Transcript Glycolysis - medscistudents

CARBOHYDRATE METABOLISM
The official spokesman of carbohydrate metabolism, ‘glucose’
speaks:
“I burn myself to provide fuel to life!
Generated through gluconeogenesis by my friends;
Engaged in the synthesis of lipids, amino acids;
Deranged in my duties due to diabetes mellitus.”
Glycolysis:
Degradation of glucose to pyruvate (Lactate under anaerobic)
generates 8 ATP.
Citric acid cycle:
The oxidation of acetyl CoA to CO2
Gluconeogenesis:
The synthesis of glucose from non-carbohydrate precursors
(amino acids, glycerol etc)
Glycogenesis:
The synthesis of glycogen from
Dr Sglucose
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Glycogenolysis
The breakdown of glycogen to glucose and then to lactate or
pyruvate.
Hexose monophosphate shunt:
It is an alternative pathway to glycolysis and TCA cycle for
the oxidation of glucose. Here the glucose is directly oxidised
to CO2 and H2O.
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GLYCOLYSIS (Embden meyerhof pathway)
 Carbohydrates are the important energy source of the
body.
 Glucose is the preferred source of energy for most of
the body tissues.
 Brain cells derive energy mainly from glucose
 Pyruvate is the end product of aerobic glycolysis
 Lactate is the end product of anaerobic glycolysis
Site: Cytoplasm
Importance of the pathway
 Pathway takes place in all the cells of the body
 It is the Source of energy in erythrocytes
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 Anaerobic glycolysis forms the major source of energy
for muscle during exercise
 Provide carbon skeletons for the synthesis of nonessential amino acids.
 Most of the reactions of glycolysis are reversible
 The entry of glucose from ECF to cell (ICF) is under
the control of insulin
 Glycolysis occurrence is the pre-requisite for the
aerobic oxidation of carbohydrates
 Aerobic oxidation takes place in the cells possessing
mitochondria.
 Glycolysis is the major pathway for ATP synthesis in
tissues lacking mitochondria (erythrocytes)
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Steps of Glycolysis
1. Irreversible
Glucokinase
Hexokinase
a. Present in liver
Present in all tissues
b. Phosphorylation of Glu
Phosphorylation of hexoses
c. Low affinity for glucose
High affinity for substrates
d. Not inhibited by Glucose 6–P Inhibited by glucose 6- P
•Glucose 6-P: Impermeable to the cell membrane.
•Central molecule with a variety of metabolic fates; glycolysis,
glycogenesis,
Steps
of Glycolysisgluconeogenesis and HMP shunt.
2. Reversible reaction
3. PFK is an allosteric inducible key enzyme and the reaction is
irreversible
4. Reversible, 6-carbon compound split into two 3 carbon
compounds, both are reversibly convertible by an isomerase
enzyme. Thus, two molecules of glyceraldehyde 3-phospahte are
obtained from one molecule of glucose.
Isomerase is inhibited by bromohydroxyacetone-phosphate
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5. Reversible, end product contains a high-energy bond.
6.
7.
8.
9.
10.
Iodoacetate and arsenite inhibit the Glyceraldehyde
3- Phosphate dehydrogenase non-competitively
The high energy of 1,3 bisphosphoglycerate is trapped to
synthesise one ATP molecule
Reversible reaction
Reversible reaction, Mg2+ act as activator
Fluoride irreversibly inhibit this enzyme with the removal
of Mg2+
High energy of Phosphoenolpyruvate is trapped into ATP
by the pyruvate kinase, irreversible reaction. Ends with
pyruvate in the tissues with mitochondria (aerobic)
If anaerobic conditions prevail, the reoxidation of NADH formed
in reaction 5 is by transfer of reducing equivalents through
respiratory chain to oxygen is prevented and get reoxidised by
conversion of pyruvate to lactate by LDH
Tissues that function under hypoxic conditions produce lactate
e.g. Skeletal muscle, smooth muscle and erythrocytes
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Steps 5 and 10 are coupled
Glycolysis is the major source of energy in anaerobiosis
For smooth operation of the pathway NADH is to be
reconverted to NAD+.
The formation of lactate allows the regeneration of NAD+
 which can be reused by glyceraldehyde 3-P Dh. So that
glycolysis proceeds even in the absence of oxygen to
supply ATP.
Fate of pyruvate depends on the presence or absence
oxygen in the cells.
The occurrence of un-interrupted glycolysis is very
important in skeletal muscle during strenuous exercise.
Brain, retina, renal medulla and GI tract derive their
energy from glycolysis.
Glycolysis in the erythrocytes leads to lactate production,
since the mitochondria, the centres for oxidation are absent
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Energetics of glycolysis:
Energy consuming steps are 1 and 3
Hexokinase and phosphofructokinase
catalysed reactions
= - 2 ATP
Energy yielding steps are: Step 5
Catalysed by Glyceraldehyde –3-PDH
Oxidative phosphorylation:NADH x 2 = 3ATP x 2 = 6 ATP
Substrate level phosphorylation Steps 6 and 9
Catalysed by Phosphoglycerate kinase &
Pyruvate kinase
2ATP x 2
= 4 ATP
Total ATP in aerobic glycolysis =10 ATP – 2 ATP
= 8 ATP/ glucose
Anaerobic glycolysis: 1 and 3 = 2 ATP used
Steps 6 and 9 2 ATP x 2 =
4–2
= 2 ATP
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Shuttle pathways:
• If the cytosolic NADH uses malate-aspartate shuttle, 3
ATP are produced. If it uses Glycerol phosphate
shuttle produces 2 ATP.
v Regulation
• Insulin favours glycolysis by activating key glycolytic
enzymes like glucokinase, phosphofructokinase(PFK)
& pyruvate kinase
• Glucose–6 P, inhibits hexokinase. This enzyme
prevents the accumulation of glucose 6-phosphate.
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
PFK-1 is an inducible enzyme that increases its synthesis in
response to insulin and decreases in response to glucagon
Pyruvate kinase is an inducible enzyme that increases its synthesis in
response to insulin and decreases in response to glucagon
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Role of Fructose 2, 6-bisphosphate:
It is the most regulatory factor for controlling PFK and ultimately
glycolysis in the liver.
The function of synthesis and degradation of F2, 6-BP is brought out by a single
enzyme (with two active sites), which is referred to as bifunctional or Tandem
enzyme. The activity of these enzymes is controlled by covalent modification,
which in turn regulated by Cyclic AMP. cAMP brings about the
phosphorylation of the tandem enzyme, resulting in inactivation of active site
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Regulation by PFK-2
There will be no stimulation when Fru-2, 6 bisphosphate decreases,
with low glucose the PFK1 remains inactive.
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Pasteur effect
The inhibition of glycolysis by oxygen
When anaerobic yeast exposed to air, the glucose
utilisation decreases.
In the aerobic condition the levels of glycolytic
intermediates from fructose 1, 6 bisphosphate onwards
decreases while the earlier intermediates accumulate.
The Pasteur effect is due to the inhibition of PFK. Citrate
and ATP inhibition explains the Pasteur effect.
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Rapoport Leubering Cycle (BPG Shunt)
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The kinase reaction is bypassed in the erythrocytes
No energy is trapped from 2, 3 BPG
The BPG when combines with Hb, reduces the affinity
of Hb towards oxygen. In the presence of 2, 3 BPG
oxyhemoglobin unload oxygen more easily in tissues
 Therefore the 2, 3 BPG increases in hypoxic condition
 15 to 25% of the lactate formed goes through this
pathway
 In hexokinase deficiency phosphorylation does not
takes place further. So 2,3 BPG decreases. Then
affinity to hemoglobin increases
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Fate of pyruvate
Under aerobic condition pyruvate is transported into
mitochondria via pyruvate transporter
Pyruvate dehydrogenase Complex
Pyruvate
Acetyl CoA
NAD+
NADH+ H+
TPP, FAD, Lipoic acid, CoASH
Lack of TPP leads to accumulation of pyruvate
In thiamine deficient alcoholics, pyruvate converted
to lactate and it leads to lactic acidosis
Lactic acidosis is caused by:
Inherited deficiency of PDH
Inability to reoxidise NADH in the electron transport
chain
Excessive NADH production, e.g., ethanol intoxication
Pyruvate dehydrogenase inhibited by arsenic and
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mercuric ions
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Ref: Essentials of Biochemistry, Dr S Nayak
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