Glycolysis • Glucose is one of the most important energy sources as it serves as a fuel and is ready to be oxidized to provide energy for other metabolic processes. • Both galactose and fructose are converted into glucose in the liver. First: glucose metabolism: Fates of glucose: a) Oxidation either for energy production as in case of glycolysis and CAC or for other purposes as in HMS and uronic acid pathway. b) Conversion to other biologically important substances as galactose which is essential for lactose formation, glycolipids and mucopolysaccharides. c) Storage: in the form of glycogen or triglyceride. d) Maintaining blood glucose level (60-110 mg/dl) e) Excretion in urine in case of hyperglycemia (>180 mg/dl) which is then called glucosuria. Glycolysis: Definition : it’s the first step of glucose oxidation to produce energy….its the degradation of glucose to Generate ATP and to provide intermediates for other synthetic and metabolic pathways. Aerobically, it ends with pyruvate. In RBCs, there is no mitochondria so anaerobic glycolysis takes place where lactate is the end product. Site: it occurs in the cell cytosol • Some cells are permeable to glucose carried on proteins as liver, kidney, brain and intestine. • While others need insulin as adipose tissue and skeletal muscles.
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Glycolysis
• Glucose is one of the most important energy sources as it serves as a fuel and
is ready to be oxidized to provide energy for other metabolic processes.
• Both galactose and fructose are converted into glucose in the liver.
First: glucose metabolism:
Fates of glucose:
a) Oxidation either for energy production as in case of glycolysis and CAC or
for other purposes as in HMS and uronic acid pathway.
b) Conversion to other biologically important substances as galactose which is
essential for lactose formation, glycolipids and mucopolysaccharides.
c) Storage: in the form of glycogen or triglyceride.
d) Maintaining blood glucose level (60-110 mg/dl)
e) Excretion in urine in case of hyperglycemia (>180 mg/dl) which is then
called glucosuria.
Glycolysis:
Definition: it’s the first step of glucose oxidation to produce energy….its the
degradation of glucose to Generate ATP and to provide intermediates for other
synthetic and metabolic pathways. Aerobically, it ends with pyruvate.
In RBCs, there is no mitochondria so anaerobic glycolysis takes place where
lactate is the end product.
Site: it occurs in the cell cytosol
• Some cells are permeable to glucose carried on proteins as liver, kidney,
brain and intestine.
• While others need insulin as adipose tissue and skeletal muscles.
Steps:
• Hexokinase can act on all hexoses but mainly on glucose. It has high affinity
to glucose so it can act on very low concentrations and it can also stimulate
its phosphorylation.
• Glucokinase can act only on glucose but it has low affinity to it so it needs
high glucose concentration to stimulate phosphorylation.
• Phosphofructokinase (PFK) is a rate limiting enzyme and this step is called
the committed step as it catalyzes the first irreversible reaction unique to
the glycolytic pathway.
• When glyceraldehyde 3 phosphates is changed into 1, 3 bisphosphoglycerate,
oxidative phosphorylation takes place.
• When 1,3 bisphosphoglycerate is converted into 3 phosphoglycerate , ATP is
produced known as energy at substrate level at the site of the chemical
reaction.
Importance of glycolysis:
A) Energy production:
• Under aerobic conditions, 2 pyruvate molecules are produced with 8
ATP……NADH is oxidized in ETC to give 3 ATP.
• Under anaerobic conditions( as in RBCs and lens or during high activity in
skeletal muscles), 2 lactate molecules are produced with 2 ATP where lactate
can then change into pyruvate by lactate dehydrogenase enzyme (LDH) using
NAD.
B) Synthetic functions:
• Dihydroxyacetone phosphate can be converted by (glycerol-3-phosphate
dehydrogenase) into glycerol 3 phosphate which can be used in TG formation
and phospholipids.
• Pyruvate can change into acetyl Co-A that is used in FA and steroids as well
as ketone bodies.
• Synthesis of different amino acids.
• E.g. Pyruvate ……….Alanine by ALT (Alanine aminotransferase)
• Phosphoglycerate can be converted into serine that can change either into
cysteine or glycine.
C) In RBCs:
• Some types of hemolytic anemia are due to inherited deficiency in glycolytic
enzymes especially pyruvate kinase.
• NADH reduces methemoglobin by NADH-cytb5 –reductase enzyme.
• 1,3 bisphosphoglycerate is converted into 2,3 bisphosphoglycerate that
combines with oxyhaemoglobin to help oxygen transfer among tissues.
Regulation:
• It’s according to body physiological state.
• Regulation occurs according to certain levels.
• Induction by stimulating the increase of protein production or repression by
stimulating decreasing protein production.
• Allosteric modification is all about Substrate and Product…..As S Inc. the
enzymes is activated while when P Inc. the enzymes are deactivated.
• Constitutive enzymes are enzymes that is neither induced nor repressed.
• It’s controlled by 3 irreversible enzymes which are hexokinase or
glucokinase, PFK and PK.
• It’s achieved by induction and repression besides allosteric and covalent
modifications.
inducer repressor Allosteric
activator
Allosteric
inhibitor
Covalent
phosphorylation
Covalent
dephosphorylation
glucokinase Insulin Glucagon ….. ….. .…. …..
hexokinase Const. Const. …... G6P ….. …..
PFK Insulin Glucagon AMP and
F6P
ATP and
citrate
Glucagon in
hypoglycemia
Insulin in fed
state
PK Insulin Glucagon F1,6 P ATP Glucagon Insulin
-Inhibitors:
If they are present they inhibit glycolytic enzymes
i) 2-deoxyglucose inhibits hexokinase.
ii) Mercury and iodoacetate bind to active site of enzyme and react with
sulfhydrile group so it inhibits the enzymatic action.
iii) Flouride changes Mg+2 into MgF2…….no enolase action
iv) Arsenate is an uncoupler of oxidation as it reacts with glyceraldehyde 3
phosphate forming 1 aresno 3 phospho glycerate instead of 1,3
bisphosphoglycerate so no ATP at substrate level is formed.
*Fates of pyruvate:
-It can be converted into:
a) Oxaloacetate: By carboxylation using biotin and ATP with CO2 and water to
give ADP and oxaloacetate.
b) Acetyl co-A: By oxidative decarboxylation using a complex enzyme (5 co-
enzymes which are TPP, Lipoic acid, Co-ASH, NAD and FAD).
*Regulation of puruvate dehydrogenase:
Arsenite and mercury inhibit it covalently by reacting with sulfhydrile group of
lipoic acid leading to change of pyruvate into lactate which may lead to lactic
acidosis.
Second: Citric Acid Cycle(CAC):
-Definition: It’s a series of reactions in mitochondria that catabolizes acetyl
residues to provide energy.
-Site: Mitochondria
-Steps:
-Importance of CAC:
1) Energy production: every one mole of acetyl Co-A releases 12 ATP
2) It has amphibolic functions:
1. Catabolic functions: it’s the final common metabolic pathway for oxidation
of CHO, Fat and Proteins.
2. the most important anabolic functions are:
1) Citrate in the cytosol by ATP citrate lyase gives acetyl Co-A which is
used for synthesis of fatty acids and cholesterol.
2) By transamination alpha ketogluteric acid is converted into glutamate
and oxaloacetate is converted into aspartate.
3) Oxaloacetate in the cytosol is converted to PEP which is converted into
glucose by gluconeogenesis.
4) Succinyl co-A is used for heme synthesis, oxidation of ketone bodies
and detoxification.
5) Malate gives pyruvate by malic enzymes in the cytosol.
6) CO2 produced is used in many important reactions including different
CO2 fixation reactions, purine and pyrimidines and urea synthesis and
synthesis of H2CO3/BHCO3 buffer system.
*Regulation of CAC:
• Substrate availability: citrate synthase is activated by high concentrations of
acety Co-A.
• High concentration of citrate causes feedback inhibition of citrate synthase
while high concentration of succinyl co-A causes competitive inhibition of the
same enzyme.
o Ex1: alpha ketoglutarate dehydrogenase is allosterically inhibited by
succinyl co-A.
o Ex2: high NADH/NAD+ and ATP/ADP ratio produces allosteric
inhibition of citrate synthase, isocitrate dehydrogenase and alpha
ketoglutarate dehydrogenase while increase in ADP allosterically
stimulates the 3 enzymes.
*Unlike pyruvate dehydrogenase, it's not regulated covalently.
*Inhibitors of CAC:
citrate
isocitrate
α-ketoglutarate
succinyl co-A
fumarate
Arsenite and Mercury
flourocitrate
Malonic acid Inhibitors of
CAC
Relation between Citric acid cycle and Gluconeogenesis, Transamination, &
Deamination
Hexose Monophosphate pathway
(HMP)
Alternative names:-
• Pentose phosphate pathway (PPP).
• Pentose pathway
• phosphogluconate oxidative pathway
• Direct oxidation of glucose
1-Definition:-
Another route (alternative route) of glucose oxidation without
direct consumption or generation of ATP.
2-Site:-
Cytosol of many cells e.g. liver, adrenal cortex, adipose tissue,
testis, ovaries, retina, lactating mammary gland and RBCs
(erythrocytes).
3-steps:-
Occurs in 2 phases; oxidative and non-oxidative.
#OXIDATIVE phase:-
• It is irreversible;
• Glucose-6-phosphate is converted to ribulose-5-phosphate.
• We get 2 NADPH from this phase.
#NON-OXIDATIVE phase:-
• It is reversible.
• And it is catalyzed by transketolase and transaldolase.
• Pentoses in phase I are converted to glucose-6-phosphate
again.
That means ------->
6 molecules of glucose-6-phosphate are converted to ribulose-5-