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CARBOHYDRATE METABOLISM & REGULATION

OUTLINE:
➢

INTRODUCTION

➢ GLYCOLYSIS
•

PREPARATORY PHASE

•

PAY OFF PHASE

➢ GLYCOLYSIS REGULATION
➢ GLUCOSE UPTAKE
➢ FEEDERS PATHWAYS FOR GLYCOLYSIS & SHUNT OF
MONOSACCHARIDE INTO GLYCOLYSIS AND RELATED DISODERS
➢ FATE OF PYRUVATE
➢ GLUCONEOGENESIS AND ITS REGULATION
➢ PENTOSE PHOSPHATE PATHWAY
➢ THE URONIC ACID PATHWAY
➢ THE POLYOL PATHWAY
➢ GLYCOGEN METABOLISM, DISORDERS AND REGULATIONS
➢ CONTROL OF GLYCOGEN METABOLISM
➢ SUGAR NUCLEOTIDES
...
Organisms store as starch (in plant) or glycogen (in
animals)
...

In plant and animals, glucose has four major fates:
I
...


Conversion to polysaccharides for extracellular spaces
Oxidation to pyruvate, to produce ATP

III
...


Stored in cell as polysaccharide

GLYCOLYSIS
Glycolysis is the series of (stepwise) enzyme catalyzed cytosolic degradation of glucose to yield
two molecule of three carbon compound; pyruvate and 2 ATP
...

Glycolysis is the sole source of energy(ATP) in some mammalian tissues e
...
RBC, renal,
medulla, brain, and sperm
...

➢ Step 1: Phosphorylation of Glucose: the glucose is activated for subsequent reaction by
its phosphorylation at C6 by ATP and enzyme; Hexokinase, to yield glucose-6phosphate (G6P)
...
Hexokinase; like any other kinase
requires Mg2+ for activity, because he proper substrate for the enzyme is MgATP2-

➢ Step 2: Conversion of glucose-6-phosphate to fructose-6-phosphate: the enzyme
“phosphohexose isomerase” catalyzes the reversible isomerization of G6P; an aldose, to
fructose-6-phosphate; a ketose
...


➢ Step 3: Phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate: this
reaction phosphorylate the C1 of fructose-6-phosphate using ATP (or Ppi) by the
enzyme “Phosphofructokinase-1 (PFK-1)”
...
PFK-1 activity is regulated by:
i
...


Activation by fructose-2,6-bisphosphate

iii
...


Inhibition by citrate & other intermediate of TCA

➢ Step 4: Cleavage of fructose-1,6-bisphosphate: The enzyme “fructose 1,6-bisphosphate
aldolase”, a class I aldolase often called simply aldolase, catalyzes a reversible aldol
condensation
...

aldehyde group of glyceraldehyde 3-phosphate is oxidized to a carboxylic
anhydride with phosphoric acid
...


first
1,3The
acid

The dehygrogenase enzyme is inhibited by iodoacetate, arsenate and heavy metal

➢ Step7: Phosphoryl transfer from 1,3-bisphosphoglycerate to ADP: the phosporyl group
on C1 of 1,3-bisphosphoglycerate is transferred reversibly to ADP, a substrate level
phosphorylation reaction that converts ADP to ATP, and leaves 3-phosphoglycerate
behind
...

This reaction occurs in two stages:
i
...


The enzyme then transfers its newly acquired H to C3 and take up the phosphate group
at C3, thus the enzyme is simply substitutively recycled
...

The enolase enzyme is inhibited by Fluoride

➢ Step10: Transfer of phosphoryl group from phosphoenolpyruvate to ADP: this is
another substrate level phosphorylation in which C2 phosphate group of
phosphoenolpyruvate is transferred to ADP to yield pyruvate and ATP by the enzyme
“pyruvate kinase” which requires either K+, Mg2+ or Mn2+ as cofactor
...


Glycolysis Energy Balance
In overall, the net reaction of glycolysis can be represented as:
Glucose + 2NAD + 2ADP + 2Pi → 2 pyruvate + 2NADH + 2H + 2ATP + 2H2O
Thus, 2ATP and 2NADH are the energetic yield of glycolysis
...

On a slightly longer range,glycolysis is regulated by change in hormone: insulin, glucagon and
epinephrine
...


Each of the glycolytic intermediate between glucose and pyruvate is phosphorylated
...
Since plasma membrane generally lack transporters for phosphorylated sugars,
phosphorylation is a mechanism to trap sugars within the cell
2
...
g
...
Binding energy resulting from binding of phosphate group to active site of enzyme plays
a catalytic role in lowering activation energy
...
The 1,3-bisphosphoglycerate formed at step 6 of glycolysis has other fate in the RBC; in
which it may be involved in the synthesis of 2, 3-bis phosphoglycerate(2,3-BPG)
...
Because of this, energy yielding
reaction catalyzed by phosphoglycerate Kinase (step 7) is bypassed
...


In the erythrocytes 2, 3-BPG product of this shunt aids unloading of oxygen by
oxyhaemoglobin
...
2, 3-BPG may be converted to 3-phosphoglycerate by “2, 3-bisphosphoglycerate
phosphatase”, and it then re-enters the glycolytic pathway
...
Most significant of these are the
storage polysaccharide i
...
starch and glycogen, and the disaccharides e
...
maltose, lactose,
sucrose, trehalose; and monosaccharides as mannose, fructose, galactose etc
➢ Dietary glycans and disaccharides undergo hydrolysis to monosaccharide: starch is the
major carbohydrate in human diet; its digestion begins in the mouth when the salivary
α-amylase randomly hydrolyze the internal α(1→4) glycosidic linkages of starch;
producing short polysaccharide fragments or oligosaccharides
...

Maltose and maltotriose are degraded to glucose by enzymes of the intestinal villi
...
Intestinal disaccharides and dextrins are hydrolyzed by enzymes (disaccharidases)
attached to the outer surface of the intestinal epithelial cells
...

Of medical importance is the genetic inefficiency of some of the said disaccharidases
...
Lactose cannot be

completely digested and absorbed in the small intestine and passes into the large intestine,
where bacteria convert it to toxic products that cause abdominal cramps and diarrhea
...
In most climes where
lactose intolerance is prevalent, milk is not used as a food by adults, although milk products (e
...


➢ Endogenous glycogen and starch are degraded by “phosphorolysis” : glycogen stored in
animal & plant tissues and in microorganismscan be mobiized for use within the cell by
phosphoroltic reaction, where “Glycogen phosphorylase (starch Phosphorylase in plant)
catalyzes the attach by inorganic phosphate (Pi) on the α(1→4) glycosidic linkage
sequentially at the “non-reducing end” , generating glucose-1-phosphate and a polymer
one glucose shorter
...

The formed glucose-6-phosphate can enter glycolysis as in skeletal muscle, or can undergo a
“phosphatase” reaction as in liver and kidney alone and thus the resulting glucose used to
replenish diminishing blood glucose

Glucose Uptake into Cells :
Glucose metabolism in mammals is limited by rate of glucose uptake into cells and its
phosphorylation by hexokinase
...
It moves through the cell to the basal surface, where it passes

into the blood via GLUT2
...
In RBC, GLUT1 is the glucose transporter, in hepatocytes; the glucose
transorter is GLUT 1 & GLUT2, in brain neurons; GLUT3 is the glucose transporters
...

In contrast, the glucose transporter in cells of skeletal muscle, cardiac muscle and adipose tissue
is GLUT4 and is always found intracellularly secluded in vesicles and moves into plasma
membrane only at the signal of the insulin hormone; secreted by the pancreatic β-cells
...
Muscles thus need to switch to stored lipids as its principal
source of fuel, thus a significant increase in ketone production, excess of which can be life
threatening in ketoacidosis condition
...

•

FRUCTOSE: catabolism of fructose in the muscle, kidney and small intestine
begins with enzyme “Hexokinase” which phosphorylates it at C6 and yield
fructose-6-phosphate which can proceed glycolysis

However, in the liver an isozyme of hexokinase; “Fructokinase” which
phosphorylates at C1 instead converts fructose to fructose-1-phosphate
...

1
...
Fructosemia and fructosuria develops on
consumption of fructose containing compounds due to impaired utilization of
fructose
...
Hereditary fructose intolerance: It is due to the deficiency of aldolase B
...
On consumption of
fructose vomiting and diarrhoea occurs
...

Other symptoms are fructosemia, fructosuria, jaundice, enlargement of liver,
growth failure, kidney damage and hepatomegaly
...

➢ GALACTOSE: it is first phosphorylated at C-1, at the expense of ATP, by enzyme
“galactokinase” to form galactose-1-phosphate
...
The
epimerization involves first the oxidation of the C4 -OH group to a ketone, then
reduction of the ketone to an -OH, with inversion of the configuration at C-4
...

The resultant glucose-1-phosphate then undergoes a “phosphoglucomutase”
reaction which converts it to glucose-6-phosphate which proceeds glycolysis
...

•

Congenital galactosemia: It is due to the deficiency of “galactose-1-phosphateuridyl transferase”
...
Vomiting and diarrhoea occurs when milk
is consumed
...
Aldose reductase catalyzes the conversion of galactose to galactitol)

The condition is fatal in early life and adult galactosemics tolerate galactose
because an alternative pathways develops later, in which, galactose-1-phosphate is
converted to UDP-galactose by UDP galactose pyrophosphorylase
...


➢ MANNOSE: D-Mannose, released in the digestion of various carbohydrate foods can be
phosphorylated at C6 by “hexokinase” enzyme to form Mannose 6-phosphate; which is
isomerized by “phosphomannose Isomerase” enzyme to yield fructose 6 phosphate,
which then proceeds with glycolysis

Fate of Pyruvate
The pyruvate end product of glycolysis is further metabolized into any of the following:
i
...


Pyruvate can also be reduced to lactate

iii
...
NAD+ must therefore be regenerated via an alternative shunt
...

Produced lactate is either converted back to pyruvate when oxygen saturation is balanced
or it can be tranported via blood to the liver; where it is use for gluconeogenesis
...


Pyruvate is decarboxylated irreversibly by “pyruvate decarboxylase” in the presence of
thiamine-pyrophosphate and Mg2+ to form acetaldehyde
...


Aceltaldehyde is then reduced to ethanol by enzyme “alcohol dehydrogenase” which
uses NADH as electron donor
...
g brain, RBC,
renal medulla; but glucose stoed as glycogen is often not sufficient as it get depleted
between meals, long fast and during vigorous exercise, thus organisms need to devise
methods for synthesizing glucose from non-carbohydrate sources
Thus, Gluconeogenesis is the formation of new sugar (glucose) from pyruvate, lactate,
glycerols, propionate, TCA cycle intermediate as well as certain amino acids
...

7 out of the 10 major steps of gluconeogenesis are the reverse of glycolytic reaction
...

Gluconeogenesis Bypasses:
follows:

comprehension of the three enzymatic bypasses are as

1
...
There are two routes for
this conversion based on the glucogenic precursor:
A
...
Because the mitochondrial membrane is impermeable to oxaloacetate, it is
therefore reduced to malate by another mitochondrial enzyme “malate dehydrogenase”
at the expense of NADH before it can be moved to the cytosol
...


B
...
In the cytosol, the lactate is converted to pyruvate and
also yield NADH by “lactate dehydrogenase”
...
But
afterwards, oxaloacetate is converted directly to phosphoenolpyruvate by the
mitochondrial “phosphoenolpyruvate carboxykinase”
2
...
Conversion of glucose-6-phosphate to glucose: this reaction is catalysed by an Mg2+
dependent “glucose-6-phosphatase” enzyme; usually found on the lumen side of
endoplasmic reticulum of hepatocytes, renal cells and epithelial cells of small intestine
only
...


➢ Gluconeogenesis is energetically expensive: for each molecule of glucose formes from
pyruvate, six high energy phosphate compounds are required: 4 ATP, 2 GTP, also two
NADH are required for reduction of 1,3-bisphosphoglycerate
➢ Gluconeogensis regulation: enzymes of gluconeogenesis are subjected to allosteric
regulation and hormone regulation
...
They are under allosteric regulation and
hormonal control
...

When the glucose is in short supply glucagon produced as response to hypoglycemia
stimulates the formation of cAMP which inhibits kinase activity of PFK-2 and activates
phosphatase activity through protein kinase mediated phosphorylation

THE PENTOSE PHOSPHATE PATHWAY OF GLUCOSE OXIDATION
...
One of the fate of glucose-6-phosphate is
its oxidation to form pentose phosphate by the “pentose phosphate pathway (PPP)” also known
as the “phosphogluconate pathway” or “hexose monophosphate pathway”
...

Rapidly dividing cells as cells of the bone marrow, intestinal mucosa, skin and tumor use the
pentose formed i
...
ribose-5-phosphate to make DNA, RNA, and coenzymes such as ATP,
NADH, FADH2, coenzymeA
...

The reactions, of pentose phosphate pathway is classified into two phase: [1] The oxidative
phase, and [2] The non-oxidative phase
...
The oxidative phase produces pentose phosphate and NADPH:
In this phase of PPP ; the first reaction is the oxidation of glucose-6-phosphate at C1 to
6-phosphoglucono-δ-lactone by the activity of the enzyme “glucose-6-phosphate dehydrogenase”
which uses Mg2+ as cofactor and NADP+ as electron acceptor
...
The non-oxidative phase recycles ribulose-5-phosphate to glucose-6-phosphate: tissues
that requires NADPH recycles the the PPP product back to glucose-6-phosphate
...
This reaction occurs as
shown on the side illustration
...
The
glyceraldehyde-3-phosphate and fructose-6-phosphate product then can proceed with
glycolysis
...
Also, NADPH and xylulose-5-phosphate(which on non-oxidative
PPP and glycolysis with PDH yield acetyl-coA) products of PPP, are precursors in lipid
biosynthesis, thus xylulose-5-phosphate assumes a central position between
carbohydrate and fat metabolism
...
Thesyndrome is common in alcoholics as excess alcohol impedes thiamine

absorption
...

There are eight reaction in this pathway:
1
...
It undergoes oxidation at C6
catalyzed by NAD dependent UDP-glucose dehydrogenase to yield UDP-glucuronicacid
...
UDP-glucuronate is the active form of
glucuronate
...
In reaction-2, UDP-glucuronate is converted to glucuronate by hydrolysis
...
Gulonate dehydrogenase reduces glucuronate to L-gulonic acid in a NADPH dependent
reduction reaction that convert aldehyde group to alkanol group
...
In man, L-gulonate is converted to L-xylulose a pentose in two
reactions involving oxidation and decarboxylation
...

5
...


7
...


L-Gluonate is oxidized at C3 by NAD+ dependent dehydrogenase to 3-keto-Lgulonate
...

In reaction, pentose L-xylulose is generated from 3-keto-L-gulonate by removing C1 of
3-keto-L-gulonate as CO2
...
Since there is
no pathway which can utilize L-xylulose it has to be converted to D-xylulose in a subtle
mechanism
...

The genetic deficiency in xylitol dehydrogenase result in accumulation of L-xylulose; a
condition termed “essential pentosuria”
NAD+ dependent D-xylulose dehydrogenase converts xylitol to D-xylulose by removingH atoms from C2
...
In the HMP shunt
pathway, it is converted to intermediates of glycolysis and used for energy production
...


Lactonase catalyzes the formation of L-gulonolactone from L-gulonate by removing one
water molecule C1 and C4
...


Gulonolactone oxidase catalyzes the oxidation of L-gulonolactone at C2 atom in
presence of oxygen to generates 2-keto-L-gulonolactone
...


iii
...


1 = Lactonase
2= Gulonolactone oxidase

GLYCOGEN METABOLISM IN ANIMALS
...

Glycogen synthesis takes place virtually in all tissues
...


The start of glycogen synthesis is formation of glucose-6-phosphate as in step 1 of
glycolysis
...
The glucose-6-phosphate is reversibly converted to to glucose-1-phosphate by the
enzyme “phosphogluco-mutase”
...


3
...
UDP-glucose then becomes the immediate donor of glucose residue in the reaction
catalysed by “glycogen synthase”; which catalyzes the transfer of glucose residue from
UDP-glucose to the non-reducing end of a growing glycogen molecule chain, thus
increasing the glycogen molecule by one glucose in an α(1→4) glycosidic linkage
...
The effect of this branching is that it increases solubility and
the number of non-reducing end on a glycogen chain
...
It often requires a preformed α(1→4) polyglucose chain
...
The priming mechanism is that glucose residue is
transferred form UDP-glucose to the –OH group of Try194 on the glycogenin, this is catalyzed
by the protein’s intrinsic “glycosyl transferase” activity
...


Regulation of Glycogen Metabolism
1
...
Mucle glycogen phosphorylase is
activated by AMP, but inhibited by ATP & G6P; on the other hand glycogen synthase is
activated by G6P, and high ATP
...
g
...

Also, the interconversion of a & b forms of both glycogen synthase and glycogen
phosphorylase is cyclically achived via a reciprocal covalent phosphorylation-

dephosphorylation relationship which is often under hormonal control
...

3
...
As a result glycogenolysis is
enhanced
...

Insulin decreases glycogenolysis by decreasing cAMP mediated phosphorylation
...

Calcium affects glycogenolysis in muscle and liver
...

One of the subunit binds Ca2+
...
Binding of Ca2+ to phosphorylase b kinase
is similar to other calcium-binding protein like calmodulin
...


Glycogen Storage Diseases
...
In these diseases, there
is an abnormal accumulation of large amount of glycogen or its metabolites in the tissues due to
deficiency or absence of enzymes of glycogen metabolism
...

(a) Von Geirke’s disease: It is due to the deficiency or absence of glucose-6-phosphatase in liver,
kidney and intestine
...

Hypoglycemia is common symptom other symptoms are hyperuricemia, hyperlipemia (due to
large PPP shunt) and ketosis
...
Lysosomes can not
utilize glycogen and accumulation of glycogen occurs in all tissues
...
It is a fatal disorder and death occurs before second year of life due
to cardio respiratory failure
...
Dextrin a
metabolite of glycogenolysis accumulates in liver
...

(d) Anderson’s disease: It is a fatal disease
...

Amylopectin an intermediate of glycogenesis accumulatres in liver, spleen and heart
...

(e) Mc Ardle’s syndrome: It is due to the absence of muscle phosphorylase
...

Affected person suffer from painful muscle cramps and diminished tolerance to exercise
...
Glycogenolysis is defective and
glycogen accumulates in liver
...
Sugar nucleotides are substrate for polymerization of
monosaccharide into disaccharide, glycogen, starch, cellulose and more complex polysaccharide
...


The suitability of sugar nucleotides for all the said metabolism is based on facts that:
1
...
Although, the atoms of the nucleotide itself are not involved in the chemical
transformation of sugar nucleotides; yet the nucleotide has many groups that undergo
non-covalent interaction with enzymes, yielding free binding energy that catalytically
contribute to the reaction
3
...
Lastly, tagging some hexose with the nucloetidyl group makes the cell set them aside in a
pool for specified purpose
...
All pieced together in a simplified easily digestible form
for all and sundry
...
Lehningher principles of biochemistry, 6th edition, David Nelson & Micheal Cox
2
...
Mallikarjuna Rao
3
...
Murray, Granner, Mayer, Rodwell
4
...
MN Chatterjea, Rana shinde
5
...
David Metzler
6
...
Donald & Judith Voet, Charlotte
Pratt

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