Leader in Dental Education's Metabolism Guide

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INDIAN DENTAL ACADEMY
Leader in continuing Dental Education

CONTENTS
INTRODUCTION
METABOLISM OF CARBOHYDRATES
GLYCOLYSIS
KREB’S CYCLE
HMP PATHWAY
GLUCONEOGENESIS
GLYCOGENESIS
GLYCOGENOLYSIS
URONIC ACID PATHWAY
METABOLISM OF GALACTOSE
METABOLISM OF FRUCTOSE

METABOLISM OF LIPIDS
BIOMEDICAL IMPORTANCE OF
LIPIDS
FATTY ACID OXIDATION
KETOLYSIS
PROTEIN METABOLISM
TRANSAMINATION
DEAMINATION
UREA CYCLE
CONCLUSION
LIST OF REFERENCES

METABOLISM
The entire spectrum of chemical reactions, occur
collectively are referred to as metabolism
1. Catabolism ( Catabolic )
breakdown of complex organic molecules into
simpler compounds
releases ENERGY
2. Anabolism ( Anabolic )
the building of complex organic molecules from
simpler ones
requires ENERGY

Carbohydrate
Metabolism

Glucose entry into cells :
Insulin dependent – muscle &
adipose tissue
Insulin independent -
hepatocytes,erythrocytes & brain

Glycolysis /
Embden-Meyerhof
Pathway
‘Glycose’– sweet/sugar ;‘lysis’–
dissolution
Elucidated in 1940
Glucose – pyruvate or lactate, + ATP
Brain,retina,skin,renal medulla & GIT
RBC – lactate production
All cells – cytosomal fraction
Major pathway for ATP in cells
without mitochondria – RBC, cornea,
lens

Glucose
Glucose 6-Phosphate
Fructose -6-Phosphate
ATP
ADP
1st
ATP
utilization
(in muscle & other
tissues)
Hexokinase or
Glucokinase(in liver)
Phosphogluc
oisomerase
ATP
ADP
2nd
ATP utilizationPhosphofructokinase
Fructose 1, 6, di-
Phosphate
Aldolase
Dihydroxy acetone
phosphate (DHAP)
Glyceraldehyde 3-
phosphate (PGAL)
Phosphotriase
Isomerase
Glycerate 3P
dehydrogenase
NAD + Pi
NADH + H+
1,3 diphosphoglycerate
ADP
ATP
Glycerate kinase
3 Phosphoglycerate (3PGA)
2 PGA
Phosphoglycerate
mutase
Enolase
2 phospho enol pyruate
(PEP)
H2
O
Pyruvate kinase Mg2+
,
K+
ADP
ATP
Pyruvate
Lactate
Lactate
dehydrogenase
NADH + H
NAD+

Reactions No. of ATP formed
1) Gluc → Glu-6-P - 1 ATP
2) Fruct 6 P → Fruct 1,6,
diphosp.
- 1 ATP
3) PGAL → 1,3 DPGA + 6 ATP (from 2 NADH)
4) 1,3 DPGA → 3 PGA + 2 ATP
5) PEP → pyruvate + 2 ATP
Net ATP formed (6 + 2 + 2) – 2
10 – 2 = 8 ATP
Energy yield in aerobic glycolysis :

Energy yield in anaerobic glycolysis :
1) Glu → Glu 6-P
- 1 ATP
- 2 ATP
2) Fruct 6P → Fruct 1,6
diphosp
- 1 ATP
3) Glycerol 3 P → 1,3 DPG -
4) 1, 3 DPG → 3P glycerate + 2 ATP
+ 4 ATP
5) PEP → 2 pyruvate + 2 ATP
6) 2 pyruvate → 2 lactate -
Net ATP formed = 4-2 = 2 ATP.
1 NADH = 3 ATP ; 1 ATP = 7600 cal of energy.
∴ 8 ATP = 8 x 7600 = 60,800 cal of energy.

Glycolysis
Glucose
Pyruvate Lactate
10 steps
No O2
Energy (ATP) and metabolites
3 regulated steps

Pathway Overview
What does glycolysis do for us?
•Process Glc (Frc) monomers
•Form 3-C metabolites
•Generate ATP and NADH
TCA
ATP
ATP
NADH
Glc
G6P
F6P
F16BP
DHAP + G3P
1,3-BPG
3-PG
2-PG
PEP
Pyr
•Input to TCA cycle
Lactate

Regulation
Glc
G6P
F6P
F16BP
DHAP + G3P
1,3-BPG
3-PG
2-PG
PEP
Pyr
PK
HK
PFK-1

Pyruvate Acetyl CoA –
oxidative decarboxylation
Irreversible --- PDH complex –
mitochond.
Cardiac muscles & kidney
TPP, Lipomide,FAD,co-enzyme A
& NAD+

CITRIC ACID
CYCLE / KREBS
CYCLE / TCA
CYCLEProposed by Hans Adolf Krebs in 1937
Important for energy, utilises 2/3 of total oxygen
Final oxidative pathway for a.a, fatty acids &
carbohydrates.
Syn of heam, non essential a.a & fatty acids,
cholesterol, vit D. steroid hormones.
Regulation of TCA :
Citrate synthetase
Isocitrate dehydrogenase
α-ketoglutarate dehydrogenase
Avaliability of ADP

ATP
Pyruvate
Acetyl Co A
NAD+
NADH + H+
CoA
CO2
PDH
Mg2+
Link b/w glycolysis & TCA
cycle
Citrate
CoA
CO2
HO2
Citrate synthetase
Cis-aconitase
HO2
Acositase Fe2+
Isocitrate
Acositase Fe2+
HO2
oxalosuccinate
NAD+
NADH + H+
Isocitrate, Mg2+
dehydrogenase
∝-keto gluterate
CO2
Isocitrate, dehydrogenase
Mg2+
Sucinyl CoA
CO2
CoA
NAD
NADH + H+
Succinate
CoA
Succinate thiokinase,
Mg2+
GTP
GDP + PI
ADP
Fumarate
Succinate
dehydrogenase Ca2+
FADH2
FAD
Malate
oxaloacetate
Malate dehydrogenase
NADH + H+
NAD+
Fumerase
HO2

Energytics of TCA cycle :
Total number of ATP formed during the oxidation of 1 acetyl Co A
through TCA cycle.
1. Isocitrate-oxalosuccinate – 1 NADH
3 ATP
2. α-ketoglutarate – succinyl CoA – 1 NADH 3 ATP
3. Succinyl CoA – succinate – 1 GTP 1 ATP
4. Succinate – Fumarate – 1 FADH2
2 ATP
5. Malate – oxaloacetate – 1 NADH 3 ATP

Total ATP
Output :
Aerobic oxidation of 1 mol. of glucose
through glycolysis & TCA :
During glycolysis -- 8 ATP
Pyruvate to 2 AcetylCoA -- 6 ATP
Oxidation of 2 AcetylCoA(TCA) – 24 ATP
so,
net ATP formed / glucose = 38 ATP

Hexose Monophosphate
Shunt / Pentose Phosphate
Pathway /
Phoshogluconate
Pathway /
Warburg-Dickman-Lipman
Pathway
Alternative to glycolysis & TCA
cycle
Liver, RBC, Testis, Ovary, Adipose
Tissue & Adrenal Glands
Cytosol
Anabolic , multi-cyclic pathway.

2 phases :
Oxidative phase
Dehydrogenation & Decarboxylation
Non-oxidative phase
Transketolase & Transaldolase
Metabolic significance :
Pentose sugars – N.A,ATP,FAD,NAD,CoA
NADPH – fatty acids,steroids,
cholesterol,sphingolipids,phenylalanine to
tyrosine
In RBC – NADPH for oxidised glutathione to
reduced glutathione.

Glu-6-P
6-phospho-gluco-lactose
Glu-6-P dehydrogenase
Mg2+
, Na+
, Ca2+
6NADP
6NADPH + H+
6-phospho gluconate
Gluconolactone
hydrolase Mg2+
, Na+
,
Ca2+
6 H2O
3-keto-6-P-gluconate
6-P-gluconate dehydrogenase
Mg2+
, Na+
, Ca2+
6NADP
6NADPH + H+
6 X
6 X
6 X
6 X
6 C2O
Ribulose-5-P
6 X
Xylulose-5-P Ribose-5-P
Phosphopentose
isomerase
Phosphopentose
epimerase
2 X4 X
Xylulose-5-P Xylulose-5-P
2 X 2 X
Sedoheptulose-7-P
Transketolase (TPP)
2 X
Glyc-3-P
2 X
+
Erythrose-4-P + Fructose-6-P
2 X
Glyc-3-P + Fruct-6-P
2 X 2 X
Fruct-6-P
Transketolase
TPP, Mg2+
1 X
2 X
Oxidative
phase
Non-Oxidative
phase
Glu-6-P 5 X
Iso
mer
isati
on

Gluconeogenesis
Biochemical process of syn. of glucose
from non-carbohydrate comp. such as
lactate,pyruvate,glucogenic a.a &
glycerol.
Liver & cortex of kidney
Cytosol & mitochondrial matrix
Importance :
Meets glucose requirements
Steady basal level of blood glucose in
starvation
Removes metabolic end products from
bloodwww.indiandentalacademy.com

Major precursors :
Lactate – anaerobic glycolysis in skeletal muscle
Through - Cori Cycle / Lactic Acid Cycle
Amino acids – from proteins in diet & during
starvation
From glucogenic a.a, through TCA intermediates
Glycerol – hydrolysis of fat

Citrate
∝-ketoglutarate
Sucinyl Co A
Fumarate
Oxaloacetate
Acetyl Co A
Isoleucine
lysine
tryptophan
Arginine
Glutamine
Histidine
Proline
glutarate
Isoleucine
Threonine
Valine
Phenylalanine
Tyrosine
Aspartate
Pyruvate
Phosphoenol
pyruvate
Aspartate
Aspargine
CO2
Glucose
Gluconeogenesis
CO2
Threonine,
alanine, glycine,
cystine, serine

Liver Blood Muscle
Glucose Blood
glucose
Glucose
(glycogen)
Pyruvate
Liver
lactate
Blood
lactate
Muscle
lactate
Pyruvate
Glyconeog
enesis
Anaerobic
glycolysis
Synthesis of glucose from lactate :
Cori cycle / Lactic acid cycle :-

Glucose
Glu-6-P
Fruct-6-P
Fruct 1,6 Di-P
Pi
H2O
Pi
H2O
Fructose 1,6
diphosphatase
Aldolase
DHAP PGAL
Tnoses P
isomerase
1,3 DPGA
NAD + Pi
NADH + H+
3 PGA
ADP
ATP
2 PGA
Phosphoenol pyruvate
HO2
ADP
ATP
CO2
Oxaloacetate
Phosphoenol pyruvate
carboxy kinase (biotin)
ADP + Pi
ATP + CO2
Pyruvate carboxylase, Mg2+
,
Biotin 2H+
H2O
Pyruvate
Amino acids
Lactate
Lactate
dehydrogenase
NAD
NADH + H+
Glycerol-3-P
NADH + H+
NAD
Glyc-3-P
dehydrogenase
ADP
ATP
Glycerol
(from fat)
Glycerol kinase,
Mg2+

Glycogen
Metabolism
Storage form of glucose
Stored in liver and muscle
Importance :-
Storage & supply of glu. between meals
Immediate blood glucose maintainace
Energy source within the muscle
Amino acid preservation
Red. the rate of ketone body formation.

Glycogenesis
Mainly in liver and muscle
Cytosol

Glycogenesis Diagrammatic Representation :
Glu – Glu – Glu – Glu –
|
Glu – Glu – Glu – Glu -
Glu – Glu – Glu – Glu – Glu
Branching
Enzyme
α 1,4 bond
α 1,6 bond
Proglycogen
UDP-glucose
Glu – Glu –
Glu Glycogen primer
Glu-1-P
UDP glucose
phosphorylase
UDP
PPi
UTP
ATP
Nucleoside
diphosphokiase
ADP
Mg2+
Phosphogluc
omutase
Glu-6-PGlucose
Glukokinase
or
hexokinase
Mg2+
ATP ADP

Glycogenolysis
Glycogen to glucose in liver & glu-
6-phosphate in muscles
Carried forward by 3 enzymes :
Phosphorylase
Glucan transferase
Debranching enzyme

Glycogenolysis diagrammatic representation :
Glu – Glu – Glu – Glu – Glu – Glu – Glu -
Glu – 1 – P
Glu – 6 – P
Phospholytic
cleavage
Phosphorylase
Pi
Phospho-
glucomutase
( In liver
In muscle)
Glu – 6 – P ase
H2
O Pi
Glucose (in liver)
Debranching enzyme
Hydrolytic
cleavage
Glu – Glu – Glu – Glu
| α 1,6 bond
α 1, 4 bond
glucan
transferase
H2
O

Inborn Errors in
Metabolism of Glycogen
Type and common
name of diseases
Enzyme deficient Tissues in which glycogen
is accumulated
Clinical features
Type I
Von-Gierkes’
Glu-6-(p) ase Liver & kidney 1. Massive enlargement
of liver
2. Severe hypoglycemia.
Type II
Pompe’s disease
Lysozomal & heart α,1,4
glucosidase
Lysozyme & heart 1. Enlargement of heart
(cardiomegaly)
Type III
Limit dextrinosis
Debranching enzyme Liver & muscles Gly. Acc. In
form of dextrin.
1. Like type I but minor
course
Type IV
Amylopectinoses
Branching enzyme Liver & spleen 1. Hepatomegaly
2. Splenomegaly
3. Cirrhosis of liver
Type V
McArdles Disease
Muscle phosphorylase Muscles 1. Painful muscle camps
2. Weakness & stiffness
of muscle
Type VI
Her’s disease
Liver phophorylase Liver 1. like type I but milder
course.

Uronic Acid Pathway /
Gluconic Acid Pathway :
Alternative oxidative pathway for
glucose
Syn. of gluconic acid, pentoses &
vitamin C
Xylulose enters this pathway
Free sugars are involved in this
pathway

Metabolism of Galactose
:
Lactose is principal source
Degeneration of glycolipids &
glycoprotein
Entry into cell is not insulin
dependent
Galactokinase galactose-1-
phosphate UDP-galactose
UDP-glucose
Not an essential nutrient

Metabolism of Fructose :
Sucrose is major dietary source
More rapidly metabolised by liver
than glucose
Inc. fructose intake inc. production
of Acetyl CoA & lipogenesis.

Lipid
Metabolism

Hetrogenous group of substances that contain :
Fatty acids
Fats
Oils
Waxes & other related substances
Soluble in :
Chloroform
Ether
Benzene
Acetone
Variously called Lipins / Lipods
Triacylglycerols – 85-90% of body lipids
Phospholipids, Cholesterol & cholesterol esters in minute
amounts

Biomedical importance of Lipids :
High energy constituents & essential
fatty acids are formed from them
1 gm of fat prod. 9.3 kcal of energy
Insulator
Structural component of cell memb.
Precursor for hormones like
adrenocorticoids,sex hormones & vit. D

Fatty Acid
Oxidation /
β-Oxidation :
Franz Knoop in 1904
Oxidation of fatty acids on β-carbon atom
Sequential removal of 2 carbon
fragment, acetyl CoA
It involves 3 steps :
Activation of fatty acids in cytosol
Transport of fatty acids into mitochondria
β-oxidation proper in mitochondrial matrix

Activation of fatty acids :
2 High energy phosphates are used
Saturated, unsaturated & hydroxy fatty acid all
are activated before oxidation
Activation takes place only once
Transport of fatty acid :
Carnitine – widely distributed & abundant in
muscles ; Lysine & Methionine in liver & kidney.

Fatty Acid
Acyl Co A
Co A
Acyl Co A
synthetase
ATP
Amp + PPi
Mg2+
Co A
Outer
memb
Carnitine
Acyl carnitine
Acyl carnitine
transferase
Inner
memb
Carnitine
Acyl carnitine
Translocase Co A
Acyl Co A
Acetyl Co A
TCA
cycle
CO2
HO2
12 ATP
Mitochondrial matrix

β-oxidation :
Catalysed by group of enzymes
called Fatty Acid Oxidases
Complex. Has 4 enzymes :
Acyl CoA Dehydrogenase
Enoyl CoA Hydratase
β-Hydroxy Acyl CoA
Dehydrogenase
β-Ketoacyl Thiolase

Fatty acid
Acyl Co A (Active f.a)
Acyl Co A
synthetase
ATP Mg2+
AMP + Pi
Co A
H2O
Acyl Co A
Mitochondrial memb. Carnitine
FAD
FADH2
Acyl Co A
dehydrogenase
α, β, unsaturated Acyl
CoA (Enoyl CoA)
(1) F.A.
activation
(2) Dehydrogenation
β - hydroxy Acyl Co A
Enoyl CoA hydratase
H2O
β - keto acyl Co A
β - hydroxy acyl Co A
dehydrogenase
NAD
NADH + H+
Acyl Co A + Acetyl Co A
β - Keto Acyl thiolase
HS CoA
(2 C less than
original f.a)
(3) Hydration
(4) Dehydration
(5) Thiolytic cleavage
Acyl Co A
Acyl Co A + Acetyl Co A

Total number of ATP formed from 7 β-oxidation = 5 x 7 = 35
Total number of ATP formed on oxidation of 8 mol of Acetyl Co A through TCA = 8 x 12 = 96 ATP.
Total number of ATP consumed by initial f.a. activation = -2 ATP
Therefore total number of ATP formed on complete oxidation of palmitic acid = (96 + 35) – 2
= 131-2 = 129 ATP.
odd carbon fatty acid
Propionyl CoA + Acetyl Co A
β- Oxidation
D-methyl melonyl Co A
Propionyl Co A
carboxylase
ATP
ADP + Pi
Biotin
L-methyl melonyl Co A
Methyl melonyl CoA
racemose
Succinyl Co A
Methyl melonyl CoA
mutase
Vit. B12
TCA cyclewww.indiandentalacademy.com

Ketolysis :
Acetoacetate, β-hydroxy butyrate, Acetone
Starvation…
Dec. pH of blood Ketoacidosis
Acetoacetate Acetoacetyl
Co A
2 Acetyl Co A
TCA cycle
Co A
transferase
Succinyl
Co A Succinat
e
CoA

Protein
Metabolism

Proteins :
Nitrogen containing macromolecules
Undergo transamination,deamination
Urea is excretory end product
A.A converted to ketoacid for :
To generate energy
For glucose synthesis
Formation of fat or ketone bodies
Prod. of non-essential amino acids

Transamination :
Transfer of amino group from amino acid to keto acid
Catalysed by transaminases
Salient features :-
Require PLP
Specific
No free NH3 liberated
Redistribution of amino group
Catabolism & anabolism
SGOT / SGPT are diagnostic
Lysine, Threonine, Proline & Hydroxyproline
Concentration of nitrogen to glutamate
Excess a.a to energy production

2 stages :
Transfer of amino group to PLP – pyridoxamine
phosphate
Transfer of amino group to keto acid
Mechanism :
R1
– CH – COO-
|
NH3
+
R1
– C – COO-
||
O
R1
– C – COO-
||
O
R2
– C – COO-
|
NH3
+
Amino acid – I
Keto acid II
Keto acid I
Amino acid –
II
Transaminase
PLP

Deamination :
Removal of amino group from amino acids as
ammonia & a.a keto acid
Transdeamination
2 types :
Oxidative deamination :-
By glutamate dehydrogenases :-
By amino acid oxidases :-

Non-oxidative deamination :-
By amino acid dehydrases
Amino acid desulfhydrases
Amino acid lyases
Amino acid hydrolases

Urea Cycle /
Krebs-Hanseleit Cycle
Elucidated by Hans Kreb & Kurt
Hanseleit (1932)
Site : liver
Upto Citrulline – mitochondria then
Cytosol
Energy expenditure : 4 high
energy bonds
Link to TCA

Reaction sequence :-
HCO3
-
2 ATP
NH4
+
2 ADP
Pi
Carbomoyl
phosphate
Carbomoyl
phosphate
synthase
Citrulline
Argentosuccinate
Arginine
Ornithine
Argentosuccinate
synthetase
Aspartat
e
ATP
AMP + Pi
Fumarate → TCA cycle
Argentosuccinate
lyase
Arginase
Urea
Pi
Ornithine trasncarboamylase

Inborn errors :-
Hyper Ammonemia I
Def. enzyme – carbomoyl phoshphate synthase
Ornithemia
Def. enzyme – ornithine transcarboamylase
Citrullinemia
Def. enzyme – argentosuccinate synthetase
Argentosuccinate Aciduria
Def. enzyme – argentosuccinate lyase
Arginemia
Def. enzyme – arginase

Hyperammonemia :
Inc. NH3 level
Slurring of speech
Blurred vision
Clinical importance of blood Urea :
Normal blood urea – 10 – 14 mg/dl
Estimation of kidney function
Defect can be :
Pre-renal
Renal
Post-renal

Biomedical Concepts :
Phenylketonuria – phenylalanine hydroxylase
Alkaptonuria - homogenisate oxidase
Tyrosine leads to prod. Melanin, Dopamine,
Norepinephrine, Thyroxine(T3)
Glycine helps in prod of Purines, Glutathione,
Conjugation, Heame, Creatinine
Aspartate helps in prod of purines &
pyrimidines
Serotonin, a neurotransmitter is produced from
Tryptophan.
Methionine is utilised for transmethylation,
coenzyme A synthesis.

Conclusion

List of References :
Biochemistry
U. Satyanarayana;2nd
edition
Text book of biochemistry
DM Vasudevan,Sreekumars;3rd
edition
Harper’s biochemistry
Robert K Murray,Daryl K Garnner;24th
edition
Principles of biochemistry
David L Nelson, Michel M Cox; 3rd
edition

Leader in Dental Education's Metabolism Guide

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