from?
 Where did the CO2 come from?
 Where did the CO2 go?
 Where did the H2O come from?
 Where did the ATP come from?
 What else is produced that is not listed
in this equation?
 Why do we breathe?
Summary of cellular respiration
C6H12O6
+ 6O2  6CO2 + 6H2O + ~40 ATP

Glycerol Phosphate Shuttle
In muscle and Brain
 Each NADH converted to FADH2 inside mitochondrion
 FADH2 enters later in the electron transport chain
 Produces 1.5 ATP
Gycerol phosphate shuttle
 2 NADH per glucose - 2 FADH2
 2 FADH2 X 1.5 ATP / FADH2……….3.0ATP
 2 ATP in glycoysis ……………………2.0ATP
 From pyruvate and Krebs
 12.5ATPX2 per glucose……………..25.0ATP
Total = 30.0 ATP/ glucose

• In Liver and Heart
• NADH oxidized while reducing oxaloacetate to
malate – Malate dehydrogenase Enzyme.
• Malate crosses membrane

• Malate –Aspartate Shuttle
2 NADH per glucose - 2 NADH
2NADHX2.5ATP/ NADH…………5.0ATP
2 ATP from glycolysis………………..2.0ATP
From pyruvate and Krebs
• 12.5ATPX2per glucose……………..25.0ATP
Total = 32.0 ATP/ glucose

• ROTENONE –Complex I
• AMYTAL –Complex II
• Piericidin –competes with CoQ
• Antimycin A –Complex III
• Cyanide, Azide, H2S,Carbon monoxide – Bind
with complex IV and inhibit transfer of electrons
to oxygen.
INHIBITORS OF ELECTRON TRANSPORT SYSTEM

Rotenone is a common insecticide that strongly
inhibits the electron transport of complex I. Rotenone is
a natural product obtained from the roots of several
species of plants. Tribes in certain parts of the world beat
the roots of trees along riverbanks to release rotenone
into the water which paralyzes fish and makes them easy
prey.
Amytal is a barbiturate that inhibits the electron transport of
complex II.
 Demerol is painkiller that also inhibits complex I.
All three of these complex I inhibitors block the oxidation of
the Fe-S clusters of complex I.

Rotenone
Antimycin A1
Cyanide Amytal

Piericidin A
Azides
Carbon Monooxide
Hydrogen Sulfide

2-Thenoyltrifluoroacetone and carboxin specifically block
electron transport in Complex II.
Cyanide, azide and carbon monoxide all inhibit
electron transport in Complex IV. The all inhibit
electron transfer by binding tightly with the iron
coordinated in Cyt a-a3.
Antimycin A1 is an antibiotic that inhibits electron transfer in
complex III by blocking the transfer of electrons between Cyt
bH and coenzyme Q bound at the QN site

Azide and cyanide bind to the iron when the iron is in the
ferric state.
Carbon Monoxide binds to the iron when it is in the ferrous
state.
Cyanide and azide are potent inhibitors at this site which
accounts for there acute toxicity.
Carbon monoxide is toxic due to its affinity for the heme
iron of hemoglobin. Animals carry many molecules of
hemoglobin, therefore it takes a large quantity of carbon
monoxide to die from carbon monoxide poisoning. Animals
have relatively few molecules of Cyt a3. Consequently an
exposure to a small quantity of azide or cyanide can be lethal.
The toxicity of cyanide is solely from its ability to arrest

Inhibitors of ATP Synthase:
DCCD,(Diclyclohexylcarbodiimide) shown to the
left, forms covalent bonds to a glutamate residue of
the c subunit of F0. When DCCD is covalently
attached it blocks the proton channel, which causes
the rotation and ATP synthesis to cease.
Oligomycin binds directly to ATP synthase F0
subunit and blocks the flow of protons through the
channel.

Uncouplers :
Uncouplers uncouple electron transport from oxidative
phosphorylation. They collapse the chemiosmotic
gradient by dissipating protons across the inner
mitochondrial membrane.
The coupling between electron transport and oxidative
phosphorylation depends on the impermeability of the inner
mitochondrial membrane to H+ translocation. The only way for
protons to go from the intermembrane space to the matrix is
through ATP synthase.

The potential energy of the proton
gradient is lost as heat.

Endogenous Uncouplers Enable Organisms to
Generate Heat.
The uncoupling of oxidative phosphorylation from electron transport
generates heat. Hibernating animals and newborne animals
(including human beings) contain brown adipose tissue. The adipose
tissue is brown due to the high mitochondria content of the tissue. An
endogenous protein called Thermogenin uncouples ATP synthesis from
electron transport by opening up a passive proton channel (UCP-1)
through the inner mitochondrial membrane. The collapse of the pH
gradient generates heat.

Thermogenin uncouples ATP synthesis from electron
transport by opening up a passive proton channel
(UCP-1) .

SUMMARY OF INHIBITORS OF ELECTRON TRANSPORT SYSTEM

All of the uncouplers shown to the left, collapse the pH
gradient by binding a proton on the acidic side of the
membrane, diffusing through the inner mitochondrial
membrane and releasing the proton on the membranes
alkaline side.
2,4-Dinitrophenol, dicumarol and carbonyl cyanidep-
trifluorocarbonyl-cyanide methoxyphenyl hydrazone
(FCCP) all have hydrophobic character making them soluble in
the bilipid membrane. All of these decouplers also have
dissociable protons allowing them to carry protons from the
intermembrane space to the matrix which collapses the pH
gradient.

It is an inborn error of metabolism when
body is unable to break galactose.
There is deficiency of enzymegalactose-3-
phosohateuridyltransferase.
Due to block of this enzyme galactose-3-
phosphate will accumulate in liver and
this will inhibitgalactokinaseas well as
glycogen phosphate.

DIAGNOSIS
Clinical manifestation
including congenital cataract
and presence of galactose in
urine as well as elevated
blood galactose levels will
help in the diagnosis.
TREATMENT
If lactose is withdrawn from
the diet most of the
symptoms recede.

SYMPTOMS – Headache, anxiety, confusion,
sweating, slurred speech, seizures and coma
and if not corrected death.
When the blood glucose concentration falls
to less than 45mg/dl, the symptoms of
hypoglycemia appear.

Post-Prandial Hypoglycemia: This is called
reactive hypoglycemia and is observed in
subjects with an elevated insulin secretion
following a meal. This causes transient
hypoglycemia associated with mild symptoms.
 Fasting Hypoglycemia: Low blood glucose
concentration in fasting is not very common.
However fasting hypoglycemia is observed in
patients with pancreatic beta-cell tumour and
hepatocellular damage.
TYPES OF HYPOGLCEMIA

 .Due to alcohol intake: This is due to
accumulation of NADH which diverts the
pyruvates and oxaloacetate to form, respectively,
lactate and malate.
Due to insulin overdose: Observed in patients
who are in intense insulin therapy regime.
In premature infants: Premature and
underweight infants have smaller store of liver
glycogen and are susceptible to hypoglycemia
CAUSES

 Metabolic diseases
 Characterized by hyperglycemia
 Divided into 2 groups
 IDDM
 NIDDM

 Type 1 Diabetes – Juvenile onset diabetes
 Occurs in childhood
 10-20% on known diabetics
 Characterized by almost total deficiency of
insulin-> due to destruction of Beta cells of
Pancreas
 Symptoms appear after 80-90% of Beta cells have
been destroyed.
 Pancreas fails to secrete insulin in response to
insulin ingestion
 Therefore, patient require insulin therapy

 Type 2 diabetes- Adult onset diabetes:
 Most common, 80-90% of diabetic population
 Occurs in adults
 Commonly occurs in obese individuals
 Decreasing insulin receptors on insulin
responsive cells.
 Increased level of Tumor Necrosis Factor

 Diagnosis of diabetes made on basis of
individual’s response to oral glucose load, oral
glucose test. (OGTT)

 Take carbohydrate for at least 3 days prior to
test
 All drugs influencing carbohydrate metabolism
should be discontinued
 Avoid strenuous exercise on days previous to
test.
 Be in overnight fasting state.

 Conducted preferably in morning (9-11 am)
 Fasting blood sample is drawn and urine
collected
 Subject given 75g glucose orally, dissolved in
300mL of water, to be drunk in 5 min.
 Blood and urine samples collected at 30 minute
intervals for at least 2 hours.
 Glucose estimation of all blood samples.
 Urine sample qualitatively tested for glucose.

 Fasting plasma glucose level = 75-
110mg/dL in normal person
Persons-> impaired glucose tolerance ->
fasting (110-126mg/dL) and 2 hour (140-
200mg/dL) plasma glucose levels are
elevated.

 Commonest cause of glucose excretion in urine.
 It is first line screening test for diabetes
 Normally, glucose does not appear in urine
until plasma glucose concentration exceeds
renal threshold (180mg/dL)

 Benign condition due to reduced
renal threshold for glucose
Unrelated to diabetes
Not accompanied by classical
symptoms of diabetes

 In some people, blood glucose level rises rapidly
after meals causing its excretion in urine. This is
Alimentary Glycosuria.
 Observed in some normal people and patients
of hepatic disease and hyperthyroidism

 For GTT in children -> oral glucose is given on the
basis of weight.
 In pregnant women, 100g oral glucose is
recommended.
 For individual with suspected malabsorption
intravenous GTT is done.
 GTT is unphysiological. To evaluate glucose handling
of body under physiological conditions, fasting
sample is drawn, subject is allowed to take heavy
breakfast, blood samples-> collected at 1 and 2 hours.

 Diabetes mellitus is associated with several
metabolic alterations. Most important among
them are
 Hyperglycemia
 Ketoacidosis
 Hypertriglyceridemia

 Atherosclerosis
 Retinopathy
 Nephropathy
 Neuropathy

 Dietary management : Low calorie , High
protein and fiber rich diet, reduce fat intake,
exercise
 Hypoglycemic drugs : Sulfonylureas
(Acetohexamide , tolbutamide) and
Biguanides
 Insulin : Short acting ( for 6 hours) and Long
acting ( for several hours )

GLYCATED Hemoglobin : Most abundant is
HbA1c which is produced by condensation of
glucose with N terminal valine of each Beta chain
of HbA.
DIAGNOSTIC IMPORTANCE
As the rate of synthesis of HbA1c is directly related
to the exposure of RBC to glucose , Thus serves
as indication of blood glucose concentration over
3 months period prior to measurement.

Glycated serum protein can also be measured .
As albumin is themost important plasma
protein , glycated albumin largely contributes to
plasma fructosamine measurements . It has
shorter half life than Hb . Thus , Glycated
albumin represents glucose status over 3 weeks
prior to its determination .

As the name suggests, Lactose Intolerance refers
to a condition when the patient becomes
intolerant to lactose.
 According to studies, 70% of adults are lactose
intolerant.
 It can also be termed as hypolactasia

 Deficiency of lactase is the basic cause of lactose
intolerance.
 Lactase is present in the Brush border region of small
intestine. Lactase hydrolyse lactose to glucose and
galactose. Therefore, deficiency of this enzyme , either
genetic or age related, causes accumulation of lactose in
body.
 This lactose cannot be directly absorbed to the wall of
small intestine, so it passes intact into colon where bacteria
metabolize lactose and resulting fermentation produces
copious amount of H2, CO2, CH3. This cause various
abdominal symptoms.

 Principal symptom of lactose intolerance is
adverse reaction to products containing lactose
such as milk, etc.
 Other symptoms include
- abdominal bloating
- Diarrhoea
- Nausea
- Vomiting

H2 Breath Test
 It is the most accurate test
 After an overnight fast, 25g of lactose is
swallowed
 If lactose cannot be digested, enteric bacteria
metabolize it and produce H2 which can be
detected in patient’s breath by clinical gas
chromatography.
 If H2 level in patient’s breath is high, they may
have lactose intolerance.

 Lactase pill prior to eating
 To use lactase treated products
 Restriction of lactose containing products in
diet
 Curd and Yeast

Inborn errors of Carbohydrate
Metabolism

Categories
1) Hemolytic anemia’s caused by deficiencies of-
A. Hexokinase
B. Pyruvate kinase
C. Glucose-6-(P)-dehydrogenase
2) Pyruvate dehydrogenase deficiency.
3) Carbohydrate intolerance disorders-
A. Lactose intolerance.
B. Fructose intolerance.
4) Fructosuria.
5) Galactosemia.
6) Pentosuria.
7) Glycogen storage disorders.
8) Mucopolysaccharidoses.

1) Hemolytic anemia caused by
different enzyme deficiencies:

A. Hexokinase deficiency:
 This is very rare among all the hemolytic disorders.
 Glycolysis in the RBC is linked with 2,3-BPG
production, essential for the oxygen transport.
 In the deficiency of the hexokinase, the synthesis and
concentration of 2,3-BPG are low in RBC, so the oxygen
unload to the tissues decreased, condition leads to
Hemolysis.

B. Pyruvate kinase deficiency:
 It is an autosomal recessive disorder and most
common red cell enzymopathy after G-6-PD
deficiency.
 PK catalyses the conversion of phosphoenolpyruvate to
pyruvate with the generation ofATP.
 Inadequate ATP generation leads to premature red
blood cell death (Prickle cells).
 On the other hand in the patients with pyruvate kinase
deficiency the level of 2,3-BPG in RBC is high, resulting
in low oxygen affinity of Hb observed.

Blood film: PK deficiency: Characteristic "prickle cells"
can be seen.

C. Glucose-6-phosphate dehydrogenase deficiency :
 G-6-PD deficiency is a X-linked recessive disorder.
 Frequency is 1 in 5,000 births.
 The deficiency occur in all the cells of affected
individuals.
 But it is more severe in RBCs.
 RBCs depend only on HMP shunt for their NADPH
requirement.
 G-6PD deficiency leads impaired NADPH production, so
oxidized glutathione is not converted to its reduced form.

 Low NADPH concentration also results the
accumulation of methemoglobin and peroxides in RBC,
causes loss of RBC membrane integrity.
 Till now it is mostly asymptomatic.

 But when the enzyme deficient subjects exposed to
severe infection, administered oxidant drugs such as
– Anti-malarial (Primaquine)
– Anti-biotic (Sulfamethoxazole)
– Acetanilide (Antipyretic)
 Favism :- Ingestion of FAVAbeans.
 Leads to  Hemolytic anemia.

B. Pyruvate kinase deficiency:
 It is an autosomal recessive disorder and most
common red cell enzymopathy after G-6-PD
deficiency.
 PK catalyses the conversion of phosphoenolpyruvate
to pyruvate with the generation ofATP.
 Inadequate ATPgeneration leads to premature red
blood cell death (Prickle cells).
 On the other hand in the patients with pyruvate kinase
deficiency the level of 2,3-BPG in RBC is high,
resulting in low oxygen affinity of Hb observed.

 Low NADPH concentration also results the
accumulation of methemoglobin and peroxides in
RBC, causes loss of RBC membrane integrity.
 Till now it is mostly asymptomatic.

B. Hereditary Fructose intolerance :-
 It is an autosomal recessive disorder.
 Incidence is 1 in 20,000.
 1 in 70 persons are carriers of abnormal gene.
 The defect is Adolase-B (fructose-1-(P) aldolase)
 Fructose -1(P) cannot be metabolized.
 Fructose-1(P) Glyceraldehyde + DHAP.×

 It leads to accumulation of fructose-1-(P),
severe hypoglycemia, vomiting, hepatic failure and jaundice.
 Fructose-1-(P) allosterically inhibits liver phosphorylase
and blocks glycogenolysis leading to hypoglycemia.
 Treatment :- Early detection and intake of diet free from
fructose and sucrose, are advised to overcome fructose
intolerance.

4) Essential fructosuria :-
 Due to the deficiency of fructokinase, fructose is not
converted to fructose-1-(P).
 Fructose Fructose-1-(P).
 This is an asymptomatic condition with excretion of
fructose in urine.
×

5) Galactosemia:-
 It is a serious serious autosomal recessive disorder
resulting from the deficiency of galactose-1-(P)
uridyltransferase, leads to accumulation of Galactose-
1-(P) in the liver and becomes toxic.
 Incidence is one in 35,000 births.
 Galactose -1-(P) UDP Galactose.×

Symptoms:
 The build up of galactose and the other chemicals can
cause serious health problems like
Swollen and inflamed liver,
Kidney failure,
Stunted physical and mental growth, and
Cataracts in the eyes.
 If the condition is not treated there is a 70% chance
that the child could die.
 Treatment :- Galactose free diet is preferred i.e. milk
will be avoided.

6) Essential pentosuria :
 It is a rare autosomal recessive disorder and benign
condition, asymptomatic.
 Individuals does not show any ill-effects.
 Incidence is one in 2,500 births.
 Primarily in Jewish population.

 Lack Xylitol dehydrogenase leads to excretion of larger
amounts of L-Xylulose in urine.
 L-Xylulose Xylitol
 It is also reported after administration of drugs such as,
Aminopyrine.
Antipyrine.
×

7) Glycogen storage diseases :
 The metabolic defects concerned with the glycogen
synthesis and degradation are collectively called as
GSD.
 All Glycogen storage disorders are Autosomal recessive
disorders (except Type-VIII)
 Incidence estimated to be between 1 in 1 lack to 1
million births per year in all ethnic groups.

Disorder Enzyme Affected Tissue
Type I
(von Gierke’s
disease)
Glucose-6-phosphatase Liver, kidney,
intestine
Type II
(Pompe’s disease)
Lysosomal α 1,4- glucosidase
(Acid maltase)
All organs
Type III
(Cori’s disease)
Amylo α 1,6- glucosidase
(debranching enzyme)
Liver, muscle, heart,
leukocytes
Type IV
(Anderson’s disease)
Glucosyl 4,6-transferase Most tissues
Type V
(Mc Ardle’sdisease)
Muscle glycogen
phosphorylase
Skeletal muscle
Type VI
(Her’s disease)
Liver glycogen phosphorylase Liver
Type VII
(Tauri’s disease)
Phosphofructokinase Skeletal muscle,
erythrocytes.

Disorder Incidence in births
(1 out of)
Chromosome
location
Type I
(von Gierke’s disease)
1,00,000 17
Type II
(Pompe’s disease)
1,75,000 17
Type III
(Cori’s disease)
1,25,000 1
Type IV
(Anderson’s disease)
1 million 3
Type V
(Mc Ardle’sdisease)
1 million 11
Type VI
(Her’s disease)
1 million 14
Type VII
(Tauri’s disease)
1 million 1

GSD Type-VIII :
 It is an X linked recessive disorder.
 Frequency is one in 1,25,000 births.
 Enzyme deficiency is Phosphorylase kinase.

Clinical Features
 Hepatomegaly and fibrosis in childhood, these symptoms
improve with age and usually disappear after puberty.
 Fasting hypoglycemia (40-50 mg/dl)
 Hyperlipidemia
 Growth retardation, Growth often normalizes by adulthood
as well.
 Elevated serum transaminase levels (Aspartate
aminotransferase and alanine aminotransferase > 500
units/ml)

8) Mucopolysaccharidoses
Type I – Hurler’s syndrome – L-Iduronidase.
Type II – Hunter’s – Iduronate sulphatase.
Type III – Sanfilippo’s –N-Acetylglucosaminidase,
Heparin sulphatase.
Type IV – Morquio’s – Galactosamine sulphatase.
Type V – Scheie’s – L-Iduronidase.
Type VI – Maroteaux-Lamy’s – N-Acetyl-β-D-
galactosamino-4-sulphatase.
Type VII – Sly’s – β-Glucuronidase.

 Symptoms :- All mucopolysaccharidoses show skeletal
deformity, corneal clouding and corneal opacity.
 Mental retardation (except type V &VI).
 Urinary excretion of respective mucopolysaccharides
(C.S, D.S, H.S and K.S) observed.
– C.S = Chondroitin sulphate
– D.S = Dermatan sulphate
– H.S = Heparan sulphate
– K.S = Keartin sulphate.

Overview of Carbohydrate metabolism
Enzyme Deficiency Disease
Hexokinase
Pyruvate kinase
Glucose-6-(P) dehydrogenase
Hemolytic Anemia
Pyruvate dehydrogenase Muscular hypotonia,
Lactic acidosis.
Lactase
Aldolase B (fructose-1-(P) aldolase)
Hereditary Lactose intolerance
Hereditary fructose intolerance
Fructokinase Essential Fructosuria
Galactose-1-(P)-Uridyl transferase
Galactokinase
Uridine di-(P)-galactose-4-epimerase
Galactosemia
L-Xylitol dehydrogenase Essential Pentosuria
Glycogen storage disorders
And Mucopolysaccharidoses

Wernicke-Korsakoff syndrome :-
 This is a genetic disorder associated with HMP
shunt.
 But it is not an inborn error.
 An alteration in transketolase activity that
reduces affinity with TPP(a Biochemical lesion).
 Symptoms are mental disorder, loss of memory
and partial paralysis.
 These symptoms manifested in chronic
alcoholics, whose diets are thiamin-deficient.

Mitochondrial
encephalopathy
occurs due to
fumarase
deficiency .
It is a
mitochondrial
myopathy affecting
both the skeletal
muscles and brain .
APPLIED
ASPECTS
OF
TCA CYCLE
16
0

GLUCONEOGENESIS
The synthesis of glucose from non-carbohydrate
compounds is known as gluconeogenesis.
Major substrate/precursors : lactate, pyruvate, glycogenic
amino acids, propionate & glycerol.
-Takes place in liver (1kg glucose) ; kidney matrix( 1/3rd).
- Occurs in cytosol and some produced in mitochondria.
16
1

Importance of Gluconeogenesis
Brain,CNS,
erythrocytes,testes
and kidney medulla
dependent on
glucose for cont.
supply of energy.
Under anaerobic
condition, glucose
is the only source
to supply skeletal
muscles.
Occurs to meet the
basal req of the
body for glucose
in fasting for even
more than a day.
Effectively
clears,certain
metabolites
produced in the
tissues that
accumulates in
blood
16
2

Reaction of Gluconeogenesis
Glucose
16
3

Cori Cycle
The cycle
involveing the
synthesis of
glucose in liver
from the skeletal
muscle lactate and
the reuse of
glucose thus
synthesized by the
muscle for energy
purpose is known
as Cori cycle.
16
4

GLYCOGEN
METABOLISM
Glycogen is a storage form of glucose in animals.
Stored mostly in liver (6-8%) and muscle (1-2%)
Due to muscle mass the quantity of glycogen in muscle = 250g
and liver =75g
Stored as granules in the cytosol.
Functions : Liver glycogen – maintain the blood glucose level
Muscle glycogen – serves as fuel reserve
16
6

GLYCOGENESIS
 Synthesis of glycogen from glucose.
 Takes place in cytosol.
 Requires UTP and ATPbesidesglucose.
 Steps in synthesis :
1) Synthesis of UDP- glucose
2) Requirement of primer to initiate glycogenesis
3) Glycogen synthesis by glycogen synthase
4) Formation of branches in glycogen
16
7

GLYCOGENOLYSIS
Degradation of stored glycogen in liver and muscle constitutes
glycogenolysis.
 Irreversible pathway takes place in cytosol.
 Hormonal effect on glycogen metabolism :
1) Elevated glucagon – increases glycogen degradation
2) Elevated insulin – increases glycogen synthesis
 Degraded by breaking majorly α-1,4- and α-1,6-glycosidicbonds.
 Steps in glycogenolysis:
1) Action of glycogen phosphorylase
2) Action of debranching enzyme
3) Formation of glucose-6-phosphate and glucose
16
9

TYPE ENZYME DEFECT CLINICALFEATURES
Type I (Von Gierke’s
disease)
Glucose-6-
phosphatase
deficiency.
Hypoglycemia, enlarged liver and kidneys,
gastro-intestinal symptoms, Nose bleed, short
stature, gout
Type II (Pompe’s
disease)
Acid maltase
deficiency
Diminished muscle tone, heart failure, enlarged
tongue
Type III (Cori’s
disease,Forbe disease)
Debranching enzyme
deficiency
Hypoglycemia, enlarged liver, cirrhosis, muscle
weakness, cardiac involvement
Type IV (Andersen’s
disease)
Branching enzyme
deficiency
Enlarged liver & spleen, cirrhosis, diminished
muscle tone, possible nervous system
involvement
Type V (Mcardle’s
disease)
Muscle phosphorylase
deficiency
Muscle weakness, fatigue and muscle cramps
Glycogen storage diseases
17
1

TYPE
17
2
ENZYME DEFECT CLINICAL FEATURES
Type VI (Her’s
disease)
Liver phosphorylase
deficiency
Mild hypoglycemia, enlarged liver, short
stature in childhood
Type VII (Tarui’s
disease)
Phosphofructokinase
deficiency
Muscle pain, weakness and decreased
endurance
TypeVIII Liver phosphorylase
kinase
Mild hypoglycemia, enlarged liver, short
stature in childhood, possible muscle weakness
and cramps
Type 0 Liver glycogen
synthetase
Hypoglycemia, possible liver enlargement

Cori’s disease, Forbe
disease
17
3

HEXOSE MONOPHOSPHATE
SHUNT
HMP Shunt/ Pentose Phosphate Pathway/
Phosphogluconate Pathway
17
4

* This is an alternative pathway to glycolysis and TCA cycle
for the oxidation of glucose.
* Anabolic in nature, since it is concerned with the
biosynthesis of NADPH and pentoses.
* Unique multifunctional pathway
* Enzymes located – cytosol
*Tissues active – liver, adipose tissue, adrenal gland,
erythrocytes, testes and lactating mammary gland. 50

Reactions of the HMP Shunt Pathway
17
6

• Pentose or its derivatives are useful for the
synthesis of nucleic acids and nucleotides.
• NADPH is required :
-For reductive biosynthesis of fatty acids and
steroids.
- For the synthesis of certain amino acids.
- Anti-oxidant reaction
- Hydroxylation reaction– detoxification of drugs.
- Phagocytosis
- Preserve the integrity of RBC membrane. 17
7
Significance of HMP Shunt

• Glucose-6-Phosphate dehydrogenase
deficiency :
- Inherited sex-linked trait
- Red blood cells
- Impaired synthesis of NADPH
- hemolysis , developing hemolytic anemia
 Resistance towards malaria [Africans]
17
8
Clinical Aspects

Clinical Aspects
• Wernicke-Korsakoff syndrome :
- Genetic disorder
- Alteration in transketolase activity
-Symptoms : mental disorder, loss of memory,
partial paralysis
• Pernicious anemia : transketolase activity
increases.
17
9

URONIC ACID PATHWAY
18
0
(Or)
Glucoronic acis pathway

 Alternative oxidative pathway for glucose.
 synthesis of glucorinc acid,pentoses and vitamin
(ascorbic acid).
 Normal carbohydrate metabolism ,phosphate
esters are involved – but in uronic acid pathway
free sugars and sugar acids are involved.
 Steps of reactions :
1) Formation of UDP-glucoronate
2) Conversion of UDP- glucoronate to L-gulonate
3) Synthesis of ascorbic acid in some animals
4) Oxidation of L-gulonate
18
1

Clinical Aspects
• Effects of drugs : increases the pathway to achieve
more synthesis of glucaronate from glucose .
- barbital,chloro-butanol etc.
• Essential pentosuria : deficiency of xylitol-
dehydrogenase
- Rare genetic disorder
- Asymptomatic
- Excrete large amount of L-xylulose in urine
- No ill-effects
18
3

 Disaccharide lactose present in milk – principle source of of galactose.
 Lactase of intestinal mucosal cells hydrolyses lactose to galactose and glucose.
Within cell galactose is produced by lysosomal degradation of glycoproteins
and glycolipids.
 CLINICALASPECTS:
- Classical galactosemia : deficiency of galactose-1-phosphate
uridyltransferase. Increase in galactose level.
- Galactokinase deficiency : Responsible for galactosemia and galactosuria.
- Clinical symptoms : loss of weight in infants, hepatosplenomegaly,jaundice,
mental retardation , cataract etc.
- Treatment : removal of galactose and lactose from diet.
18
5

METABOLISM OF
FRUCTOSE
Sorbitol/Polyol Pathway:
 Conversion of glucose to fructose via sorbitol.
 Glucose to Sorbitol reduction by enzyme aldolase (NADPH).
Sorbitol is then oxidized to fructose by sorbitol dehydrogenase and
NAD+.
Fructose is preferred carbohydrate for energy needs of sperm cells
due to the presence of sorbitol pathway.
Pathway is absent in liver.
Directly related to glucose : higher in uncontrolleddiabetes.
18
6

METABOLISM OF AMINO
SUGARS
When the hydroxyl group of the sugar is replaced by theamino
group, the resultant compound is an amino sugar.
Eg. Glucosamine,galactosamine,mannosamine,sialic acid etc.
Essential components of glycoproteins, glycosaminoglycans,
glycolipids.
Found in some antibiotics.
20% of glucose utilized for the synthesis of amino sugars–
connective tissues.
18
7

Electron transport chain
reactions
• Electron transport chain is a series of protein
complexes located in the inner membrane of
mitochondria .
18
8

POLYSACCHARIDES
&
CLINICAL ASPECTS
19
0

Proteoglycans & Glycosaminoglycans
19
1
 Seven glycosaminoglycans :
1 ) Hyaluronic acid
2) Chondriotin sulfate
3 ) Keratan sulfate I
4 ) Keratan sulfate II
5 ) Heparin
6 ) Heparan sulfate
7 ) Dermatan sulfate

• Structural components of extracellular matrix.
• Act as sieves in extracellular matrix.
• Facilitate cell migration.
• Corneal transparency.
• Anticoagulant (Heparin).
• Components of synaptic & other vesicles.
19
2
Functions of glycoaminoglycans

MPS
19
3
Defect Symptoms
MPS I (Hurler
syndrome)
Alpha-L-Iduronidase Mental retardation, micrognathia, coarse facial
features, macroglossia, retinal degeneration,
corneal clouding, cardiomyopathy,
hepatosplenomegaly
MPS II (Hunter
syndrome)
Iduronate sulfatase Mental retardation (similar, but milder,
symptoms to MPS I). This type exceptionally
has X-linked recessive inheritance
MPS IIIA
(SanfilippoA)
Heparan sulfate N
sulfatase
Developmental delay, severe hyperactivity,
spasticity, motor dysfunction, death by the
second decade
MPS IIIB
(Sanfilippo B)
Alpha-
Acetylglucosaminidase
MPS IIIC
(Sanfilippo C)
Acetyl transferase
Mucopolysaccharidoses

MPS Defect Symptoms
MPS IVA
(Morquio A)
Galactose-6-sulfatase
Severe skeletal dysplasia, short stature, motor
MPS IVB (Morquio
B)
Beta galactosidase dysfunction
MPS VI N acetylgalactosamine 4 Severe skeletal dysplasia, short stature, motor
(Maroteaux Lamy
syndrome)
sulfatase dysfunction, kyphosis, heart defects
MPS VII (Sly) Beta glucoronidase Hepatomegaly, skeletal dysplasia, short
stature, corneal clouding, developmental delay
MPS IX (Natowicz
syndrome)
Hyaluronidase deficiency Nodular soft-tissue masses around joints,
episodes of painful swelling of the masses,
short-term pain, mild facial changes, short
stature, normal joint movement, normal
intelligence 68

Hunter’s syndrome
• Short and broad mandible
•Localized radiolucent
lesions of the jaw
•Flattened
temporomandibular joints
• Macroglossia
• Conical peg-shaped teeth
with generalized wide spacing
•Highly arched palated with
flattened alveolar ridges
• Hyperplastic gingiva
19
5

ROLE OF HORMONES IN
CARBOHYDRATE
METABOLISM
19
6

• Postabsorptive state: Blood glucose is 4.5-
5.5mmol/L.
• After carbohydrate meal: 6.5-7.2mmol/L
• During fasting : 3.3-3.9mmol/L
19
7
Regulation of Blood glucose

Metabolic & hormonal mechanisms
regulate blood glucose level
Maintenance of stable levels of glucose in blood is by
 Liver.
 Extrahepatic tissues.
 Hormones .
19
8

Regulation of blood glucose levels
Insulin
19
9

Role of thyroid hormone
20
1
 It stimulates glycogenolysis & gluconeogenesis.
Hypothyroid
Fasting blood glucose
is lowered.
Patients have
decreased ability to
utilise glucose.
Patients are less
sensitive to insulin
than normal or
hyperthyroid patients.
Hyperthyroid
Fasting blood
glucose is elevated
Patients utilise
glucose at normal or
increased rate

Glucocorticoids
20
2
 Glucocorticoids are antagonistic to insulin.
 Inhibit the utilisation of glucose in extrahepatic
tissues.
 Increased gluconeogenesis .

Epinephrine
20
3
Secreted by adrenal medulla.
It stimulates glycogenolysis in liver & muscle.
It diminishes the release of insulin from pancreas.

Other Hormones
20
4
 Anterior pituitary hormones
Growth hormone:
 Elevates blood glucose level & antagonizes action of
insulin.
 Growth hormone is stimulated by hypoglycemia
(decreases glucose uptake in tissues)
 Chronic administration of growth hormone leads to
diabetes due to B cell exhaustion.

SEX HORMONES
20
5
Estrogens cause increased liberation of
insulin.
Testosterone decrease blood sugar level.

Hyperglycemia
20
6
 Thirst, dry mouth
 Polyuria
 Tiredness, fatigue
 Blurring of vision.
 Nausea, headache,
 Hyperphagia
 Mood change
Hypoglycemia
 Sweating
 Trembling,pounding
heart
 Anxiety, hunger
 Confusion, drowsiness
 Speech difficulty
 Incoordination.
 Inability to concentrate

Clinical aspects
20
7
Glycosuria: occurs when venous blood
glucose concentration exceeds
9.5-10.0mmol/L
Fructose-1,6-Biphosphatase deficiency causes
lactic acidosis & hypoglycemia..

Diabetes Mellitus
A multi-organ catabolic response caused by insulininsufficiency
Muscle
– Protein catabolism for gluconeogenesis
Adipose tissue
– Lipolysis for fatty acid release
Liver
– Ketogenesis from fatty acid oxidation
– Gluconeogenesis from amino acids and glycerol
Kidney
– Ketonuria and cation excretion
82
– Renal ammoniagenesis.

DENTAL ASPECTS OF
CARBOHYDRATES
METABOLISM
20
9

Role of carbohydrates in dental caries
• Fermentable carbohydrates causes loss of
caries resistance.
• Caries process is an interplay between oral
bacteria, local carbohydrates & tooth surface
Bacteria + Sugars+ Teeth Organic acids
Caries
21
0

Role of carbohydrates in periodontal
disease
Abnormal
glucose metabolism
Diabetes Mellitus
Periodontal disease
Excessive carbohydrate
intake
Obesity
Periodontal disease
21
1

RECENT CLINICAL ISSUES
RELATED TO
CARBOHYDRATES
METABOLISM
21
2

Cystic Fibrosis
21
3
• CMD in Cystic Fibrosis is characterized by its high
rates and latent course.
• The patients with CMD have retarded physical
development, more pronounced morphofunctional
disorders in the bronchopulmonary system, lower lung
functional parameters, and more aggressive sputum
microbial composition. (Samoĭlenko VAet al.)

CMD in Gout
21
4
• OGTT causes a 34% increase in the detection rate of
T2D in patients with gout.
• Carbohydrate metabolic disturbances are revealed in
the majority of patients with gout and associated with
obesity, hypertriglyceridemia, high serum UA levels,
chronic disease forms, the high incidence of CHD and
arterial hypertension.(Eliseev MS et al.)

SUMMARY OF CARBOHYDRATE
METABOLISM
21
5

PER DAY INTAKE OF
CARBOHYDRATE
21
6
• Carbohydrate Calculator
http://www.calculator.net/carbohydrate-
calculator.html?ctype=metric&cage=25&csex
=f&cheightfeet=5&cheightinch=10&cpound=
160&cheightmeter=163&ckg=74&cactivity=1.
375&x=85&y=10#

CONCLUSION
• Carbohydrate are the measure source of energy
for the living cells. Glucose is the central
molecule in carbohydrate metabolism, actively
participating in a number of metabolic
pathway.
• One component of etiology of dental caries is
carbohydrate which act as substrate for
bacteria. Every effort should be made to
reduce sugar intake for healthy tooth.
21
7

REFERENCES
1) Biochemistry – U.Satyanarayana-3rd Ed.
2) Textbook of Biochemistry- D.M.Vasudevan -14th
Ed.
3) Textbook of Medical Biochemistry –
M.N.Chattergy – 17th Ed.
4) Text book of Physiology –Ganong – 24th Ed.
5) Text book of Oral Pathology – Shafers- 7th Ed.
6) Principles & practice of Medicine-Davidson –
21st Ed.
21
8

Carbohydrates and carbohdrates metabolism Rajesh Kumar Kushwaha

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