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CORRELATION BETWEEN
METABOLIC PATHWAYS
ALAKSH CHOUDURY
SHASHWAT MOHAN VAJPEYI
CONTENTS
Importance of regulation.
 Homeostasis.
 Importance of cofactor concentrations.
 Correlation, an explanation using liver as an
example.
 Then we show various correlations through
citations at regulation of pathways.

AN OVERVIEW

1.
2.
3.
The basis of this seminar is to explain the
correlation of various pathways by 3 approaches:By considering regulation and understanding
how regulation interrelates various metabolic
pathways.
By taking hepatocytes as a basis to understand
the correlation of various pathways.
And lastly we consider TCA which is the heart
of all metabolic reactions by influencing them in
some way or the other.
DIAGRAMMATIC REPRESENTATION OF THE
CORRELATION
Some basic
facts:1.A typical eukaryotic
cell has a capacity to
make about 30000
different proteins.
2.These catalyze about
thousands of different
reactions involving
many hundreds of
metabolites most
shared by more
than one pathway.
INTRODUCTION TO REGULATION
The basic topic of discussion is the
interconnection between the various metabolic
pathways and for understanding this the first
and foremost task is to understand the concept of
regulation.
 Very complex regulatory mechanisms have
evolved to ensure that metabolites move through
each pathway in the correct direction and at the
correct rate to match the organism’s or the cell’s
current circumstances.
 There can be dramatic change in circumstances
can occur for eg; the demand for ATP production
can increase 100 folds in the muscle in a few
seconds in response to exercise.

HOMEOSTASIS
The need for regulation ca be very well
understood by understanding the phenomenon of
homeostasis.
 A general cellular reaction can be represented
as:
v1
v2
A
S
P
where v1=v2, S =constant.
 At molecular level, in each metabolic reaction in
a pathway ,the substrate is provided by the
preceding reaction at the same rate at which it is
converted to product. Thus, although the rate of
the metabolite flow, the flux, may be high but
the concentration of substrate, S, remains
constant.




This above mentioned
phenomenon is called as
Homeostasis.
When the steady state is
disturbed by some change in
external circumstances or
energy supply, the temporarily
altered fluxes through
individual metabolic pathways
trigger regulatory mechanisms
intrinsic to each pathway.
Hence it can be very well stated
that homeostasis is the basis of
regulation.
Next we move on to explain the
phenomenon of homeostasis
using the ratio of ATP to AMP
as an example.
Basic facts:In humans about 4000
genes (12% of all genes)
encode regulatory proteins
that include a variety of
receptors, regulators of
gene expression and about
500 different protein
kinases.
CONNECTING LINK BETWEEN ALL
PATHWAYS; [ATP]/[AMP]




The ATP concentration in a typical cell is about 5mM.
Because ATP is converted to ADP and AMP, the
[ATP]/[ADP] or [ATP]/[AMP] ratio profoundly effects
all the reaction rates that employ these cofactors
same is the case with [NADH]/[NAD+] and
[NADPH]/[NADP+] ratio.
One important mediator of regulation is AMP
dependent protein kinase (AMPK).
The action of AMPK increases glucose transport and
activates glycolysis and fatty acid oxidation while
suppressing energy requiring processes like fatty acid
synthesis, cholesterol biosynthesis and protein
biosynthesis. Thus we can observe that the cofactor
ratios play a key role is the correlation of the
regulatory actions of various metabolism.
UNDERSTANDING CORRELATION
Using liver cells as an example.
cytosol
Intracellular location of major metabolic pathways liver parenchymal cell.
SUGARS
Glucose is phosphorylated to
glucose-6-phosphate by enzyme
glucokinase
•In hepatocytes……it can undergo
one of the following metabolic
pathways depending upon current
metabolic needs.
•It is dephosphorylated to glucose
by glucose-6-phosphatase to
replenish blood sugar.
•It can be converted to liver
glycogen or it can undergo
glycolysis to produce pyruvate and
then acetyl coA.
•
acetyl coA undergoes TCA cycle, with ensuing
electron tranfer and oxidative phosphorylation to
yield ATP.
•
•
•

Acetyl coA can also serve as a precursor of fatty
acids.
Finally, glu-6-phosphate can enter PPP
pathway,yeilding reducing power NADPH required
both for biosynthesis of fatty acid and cholesterol
and to yield ribulose-5-phosphate for nucleotide
biosynthesis.
FATTY ACIDS
Metabolism of fatty acids in
liver
The fatty acid components of fatty acids entering
hepatocytes have following fates :
•Some are converted to liver lipids
•Fatty acids are primary oxidative fuel in the liver. Free
fatty acids may be activated and oxidized to yield acetyl
coA and NADH.
•Acetyl coA can enter TCA cycle to drive ATP synthesis .
•Excess fatty acids may be converted to ketone bodies.
• Some of the acetyl coA derived from fatty acids is used for
biosynthesis of cholesterol, which is a precursor for steroid
hormones and bile salts.
•Fatty acids are converted to phospholipids and to TAG’s of
plasma lipoprotiens.
•Some free Fatty acids become bound to albumin and are
carried to heart and skeletal muscles
AMINO ACIDS
Metabolism of amino acids in liver
Amino acids entering liver follow several important
metabolic routes:
•Amino acids are precursors in biosynthesis of
nucleotides, hormones and other nitrogenous
compounds.
•Amino acids may be transaminated or deaminated
and degraded to yield pyruvate and citric acid cycle
intermediates with various fates.
•Pyruvate can be converted to glucose and glycogen via
gluconeogenesis or
• it can be converted to acetyl coA which has several
possible metabolic fates eg. ATP synthesis and lipid
synthesis.
•Amino acids donate their amino groups(by
transamination) to pyruvate, the product of glycolysis
to yield alanine which is transported to the liver and
deaminated ,resulting pyruvate is converted to blood
glucose by hepatocytes.
UNDERSTANDING KEY REGULATIONS.
As we have seen in the previous slides, all the
metabolic pathways are closely interwoven as
they share many common substrates as well as
enzymes.
 Now lets move deeper into their networking by
understanding the regulation mechanisms of
various pathways; as in understanding how the
substrates of one pathway regulate the reactions
of the other.
 Hence now we can have a close look upon the
interconnection between the pathway on a
molecular basis. As in comparing the allosteric
effects.

UNDERSTANDING ALLOSTERIC
REGULATION
How one cycle substrate can influence the rate of
reaction in other.
ALLOSTERIC & HORMONAL MECHANISMS ARE
IMPORTANT IN THE METABOLIC CONTROL OF
ENZYME-CATALYZED REACTIONS

A hypothetical metabolic pathway in which reactions A ↔ B and C ↔
D are equilibrium reactions and B → C is a non equilibrium reaction .
The flux through such a pathway can be regulated by the availability
of substrate A. This depends on its supply from the blood, which in
turn depends on either food intake or key reactions that maintain and
release substrates from tissue reserves to the blood, eg, the glycogen
phosphorylase in liver and hormone- sensitive lipase in adipose tissue.
The flux also depends on the transport of substrate A across the cell
membrane. Flux is also determined by the removal of the end product
D and the availability of co-substrate or cofactors represented by X
and Y. Enzymes catalyzing nonequilibrium reactions are often
allostericproteins subject to the rapid actions of “feedback”or “feedforward” control by allosteric modifiers in immediate response to
the needs of the cell . Frequently, the product of a biosynthetic
pathway will inhibit the enzyme catalyzing the first reaction in the
pathway. Other control mechanisms depend on the action of
hormones responding to the needs of the body as a whole; they
may act rapidly, by altering the activity of existing enzyme molecules,
or slowly, by altering the rate of enzyme synthesis.
IMPORTANT EXAMPLES CITING LINKS
THROUGH REGULATION:Citrate, the product of the first step of TCA is an
allosteric inhibitor of PFK-1 in glycolytic
pathway.
 AcetylCoA Carboxylase (de-phosphorylation,
active) malonyl-CoA inclreases Substrate conc
increase in FA Synthesis (plenty of malonyl-CoA)
 And this malonyl coA acts as an inhibitor for the
carnitine shuttle.

. Major pathways and
regulation of
gluconeogenesis and
glycolysis in the liver. Entry
points of glucogenic amino
acids after transamination are
indicated by arrows extended
from circles.
(See also Figure 16–4.) The key
gluconeogenic enzymes are
enclosed in double-bordered
boxes. The
ATP required for
gluconeogenesis is supplied by
the oxidation of long-chain
fatty acids. Propionate is
of quantitative importance
only in ruminants. Arrows
with wavy shafts signify
allosteric effects; dashshafted
arrows, covalent modification
by reversible phosphorylation.
High concentrations of alanine
act as a “gluconeogenic signal”
by inhibiting glycolysis at the
pyruvate kinase step.
CITRIC ACID CYCLE
The heart of all metabolic pathways:
To describe how ultimately TCA being a classic
example of an anaplerotic reaction correlates all
catabolic and anabolic pathways.
TCA AS THE HEART OF ALL METABOLIC
PATHWAYS
Catabolism of proteins, fats, and
carbohydrates in the
three stages of cellular respiration.
Stage 1: oxidation of fatty
acids,glucose, and some amino acids
yields acetyl-CoA.
Stage 2: oxidation
of acetyl groups in the citric acid
cycle includes four steps in which
electrons are abstracted.
Stage 3: electrons carried by NADH
andFADH2 are funneled into a chain
of mitochondrial (or, in
bacteria,plasma membrane–bound)
electron carriers—the respiratory
chain—ultimately reducing O2 to
H2O. This electron flow drives the
production
of ATP.
CONCLUSION.
Hence it can be clearly seen that all the
metabolic pathways are closely interwoven.
 Indeed it can be rightly said that a cell or an
organism is actually a bioreactor with complex
mechanisms which have long been developed to
maintain the homeostasis in them.
 And the credit for this can be given to either
evolution or to God the choice for which lies
entirely in your belief. But keeping that aside,
you should sure take some time out to appreciate
the beauty of it.
